Type 1 Diabetes Clinical Management of the Athlete

Views:
 
Category: Entertainment
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

slide 1:

Ian Gallen Diabetes Centre High WycombeUK TYPE 1 DIABETES

slide 2:

Type 1 Diabetes Clinical Management of the Athlete Want To Diabetes Free Life Click Here

slide 4:

Ian Gallen Editor Type 1 Diabetes Clinical Management of the Athlete To Kill Diabetes Forever Click Here

slide 5:

Editor Ian Gallen Diabetes Centre Wycombe Hospital High Wycombe UK ISBN 978-0-85729-753-2 e-ISBN 978-0-85729-754-9 DOI 10.1007/978-0-85729-754-9 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2012934821 © Springer-Verlag London Limited 2012 Apart from any fair dealing for the purposes of research or private study or criticism or review as permitted under the Copyright Designs and Patents Act 1988 this publication may only be reproduced stored or transmitted in any form or by any means with the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names trademarks etc. in this publication does not imply even in the absence of a specific statement that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media www.springer.com

slide 6:

This book is dedicated to my parents Louis and Barbara for their lifelong love encouragement and support to my wife Susan for our happy life together and to our children Robert and Hannah who make my life meaningful. I thank all my outstanding and inspirational medical teachers the many colleagues with whom I have been privileged to work and the people with diabetes who have trusted me to help them.

slide 8:

Foreword I was diagnosed with diabetes at the start of training for the 2000 Sydney Olympic Games having won gold medals in rowing events at the previous four Olympic Games. The diagnosis was a shock and I felt my sporting world was over. I had a grandfather who had the condition in his late 60s and even though I was very young at the time and didn’t know very much about diabetes I felt I knew enough to know that I wouldn’t be able to carry on my sporting path. I was sent up to my local dia- betic center where my diabetes was confirmed and I was taught to inject insulin and all the life-changing routines and dietary adjustments that needed to be implemented immediately. At the end of the consultation when I was expecting to be told that this was it my sporting career was over my consultant said to me “I can’t see any rea- son why you can’t still achieve your dreams in 3 years time by competing at the Sydney Olympics in 2000.” This was a bigger shock to me than being told I wouldn’t be able to compete. All my instincts and limited knowledge as a newly diagnosed diabetic told me otherwise. He did say it would be a tough path but immediately I thought if he thinks I can do it I will give it my best shot. The path over the next few months was very traumatic. Firstly of coming to terms with the condition and secondly as an athlete with a certain pride in your performance at the highest level is about consistency within training and racing. In the early days of my diabetes it was the consistency that had gone. The main issue was not actually the controlling of the diabetes it had more to do with the refueling of my body. To compete in rowing at Olympic level you have to train somewhere in the region of 18–24 sessions a week averaging about 1½ h a session of intensive endurance work splitting these sessions between three and four a day. There is very little time to regain the energy when you are limited to the insulin you can take because of the fear of hypoglycemia. I was put onto the normal diabetic diet and session after session I was not gaining the energy to perform. The way I felt after each session was convincing me I was never going to be the athlete that I was. Over time my consultant changed the patterns of refueling. In fact this meant going back to my old diet. He knew that I had been successful on this before but he had to come up with a regime that allowed me to eat 6–7000 cal a day and still control my diabetes. When you are first diagnosed you are given so much information and this is vii

slide 9:

viii Foreword so difficult to take on board – even as an athlete when you need to have the freshness of mind to adapt to your needs. I feel that if you could be drip-fed information over time this would be a better process. There wasn’t any information for athletes to achieve at the highest level and books like this really do help the athlete and give the consultants a good foresight. Since I was diagnosed in 1997 the world looks at diabetes and elite sport in a very different way and there are so many more diabetic athletes achieving their dreams now. With all the help I was given I decided very early on that diabetes was going to live with me not me live with diabetes. I very much welcome this book in which leading experts highlight the many advances in the understanding of the effects of diabetes and insulin treatment during and following exercise and on how diabetes management can be optimized. This will help clinicians in turn help those people with diabetes who want to play sport and even for some like me achieve the highest level of sporting success. Sir Steve Redgrave

slide 10:

Preface To Cure Diabetes Naturally Click Here In this year of the London Olympic Games our attention is drawn to sport and physical performance. Type 1 diabetes is initially a disorder of the young and in this age group and for many older people physical activity is a very important compo- nent of lifestyle. Whilst it is of undoubted importance for physicians to optimize insulin therapy programs and other treatments to avoid or treat the chronic compli- cations of type 1 diabetes people with diabetes also seek to normalize their life- style. Some will want to advance their sporting ambitions and the examples of outstanding sportsmen with diabetes such the rower Sir Stephen Redgrave or the Rugby Union player Chris Pennell show us that type 1 diabetes per se is not a bar- rier to maximum physical performance in sport. These examples encourage people with type 1 diabetes to engage in all types of physical activity and they will seek best advice on how to manage their diabetes with exercise. There are some significant barriers for people with type 1 diabetes performing sports and exercise. They are likely to experience marked fluctuations in blood glu- cose control and frequent hypoglycaemia with exercise. The occurrence of hypogly- caemia may seem both unpredictable and inexplicable to the person with diabetes which may force the response of excess replacement of carbohydrate before and following exercise with resultant hyperglycaemia adding to the burden of dysgly- caemia. Perhaps of more concern to people with diabetes is the risk of hypoglycae- mia during and nocturnal hypoglycaemia following exercise. When hypoglycaemia is severe requiring assistance from another person it may cause embarrassment to people with diabetes and is likely to cause concern to parents teachers and coach- ing staff as to the safety of physical activity. Excessive fatigue and weakness during prolonged exercise compared with peers without diabetes may be experienced and this may reduce the wish to continue in sport. For the outstanding athlete with dia- betes there is potential that diabetes and insulin treatment may cause loss of maxi- mum physical performance which also may discourage progression in sport. We now know many of the causes of impaired physical performance and how these may be rectified through augmented diabetes management strategies. Evidence from people with type 1 diabetes suggests that advice from healthcare professionals to people with type 1 diabetes on the management of physical exercise ix

slide 11:

x Preface may be simplistic. Over the last decade we have established a specialist clinic to help sportspeople and athletes manage their diabetes and physical activity success- fully to reduce dysglycaemia with and following exercise and to normalize physical performance. Athletes and sports people explained in our clinic what problems they had found during exercise and how they had tried to overcome those difficulties. This experiential evidence has produced many effective clinical strategies. These are now strongly supported by the growth in the clinical research knowledge base of the effects of diabetes on the physiological response to exercise on the effect of exercise on the response to hypoglycaemia and on effective dietetic and insulin management of diabetes during and following exercise. There have also been sig- nificant technological improvements in the support of the management of type 1 diabetes with continuously infused insulin infusion pump therapy and continuous sub- cutaneous glucose monitoring equipment. People with type 1 diabetes will seek to be effectively supported in any sporting ambition presenting an interesting challenge to healthcare professionals. This book aims to provide the evidence on the management of type 1 diabetes and exercise bringing together outstanding clinical science clinical practice from experts in the field and the evidence of the real experts the athletes themselves. The book outlines potential dietetic and therapeutic strategies which may be employed to promote these aims. Our aim is that if applied the evidence will equip the healthcare profes- sional with the knowledge base to support the development of clinical skills to sup- port any person with type 1 diabetes perform physical activity safely and for some talented individuals to pursue their sporting ambitions to the highest level.

slide 12:

Contents To Get Rid Of Diabetes Permanently Click Here 1 Endocrine and Metabolic Responses to Exercise ............................... Kostas Tsintzas and Ian A. MacDonald 1 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise ........................................................................... Michael C. Riddell 29 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual ..................................................... Richard M. Bracken Daniel J. West and Stephen C. Bain 47 4 Physical Activity in Childhood Diabetes ............................................. Krystyna A. Matyka and S. Francesca Annan 73 5 The Role of Newer Technologies CSII and CGM and Novel Strategies in the Management of Type 1 Diabetes for Sport and Exercise .......................................................... 101 Alistair N. Lumb 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise............................................................ Lisa M. Younk and Stephen N. Davis 115 7 Fueling the Athlete with Type 1 Diabetes ........................................... Carin Hume 151 8 Diabetes and Doping ............................................................................. Richard I.G. Holt 167 9 Synthesis of Best Practice ..................................................................... Ian Gallen 193 10 The Athlete ’s Perspective ..................................................................... 203 Index............................................................................................................... 219

slide 13:

Contents xi

slide 15:

Contributors Click Here If You Also Want To Be Free From Diabetes Jen Alexander B.Math. Bed Halifax NS Canada S. Francesca Annan B.Sc. Hons PGCert Department of Nutrition and Dietetics Alder Hey Children’s NHS Foundation Trust West Derby Liverpool Merseyside UK Stephen C. Bain M.A. M.D. FRCP Institute of Life Sciences College of Medicine Swansea University Swansea Wales UK Mark S. Blewitt M.A. Forton Lancashire UK Richard M. Bracken B.Sc. M.Sc. PGCert Ph.D. Health and Sport Science College of Engineering Swansea University Swansea UK Russell D. Cobb B.Sc. Hons DMS Department of Supply Chain Coco-Cola Enterprises Uxbridge Middlesex UK Stephen N. Davis M.B.B.S. FRCP FACP Department of Medicine University of Maryland School of Medicine Baltimore MD USA Ian Gallen B.Sc. M.D. FRCP Diabetes Centre Wycombe Hospital High Wycombe UK Fred H.R. Gill B.A. Cantab Deloitte Reading Buckinghamshire UK Monique S. Hanley HypoActive North Fitzroy VIC Australia Richard I.G. Holt M.A. M.B. B.Chir. Ph.D. FRCP FHEA Human Development and Health Academic Unit University of Southampton Faculty of Medicine Southampton General Hospital Southampton Hampshire UK Carin Hume B.Sc. M.Sc. Department of Nutrition and Dietetics Buckinghamshire Hospitals NHS Trust High Wycombe Buckinghamshire UK Alistair N. Lumb B.A. Ph.D. M.B.B.S. MRCP Diabetes Centre Wycombe Hospital Buckinghamshire Healthcare NHS Trust High Wycombe Buckinghamshire UK

slide 16:

Contributors xiii

slide 17:

xiv Contributors Ian A. MacDonald Ph.D. School of Biomedical Sciences Queen’s Medical Centre University of Nottingham Medical School Nottingham Nottinghamshire UK Krystyna A. Matyka M.B.B.S. M.D. M.R.C.P.C.H. Division of Metabolic and Vascular Health Warwick Medical School Clinical Sciences Research Laboratories University Hospital Coventry UK Christopher J. Pennell Sixways Stadium Worcester Worcestershire UK Michael C. Riddell Ph.D. Physical Activity and Diabetes Unit School of Kinesiology and Health Science Muscle Health Research Centre York University Toronto ON Canada Sébastien Sasseville Quebec City QC Canada Kostas Tsintzas B.Sc. M.Sc. Ph.D. School of Biomedical Sciences Queen’s Medical Centre University of Nottingham Medical School Nottingham Nottinghamshire UK Daniel J. West B.Sc. Ph.D. Department of Sport and Exercise Northumbria University Newcastle upon Tyne Tyne and Wear UK Lisa M. Y ounk B.S. Department of Medicine University of Maryland School of Medicine Baltimore MD USA

slide 18:

Chapter 1 Endocrine and Metabolic Responses to Exercise Kostas Tsintzas and Ian A. MacDonald To Cure Diabetes Naturally Click Here 1.1 Introduction The successful completion of any human physical movement requires the transfor- mation of chemical energy into mechanical energy in skeletal muscles at rates appropriate to their needs. The source of this chemical energy is the hydrolysis of adenosine triphosphate ATP. However the amount of ATP stored in skeletal mus- cle is limited and would only last for a few seconds of contraction. Therefore the ATP must be regenerated continuously at the same rate as it is broken down if the work rate is to be maintained for a prolonged period of time. Generating this con- tinuous supply of energy places a great demand on the capacity of the human body to mobilize and utilize the energy substrates required for muscle contraction and to maintain blood glucose homeostasis in the face of substantial increases in both mus- cle glucose utilization and hepatic glucose production during exercise. In fact blood glucose concentrations are normally maintained within a narrow physiological range during exercise as the central nervous system CNS relies heavily upon con- tinuous blood glucose supply to meet its energy requirements. In order to achieve this a decrement in blood glucose concentration during exercise is counteracted by a complex and well-coordinated neuroendocrine and autonomic nervous system response. This counterregulatory response aims to prevent and when necessary correct any substantial decreases in blood glucose concentration and thus the devel- opment of hypoglycemia. This chapter will describe the main metabolic and neu- roendocrine responses to exercise of varying intensity and focus on factors affecting blood glucose utilization in humans. It will also examine gender differences in the K. Tsintzas B.Sc. M.Sc. Ph.D. • I.A. MacDonald Ph.D. School of Biomedical Sciences Queen’s Medical Centre University of Nottingham Medical School Nottingham Nottinghamshire NG7 2UH UK e-mail: kostas.tsintzasnottingham.ac.uk ian.macdonaldnottingham.ac.uk I. Gallen ed. Type 1 Diabetes 1 DOI 10.1007/978-0-85729-754-9_1 © Springer-Verlag London Limited 2012

slide 19:

2 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 2 2 max 2 max Energy expenditure kJ min −1 Fig. 1.1 Energy expenditure and the contribution of different metabolic fuels during exercise of varying intensity in humans Reprinted by permission of the publisher from van Loon et al. 2 John Wiley Sons Other fat sources Plasma FFA 8 0 6 0 Plasma glucose Muscle glycogen 4 0 2 0 0 rest 4 0 5 5 7 5 Exercise intensity W max endocrine response and substrate utilization during exercise and examine how these responses might be altered in exercising children and adolescents. Finally this chapter will describe the effects of glucose ingestion before and during exercise on counterregulatory responses substrate utilization and exercise performance. 1.2 Energy Metabolism and Fuel Utilization During Exercise To Kill Diabetes Forever Click Here Carbohydrate blood glucose and muscle glycogen and fat plasma free fatty acids FFA and intramuscular triglycerides TGs are the main energy substrates for aerobic synthesis of ATP during exercise. Both muscle glycogen and blood glucose oxidation rates are markedly increased with increasing exercise intensity Fig. 1.1. The rate of fat oxidation also increases up to about 60 of maximal oxygen con- sumption V ˙ O 1 2. However a reduction in the rate of fat oxidation is observed at higher exercise intensities. This decrease in fat contribution to energy metabolism is a result of a significant decline in the oxidation rate of both plasma FFAs and intramuscular TGs and is not entirely related to a decline in plasma FFA availability that normally occurs at high exercise intensities 2. Pioneering studies in the 1960s and 1970s showed that fatigue during prolonged exercise at intensities between 65 and 85 V ˙ O is associated with depletion of

slide 20:

3 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 3 glycogen in active skeletal muscle 3 4. Although the precise mechanism by which glycogen depletion causes fatigue is still unclear it appears to be related to a decrease in the rate of oxidative A TP production 5 6. The A TP concentrations in skeletal muscle at the point of fatigue are usually maintained at their preexercise levels

slide 21:

4 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 4 2 max 2 max 2 max 6–9 but a decline in phosphocreatine PCr concentration is normally observed. The extent of PCr decline during prolonged constant intensity exercise which leads to muscle glycogen depletion reflects the extent of the inability of the working muscles to maintain oxidative A TP production 10 11. Indeed a strong positive correlation is observed between changes in PCr and glycogen concentrations in skeletal muscle which supports the presence of a close functional link between oxidative ATP production and glycogen depletion during prolonged exercise 6. Human skeletal muscles are composed of at least two major fiber types which differ in their physiological metabolic and contractile characteristics 12 13. Using a quantitative biochemical method to examine the glycogen changes in pools of muscle fibers of different types Tsintzas et al. 9 showed that glycogen deple- tion occurs exclusively in type I slow-twitch fibers during running exercise at 70 V ˙ O performed in the fasted postabsorptive state. It appears that rela- tively little glycogen is utilized in type II fast-twitch fibers during the first hour of submaximal exercise 7 9 14–16. In contrast a substantial breakdown of glycogen occurs in type II fibers toward the end of exercise at a time when an increase in the recruitment of type II fibers occurs to compensate for loss of recruitment of type I fibers as a result of glycogen depletion in the latter fiber type. Apart from muscle glycogen blood glucose is also an important energy substrate during exercise. The liver is the only significant source of blood glucose both at rest and during exercise performed in the fasted postabsorptive state. Indeed the contri- bution of kidney to glucose production during exercise is minimal 17. Blood glu- cose utilization in the fasted postabsorptive state is mainly a function of the intensity and duration of exercise 17–19 and in particular shows a positive curvilinear rela- tionship with exercise intensity 20. Hence the liver plays a key role in the mainte- nance of blood glucose homeostasis during exercise in humans by increasing its glucose production by two- to threefold when compared to rest to match the increase in glucose utilization during low- and moderate-intensity exercise up to 70 V ˙ O Fig. 1.2 17 21. During intense exercise 80 V ˙ O 2 max hepatic glucose produc- tion may increase up to eightfold 22. A mismatch between hepatic glucose produc- tion and utilization may occur during intense exercise 80 V ˙ O in which the increase in hepatic glucose output exceeds the increase in glucose utilization by skeletal muscle Fig. 1.2 leading to transient hyperglycemia 22. Blood glucose utilization also increases with the duration of exercise 18. Therefore toward the latter stages of prolonged exercise 23 24 at a time when muscle glycogen levels are very low the contribution from blood glucose could account for the majority of total CHO oxidation rate. Furthermore when endogenous liver glycogen stores are becoming depleted during prolonged exercise continued to the point of fatigue a mis- match between the glucose production and glucose utilization may occur Fig. 1.3 resulting in a decrease in blood glucose concentration 25. Both hepatic glycogenolysis and gluconeogenesis glucose formed from noncar- bohydrate sources such as glycerol lactate and amino acids contribute to the body’s ability to maintain blood glucose homeostasis during exercise 26. During

slide 22:

5 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 5 mmol/min mmol/min Glucose exchange Splanchnic 5 Leg 4 3 2 1 0 Rest Light Moderate Short-term exercise Strenuous Fig. 1.2 Splanchnic yellow and leg gray glucose exchange during exercise of varying intensity in healthy subjects. Gluconeogenesis is indicated in green Reprinted by permission of the pub- lisher from Wahren and Ekberg 182 Annual Reviews Glucose exchange Splanchnic Leg 3 2 1 0 Rest 40 min 90 min 180 min Prolonged exercise 240 min Fig. 1.3 Splanchnic yellow and leg gray glucose exchange during prolonged exercise. Glu- coneogenesis is indicated in green Reprinted by permission of the publisher from Wahren and Ekberg 182 Annual Reviews

slide 23:

6 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 6 acute exercise of varying intensity hepatic glycogenolysis is the main source of endogenous glucose production Fig. 1.2. As liver glycogen stores are becoming depleted during prolonged submaximal exercise the contribution of hepatic gluco- neogenesis increases and may account for up to 50 of total hepatic glucose output after 4 h of low intensity exercise Fig. 1.3. Furthermore during prolonged exercise under fasting conditions a much greater contribution of hepatic glucose output is derived from gluconeogenesis 27 28. These findings further emphasize the impor- tance of blood glucose as an energy substrate during exercise. Apart from the inten- sity and duration of exercise other factors that can affect the rate of blood glucose utilization during exercise include antecedent nutritional status see also last section in this chapter endurance training and muscle mass involved in exercise. In par- ticular glucose uptake is inversely related to muscle mass involved 29 which may explain the higher occurrence of hypoglycemic episodes during cycling when com- pared with running. Conversely a diet rich in CHO may increase blood glucose utilization whereas a low CHO diet would lower it 30. Endurance training decreases blood glucose utilization 31 but has no effect on exogenous glucose utilization 32. 1.3 Exercise and Hyperinsulinemia Stimulate Glucose Uptake in Skeletal Muscle Both muscle contraction and insulin stimulate muscle glucose uptake through a rapid increase in the translocation of the glucose transporter protein GLUT4 from intracellular vesicle compartments to both the sarcolemma and transverse tubules at the plasma membrane using distinct at least proximally signaling pathways 33–35. Interestingly in response to insulin there is a delay in GLUT4 translocation and its reinternalization from the transverse tubules when compared with the sarcolemma 34 36 whereas the kinetics of contraction-stimulated GLUT4 translocation and reinternalization are similar for the two compartments 35. The effect of insulin on GLUT4 translocation is mediated through a well- described intracellular signaling pathway that involves tyrosine phosphorylation of insulin receptor substrate-1 IRS-1 activation of IRS-1-associated phosphati- dylinositol 3-kinase PI3K and phosphorylation of Akt/PKB and TBC14D/AS160 a downstream target of Akt in the distal insulin signaling pathway 37–42. The signaling pathway underlying the exercise-induced translocation of GLUT4 is less defined and it appears to include factors such as LKB1 Ca 2+ /calmodulin-dependent protein kinase II CaMKII and their downstream target AMP-activated protein kinase AMPK 33 43 44. The TBC14D/AS160 protein may also play a role in exercise-induced GLUT4 translocation and appears to be the point of convergence for the two signaling pathways 45. More recently Myo1c an actin-associated motor protein that is part of the GLUT4 vesicle carrier complex that mediates GLUT4 translocation to the plasma membrane was shown to mediate both insulin and exercise-induced glucose uptake in skeletal muscle 46.

slide 24:

7 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 7 Circulating insulin glucose availability Exercise Plasma membrane Cytosol GLUT4 HKII G-6-P Pyruvate PDC Mitochondrion Pyruvate insulin Acetyl-CoA NADH PDK inactive P PDC active PDP P Calcium insulin PDK4 Insulin resistance Acetyl-CoA TCA cycle CHO ox Fig. 1.4 Schematic diagram of hyperinsulinemia hyperglycemia and exercise-induced increase in pyruvate flux stimulation of PDC the formation of acetyl-CoA and a concomitant increase in CHO oxidation. In insulin-resistant states skeletal muscle PDC activation which controls the rate-limit- ing step in CHO oxidation is impaired through a selective upregulation of PDK4 55 56 183 Superimposing hyperinsulinemia on muscle contraction exerts a synergistic stimulatory effect on glucose uptake and oxidation 47 48. Skeletal muscle is the primary tissue responsible for this synergism which might be explained at least in part by an increase in blood flow and hence glucose delivery to the tissue 47 49. Indeed both insulin and muscle contraction can increase blood flow to skeletal muscle 50 although a debate exists whether this is mediated by increasing the number of perfused capillaries capillary recruitment 50 or simply an increase in capillary blood flow 51. Regardless of the mechanism involved an augmented increase in tissue perfusion will further increase insulin and glucose delivery and/ or fractional glucose extraction by the exercising muscle. Unlike resting condi- tions the primary route of insulin-stimulated glucose metabolism during exercise is oxidative metabolism 48. The pyruvate dehydrogenase complex PDC con- trols the rate-limiting step in CHO oxidation the oxidative decarboxylation of pyruvate to acetyl-CoA Fig. 1.4. The activity of PDC increases during exercise in a calcium-dependent manner resulting in an increase in pyruvate flux the forma- tion of acetyl-CoA and a concomitant increase in CHO oxidation 52. Both hyperglycemia and hyperinsulinemia increase the activity of PDC in resting human

slide 25:

8 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 8 skeletal muscle 53–56. Hyperglycemia is thought to stimulate PDC through an increase in pyruvate availability as a result of increases in glucose uptake and gly- colysis 53. On the other hand an increase in circulating insulin concentration has been shown to activate the PDC phosphatase PDP the regulatory enzyme respon- sible for the dephosphorylation and hence activation of PDC 54 57. Interestingly the stimulatory effect of insulin on skeletal muscle PDC activation is impaired in insulin-resistant states through a selective upregulation of pyruvate dehydrogenase kinase 4 PDK4 one of the four isoforms of the kinase responsible for the phos- phorylation and hence inactivation of PDC 55 56. Carbohydrate ingestion immediately before exercise resulting in increased blood glucose and insulin con- centrations augments the exercise-induced activation of PDC in human skeletal muscle 58 which facilitates the increase in insulin-stimulated glucose oxidation under those conditions. 1.4 Effect of Acute Exercise on Insulin Action in Human Skeletal Muscle Click Here For Best Diabetes Treatment Exercise is beneficial in the treatment of diabetes and a single bout of exercise was shown to increase insulin sensitivity in insulin-resistant individuals by reversing a defect in insulin-stimulated glucose transport and phosphorylation 59. However despite a plethora of studies in this area the exact cellular mechanisms underlying the well-documented increase in insulin-stimulated skeletal muscle glucose uptake and glycogen synthesis observed up to 2 days following a single bout of exercise 60 61 remain unresolved. It is well established that a single bout of exercise increases the transcription 62 and protein content of both whole muscle 63 64 and plasma membrane 62 65 66 fractions of glucose transporter GLUT4. A single bout of exercise also increases skeletal muscle hexokinase II HKII activity transcription and protein content for a number of hours after the end of exercise 67–70. HKII is the predominant hexokinase isoform in skeletal muscle where it phosphorylates internalized glu- cose thus ensuring a concentration gradient across the plasma membrane and sus- tained glucose transport into muscle. Exercise also increases glycogen synthase GS activity 40 and it appears that exercise-induced depletion of muscle glyco- gen content plays a role in enhancing postexercise insulin sensitivity as it is tightly coupled with GS activity 71. Postexercise augmentation of the classical insulin signaling cascade may not be involved in this positive effect of exercise on insulin action as many studies have demonstrated that a single bout of exercise does not increase IRS-1 tyrosine phos- phorylation IRS-1-associated PI3K activity serine phosphorylation of Akt and glycogen synthase kinase 3 GSK3 in response to insulin for up to 1 day after exercise 37–41 70. Therefore the enhanced insulin action observed after exer- cise may involve signaling proteins downstream of Akt enhanced activation of

slide 26:

9 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 9 GS and/or increased glucose transport and phosphorylation capacity. Indeed Treebak et al. 72 demonstrated increased phosphorylation of TBC14D/AS160

slide 27:

10 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 10 a downstream target of Akt in response to insulin 4 h following a single bout of one-legged exercise compared to the nonexercised leg suggesting it may play a role in increased postexercise insulin sensitivity. Recently it was also shown that acute exercise enhances insulin action in skeletal muscle by increasing its capacity to phosphorylate glucose via upregulation of HKII and divert it toward glycogen synthesis rather than oxidize it 70. Although the molecular mechanisms respon- sible for the upregulation of HK and GLUT4 content following an acute bout of exercise are unclear possible candidates include the activation of transcription fac- tors such as the peroxisome proliferator-activated receptor-g PPARg coactivator 1a PGC1a 73 sterol regulatory binding protein 1c SREBP1c 74 75 and peroxisome proliferator-activated receptor-d PPARd 76. 1.5 Hormonal Regulation of Glucose Metabolism Want To Diabetes Free Life Click Here As discussed previously the liver plays a key role in the maintenance of blood glu- cose homeostasis during exercise by increasing its glucose production through increased glycogenolysis and gluconeogenesis in response to the increase in glu- cose utilization by the contracting skeletal muscles. Hepatic glycogenolysis is regu- lated by allosteric factors acting upon the hepatic phosphorylase and glycogen synthase enzymes whereas hepatic gluconeogenesis is controlled by factors that affect the delivery of gluconeogenic precursors to the liver their extraction by the tissue and the activation of key intracellular gluconeogenic enzymes such as the phosphoenolpyruvate carboxykinase PEPCK. In general a number of circulating hormones insulin glucagon catecholamines cortisol and growth hormone and autonomic nerve impulses to the liver are implicated in the regulation of hepatic glucose production during exercise. The typical hormonal response to exercise is characterized by a reduction in plasma insulin concentration 17 77 and an increase in the levels of glucagon catecholamines both adrenaline and noradrenaline cortisol and growth hormone 78. These hormonal effects are more pronounced during prolonged or high- intensity exercise 79 80 and collectively facilitate the increase in hepatic glucose production required to counteract the stimulation of muscle glucose uptake that occurs during exercise. The decrease in insulin levels during exercise appears to be due to inhibition in its secretion by the pancreas which is mediated by activation of the sympathetic nervous system and in particular increased a-adrenergic stimula- tion of the pancreatic b cells 17 81. The greater catecholamine stimulation at higher exercise intensities results in greater suppression of insulin secretion com- pared with low exercise intensities. A decrease in insulin secretion augments the liver’s sensitivity to the actions of glucagon and even a small increase in plasma glucagon is sufficient to increase hepatic glucose output under those conditions 82. Plasma glucagon levels increase with the duration and intensity of exercise and this response is augmented in the presence of hypoglycemia 79.

slide 28:

11 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 11 Insulin suppresses both net hepatic glycogenolysis through an increase in GSK3- mediated activation of glycogen synthase activity and gluconeogenesis although the former effect is more potent 83 84. Insulin can suppress hepatic gluconeogenesis directly by decreasing the delivery and extraction of gluconeo- genic precursors such as amino acids lactate and glycerol and indirectly by sup- pressing lipolysis in adipose tissue and thus circulating FFAs which provide the energy source required to support gluconeogenesis 85. Glucagon exerts a rapid and potent increase in hepatic glucose production pos- sibly through an AMPK-mediated increase in the hepatic glycogen phosphorylase to glycogen synthase activity ratio which favors an increase in net hepatic glycog- enolysis 86. Glucagon can also increase hepatic gluconeogenesis through an increase in gluconeogenic precursor such as lactate extraction by the liver and their conversion to glucose 87 although this process is modest and slower when compared with the effect of glucagon on hepatic glycogenolysis 88. Given the antagonistic effects of insulin and glucagon on hepatic glycogenolysis and gluco- neogenesis it is not surprising that glucagon and insulin concentrations in the portal vein 87 and in particular the glucagon-to-insulin ratio are important regulators of hepatic glucose production during low and moderate intensity exercise 89 90. Indeed an increase in glucagon is required for the maximum stimulation of hepatic glycogenolysis and gluconeogenesis 87 whereas a reduction in circulating insulin is necessary for the full increase in hepatic glycogenolysis 91. Prevention of this physiological response of the islet hormones with somatostatin infusion attenuates the normal exercise-induced increase in hepatic glucose output 92 93. In addition to glucagon and insulin small changes in arterial blood glucose con- centration and in particular portal vein glucose concentration can also alter hepatic glucose output. Indeed during prolonged exercise the decline in both circulating glucose and insulin appears to play a major role in preserving glucose homeostasis by facilitating an increase in hepatic glucose output 94. Conversely hyperglyce- mia and hyperinsulinemia inhibit hepatic glucose output 84 95. Indeed carbohy- drate ingestion during exercise and the associated increases in blood glucose and insulin concentrations can completely suppress hepatic glucose production 96. It must be pointed out however that under normal physiological conditions the liver extracts a great proportion up to 50–60 of insulin secreted in the portal vein and therefore the insulin concentration in the latter can be two- to threefold higher than peripheral arterial insulin concentration 97. However only about a fifth of secreted glucagon is extracted by the liver 97. Therefore arterial insulin concentrations underestimate those in the portal vein to a greater extent than the corresponding glucagon concentrations. Furthermore the gradient of portal to arte- rial concentrations for both hormones is widened during exercise because of a reduction in hepatic blood flow and in the case of glucagon increased secretion 98. This is important not only because the glucagon-to-insulin ratio is an impor- tant regulator of hepatic glucose production during exercise but also because portal venous hyperinsulinemia appears to be more potent than peripheral hyperinsuline- mia in suppressing hepatic glucose production during the early stages of exercise. In contrast peripheral arterial hyperinsulinemia becomes more important as the

slide 29:

12 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 12 duration of exercise increases through suppression of lipolysis in adipose tissue and hence reduction in circulating glycerol and FFAs which will further suppress hepatic glucose output 99. Studies in humans 92 93 and dogs 87 have clearly demonstrated the impor- tance of increased circulating glucagon levels in the stimulation of hepatic glucose production during exercise. Although the rise in glucagon can account for 60 of total splanchnic glucose output during exercise 100 other factors also seem to play important roles 101. Catecholamine adrenaline and noradrenaline plasma concentrations increase with exercise intensity and duration and these changes coincide with increased hepatic glucose output although a causal relationship between these parameters has not been established. It should be noted that a large proportion of circulating catecholamines are extracted by the gut 102 which sug- gest that the liver is exposed to portal vein concentrations that are considerably lower than the corresponding levels in peripheral circulation. Catecholamines can enhance both hepatic glycogenolysis by stimulating glycogen phosphorylase and adipose tissue lipolysis by activating hormone-sensitive lipase resulting in increased levels of circulating glycerol and FFAs 103–105. However it appears that adrena- line is significantly more potent than noradrenaline in stimulating hepatic glucose output 106. At rest under conditions of basal circulating insulin and glucagon concentrations a 20-fold increase in plasma adrenaline concentration in humans through infusion of adrenaline for 90 min resulted in a biphasic increase in hepatic glucose production during the first hour of infusion an increase in hepatic glycog- enolysis was responsible for the majority 60 of the increase in glucose produc- tion whereas during the last 30 min of infusion the rate of hepatic glucose production declined and the contribution of hepatic gluconeogenesis increased 2.5-fold account- ing for 80 of glucose production 107. It is also well established that adrenaline inhibits insulin-stimulated glucose uptake and that skeletal muscle appears to be the major site of this temporary insulin-resistant state 108. The role of the neural input to the liver and catecholamine stimulation in the regulation of hepatic glucose production during exercise has been questioned 109. Indeed combined a-and b-adrenergic blockade in healthy humans in contrast to type I diabetics failed to demonstrate an important role for adrenergic nervous sys- tem in controlling exercise-induced hepatic glucose output 110. Further evidence that catecholamines may not be important in stimulating the exercise-induced increase in hepatic glucose output at least during low and moderate intensity exer- cise comes from animal studies that used pharmacological blockade of the sympa- thetic nervous system 102 and studies on adrenalectomized humans 111 in which a normal increase in hepatic glucose output was observed during moderate exercise. In contrast during high-intensity exercise there is rapid and marked elevation in circulating catecholamine levels 112–115. Interestingly infusion of both adrena- line and noradrenaline during moderate intensity exercise designed to reproduce the pattern of catecholamine release during intense exercise resulted in an augmented hepatic glucose output of the same magnitude as during intense exercise 116.

slide 30:

13 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 13 This suggests that unlike light and moderate exercise catecholamines may play an important role in the regulation of glucose homeostasis during high-intensity exercise. However it should be noted that in humans there appears to be some redun- dancy in the hormonal regulation of hepatic glucose production. For example when both the fall in insulin and rise in glucagon concentrations were prevented during 60 min of moderate exercise by infusion of somatostatin along with insulin and glucagon replacement at fixed rates islet clamp technique hepatic glucose produc- tion did not increase and plasma glucose initially decreased from 5.5 to 3.4 mmol/l from 100 to 62 mg/dl and then leveled off and was 3.3 mmol/l 60 mg/dl at the end of exercise 93. In contrast when insulin was allowed to decrease and gluca- gon to increase simultaneously which represents the normal response to exercise there was an increase in hepatic glucose production and the plasma glucose level was 4.5 mmol/l 80 mg/ml at the end of exercise 93. Since hypoglycemia did not occur when the normal insulin and glucagon response was prevented it is likely that other counterregulatory hormones such as adrenaline play a more important role in the regulation of hepatic glucose production during exercise when the islet hor- mone responses are disturbed. Indeed if changes in circulating glucagon and insu- lin levels are prevented in the presence of adrenergic blockade during exercise progressive hypoglycemia 2.6 mmol/l or 50 mg/dl will ensue 117. Growth hormone GH secreted from the anterior pituitary gland and cortisol secreted from the adrenal cortex appear to play a minor role in the regulation of glucose homeostasis during short-term exercise but as the duration of exercise increases they contribute to the stimulation of whole body lipolysis and therefore release of FFAs and glycerol into the circulation and the increase in hepatic gluco- neogenesis 118 119. During moderate-intensity running exercise to exhaustion in humans plasma GH concentrations may increase by up to tenfold above postab- sorptive levels whereas cortisol concentrations may double 120 121. This increase occurs in the absence of a decrease in blood glucose concentration which suggests that blood glucose concentration is not the sole determinant of hormonal response to prolonged exercise 122. Carbohydrate ingestion or infusion during prolonged exercise suppresses the increase in cortisol secretion usually observed during exer- cise without exogenous carbohydrate supply 123. Interestingly carbohydrate ingestion immediately before and during the first hour of prolonged running exer- cise also attenuated the normal increase in GH concentration along with suppres- sion of lipolysis and attenuation of plasma glycerol and FFA levels 121. However when carbohydrate ingestion was discontinued after the first hour of exercise plasma GH and FFA levels were quickly increased and at exhaustion reached levels comparable with those observed in the control nonsupplemented trial 121. Since the changes in GH paralleled those in FFA and glycerol it appears that during pro- longed exercise continued to the point of exhaustion secretion of GH is important for fat mobilization from adipose tissue and therefore indirectly for glucose metab- olism by enhancing liver glucose output during exercise performed in the postab- sorptive state.

slide 31:

14 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 14 1.6 Counterregulatory Responses to Hypoglycemia During Exercise To Stop Diabetes In Few Days Click Here Blood glucose concentration is normally maintained within a narrow physiological range during exercise. It may fall however during prolonged exercise performed in the fasted state and continued to the point of fatigue when endogenous muscle and liver glycogen stores are becoming depleted resulting in a mismatch between hepatic glucose production and working muscle glucose utilization. In resting healthy humans even a small decrement in blood glucose concentra- tion to 80 mg/dl 4.4 mmol/l would provoke a reduction in insulin secretion in an initial effort to counteract the fall in blood glucose 124. There is a hierarchy of glycemic thresholds for activation of counterregulatory hormone secretion autonomic symptoms and cerebral dysfunction which allows for a more effec- tive and redundant response to hypoglycemia 125. Increased secretion of gluca- gon and adrenaline occurs at blood glucose concentration of 68–70 mg/dl 3.8–3.9 mmol/l secretion of noradrenaline and growth hormone at 65–67 mg/ dl 3.6–3.7 mmol/l and secretion of cortisol at 55 mg/dl 3.0 mmol/l. Autonomic symptoms begin to develop at 58 mg/dl 3.2 mmol/l whereas deterioration in cognitive function is observed at glucose concentrations of around 50–55 mg/dl 2.8–3.0 mmol/l 125 126. As discussed in the previous section insulin glucagon and catecholamines also respond in a hierarchical fashion to regulate hepatic glucose production and prevent exercise-induced hypoglycemia. However the normal counterregulatory hormone catecholamines glucagon cortisol and GH response to exercise is amplified by simultaneous hypoglycemia in nondiabetic individuals 127. In fact the counter- regulatory hormone response to exercise and insulin-induced hypoglycemia is syn- ergistic when the two stimuli are combined 128. Furthermore it appears that the catecholamine and in particular adrenaline response to hypoglycemia can be dis- sociated from the corresponding response to exercise 127. It appears that exercise augments the adrenaline response to hypoglycemia in an effort to reduce glucose utilization by peripheral tissues 89. Therefore the potent effect of exercise on the counterregulatory hormone response to hypoglycemia is important in both increas- ing hepatic glucose output and limiting peripheral glucose utilization in a coordi- nated effort to minimize the magnitude of hypoglycemia during exercise. During exercise hepatic glucose output is very sensitive to small changes in plasma glucose concentration resulting from changes in the balance between glu- cose supply and utilization 95. Indeed in both humans and dogs the normal exer- cise-induced increase in hepatic glucose output can be completely prevented when glucose is infused in an attempt to match systemic glucose supply with the increase in glucose utilization by skeletal muscle 95 129. Interestingly although this sup- pression of hepatic glucose output occurred in the presence of elevated portal vein insulin levels when compared with those seen in the control trial the response of glucagon catecholamines and cortisol was not altered indicating that the counter- regulatory hormone response to exercise is less sensitive than hepatic glucose output

slide 32:

15 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 15 to changes in glucose supply 129. Based on human and animal studies that observed reduced counterregulatory response to induced systemic hypoglycemia

slide 33:

16 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 16 2 max Obesity Childhood Prior hypo- glycaemia Prior hypo- glycaemia Reduced CR to exercise Prior exercise males only Prior exercise Reduced CR to hypo- glycaemia Females Fig. 1.5 Factors blunting the normal counterregulatory hormone response CR to subsequent exercise left and hypoglycemia right Data taken from 2 134 135 137 138 153–155 184 when portal vein glucose concentrations were elevated through local infusion or oral ingestion of glucose it appears that in addition to glucose-responsive neurons in the brain glucose-sensitive neurons in the portal vein or the liver itself may also play an important role in mediating glucose-induced changes in hepatic glucose output 130–132. However the extent to which this feedback mechanism operates in humans during exercise requires further investigation. Interestingly the occurrence of preexercise hypoglycemia is associated with blunted counterregulation and impaired hepatic glycogenolysis during subsequent exercise 133. Conversely prior exercise also blunts the counterregulatory hormone response to subsequent hypoglycemia 134. In healthy humans two prior episodes of moderate hypoglycemia 2.9 mmol/l or 50 mg/dl for 120 min result in consid- erable attenuation 50 of the neuroendocrine glucagon insulin and cate- cholamines and metabolic hepatic glucose production lipolysis and ketogenesis responses to moderate exercise 50 V ˙ O performed the next day 133. This blunted response became more apparent after the first 30 min of exercise and hepatic glucose production despite an initial increase declined to basal levels by the end of exercise 90 min. However the opposite is also true as two 90-min bouts of exercise at 50 V ˙ O separated by 3 h were shown to markedly blunt by 30–60 the 2 max counterregulatory hormone response adrenaline noradrenaline glucagon pancre- atic polypeptide ACTH and GH but surprisingly not cortisol hepatic glucose pro- duction by 60 and muscle sympathetic nerve activity by 90 response to a 2-h bout of moderate hypoglycemia 3.0 mmol/l or 54 mg/dl the day after 134. The similarity between the latter responses and those reported after antecedent hypoglycemia led to the hypothesis that a common mechanism underlies both set of responses. A number of factors including elevations in circulating cortisol ketone bodies and lactate levels have been proposed as mediators of the hypoglycemia- induced blunting effect on glucose counterregulation during a subsequent episode of hypoglycemia 134–136. Whether this is the case in exercise-induced responses requires further investigation. In addition to antecedent exercise and hypoglycemia other factors that can also modulate the normal counterregulatory response to exercise are obesity and matura- tion Fig. 1.5. Obesity blunts catecholamine and growth hormone responses to acute intense and submaximal exercise in both adults 137 138 and children 139.

slide 34:

17 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 17 2 max Despite this blunting effect on counterregulatory response to exercise and higher circulating insulin levels during exercise none of the studies reported any incidents of hypoglycemia possibly because of a concurrent decrease in peripheral glucose utilization during exercise in the obese population as a result of insulin resistance. In general when compared with adults children both boys and girls rely more on fat and less on carbohydrate as a metabolic fuel during exercise of similar rela- tive intensity performed both in the fasting state and with carbohydrate feeding 140 141. Although the typically observed decrease in circulating insulin and increase in glucagon during exercise in adults occurs in children too other responses such as catecholamine and cortisol secretion appear to be blunted in children however this is a not a uniform finding in the literature for extensive review on this topic see Riddell 140. Despite potential differences in the hormonal response to exercise between children and adults there is no evidence that children are at greater risk for developing hypoglycemia during prolonged exercise perhaps because they rely less on carbohydrate as a metabolic fuel at a given exercise intensity which compensates for any deficiency in glucose counterregulation. 1.7 Gender Differences in the Endocrine and Metabolic Responses to Exercise During moderate- and high-intensity exercise 60–85 V ˙ O performed in the 2 max postabsorptive fasting state women oxidize more lipid and less CHO than men 142–144. This may explain the greater plasma glucose clearance rate and ten- dency for a decline in plasma glucose concentration during exercise in the fasting state in men compared with women 144. However this gender difference is rela- tively small during low intensity 40 V ˙ O exercise 145 and therefore exer- cising at moderate to high intensity which is known to increase muscle glucose uptake and oxidation 1 2 19 may present a greater challenge for glucose counter- regulation in men than women. Interestingly studies that compared the metabolic responses to exercise per- formed with CHO ingestion in men and women reported that the contribution of exogenous CHO to energy production was either similar 146 or slightly higher in women than men 147. In support of this moderate exercise performed in the post- prandial state resulted in similar glycemic response and substrate oxidation rates during exercise after either oral high glycemic index meal or intravenous CHO glucose loads in men and women 148. This may at least in part have been due to the similar pancreatic insulin secretory response and whole body insulin sensitiv- ity observed in the men and women studied. However it should be noted that there is no consensus in the literature with regard to insulin sensitivity differences in men and women. Indeed although some studies demonstrated greater whole body insu- lin sensitivity in women than in men 149 150 others did not observe a gender difference in this parameter 151. Regardless of the mechanism involved it appears that moderate exercise performed in the postprandial state abolishes the gender

slide 35:

18 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 18 2 max 2 max difference in substrate utilization normally observed during exercise in the fasting state and appears to present a similar challenge to the ability of healthy men and women to perform exercise without a substantial decline in plasma glucose concentration. Higher adrenaline noradrenaline and pancreatic polypeptide responses have been reported in men than women during 90 min of cycling exercise at approxi- mately 50 V ˙ O with euglycemia maintained through an exogenous glucose infusion. However insulin glucagon cortisol and GH levels responded similarly in both genders which may have accounted for the absence of a gender difference in hepatic glucose production 152. Interestingly in healthy humans exercise performed in the morning can suppress the counterregulatory response to exercise performed in the afternoon and this effect appears to be gender specific 153. Indeed 90 min of cycling at 50 V ˙ O blunts the adrenaline noradrenaline cortisol and GH responses to subsequent exer- cise of similar duration and intensity performed 3 h later in men but not women. Despite this differential neuroendocrine response between the two genders the exogenous glucose infusion rate required to maintain euglycemia was fivefold higher during the second bout of exercise most likely as a result of decreased hepatic glucose production and no gender difference was observed 153. The gen- der difference in the counterregulatory responses to exercise is also present after two episodes of antecedent hypoglycemia in individuals with type I diabetes 154. Furthermore there is also a gender difference in the counterregulatory responses to moderately controlled hypoglycemia at rest with women showing lower cate- cholamine responses when compared with men 155. The functional significance and origin of this gender difference in the neuroen- docrine response to exercise after either antecedent exercise or hypoglycemia is not clear Fig. 1.5 but it is possible that antecedent exercise may present a greater risk for developing hypoglycemia during subsequent exercise in men than women by shifting the glycemic threshold for the initiation of counterregulatory responses to lower plasma glucose concentrations. 1.8 Glucose Ingestion During Exercise and Effects on Counterregulatory Responses Substrate Utilization and Exercise Performance Fatigue during prolonged intense exercise in a thermoneutral environment appears to be associated with either glycogen depletion in working muscles 3 4 25 or hypoglycemia 156. However it is possible that during exhaustive intense exercise volitional fatigue is a multifactorial process that involves both peripheral and central mechanisms. When the endogenous carbohydrate stores are severely reduced dur- ing the latter stages of prolonged exercise a reduction in plasma glucose concentra- tion may pose a threat to cerebral metabolism which depends on constant glucose supply. This threat to normal cerebral function may be prevented by discontinuing

slide 36:

19 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 19 exercise as a result of impaired mental drive for motor performance 157 158. However the extent to which a central mechanism operates during exercise in humans remains to be elucidated. It should be noted that moderate exercise to exhaustion can be continued in the presence of hypoglycemia 25. Furthermore plasma glucose concentrations do not consistently fall during prolonged exhaustive exercise in the absence of CHO sup- plementation. Indeed a 30-km running race and even marathon running performed after an overnight fast and without CHO supplementation may not always challenge euglycemia 120 159. This may not be surprising given that glucose uptake is inversely related to the amount of muscle mass involved during exercise 29. A greater active muscle mass is involved during running when compared with cycling and this may explain the higher occurrence of hypoglycemic episodes dur- ing the latter when compared with the former mode of exercise. It is well estab- lished that oral CHO ingestion during prolonged glycogen-depleting exercise can delay the onset of fatigue and thus substantially increase endurance performance in humans 160. The typical metabolic response to exercise with oral CHO ingestion is characterized by elevated plasma glucose and insulin concentrations an increase in exogenous glucose uptake and utilization suppression in hepatic glucose output and a reduction in plasma FFA and glycerol concentrations 96 120 121 161. In healthy subjects carbohydrate ingestion or glucose infusion before or during exercise suppresses the increase in cortisol 123 162 adrenaline 25 glucagon 30 163 and growth hormone 121 secretion usually observed during prolonged exercise without exogenous CHO supply. These reciprocal changes in insulin on one hand and glucagon cortisol adrenaline and growth hormone on the other hand during exercise with CHO ingestion are important in facilitating suppression in both hepatic glucose output and adipose tissue lipolysis under conditions of increased exogenous glucose supply and utilization. Exogenous CHO administration may either spare endogenous muscle glycogen utilization during prolonged continuous or intermittent exercise 6 9 164 165 or better maintain blood glucose concentration and whole body CHO oxidation rate late in exercise at a time when a significant reduction in muscle glycogen stores occurs 166. The sparing of muscle glycogen occurs in type I slow-twitch fibers during continuous exercise 6 9 and mainly in type II fast-twitch muscle fibers during high-intensity intermittent exercise 164. During exhaustive continuous exercise this ergogenic effect of CHO ingestion is associated with attenuated decline in oxidative ATP resynthesis in type I fibers 6. It is important however that CHO ingestion starts immediately before or as early as possible during exercise. Once muscle glycogen concentrations are depleted and fatigue is imminent the provision of exogenous CHO cannot sustain exercise at high intensity 70 V ˙ O 2 max 30 possibly as a result of a mismatch between the rate of blood glucose uptake by the working muscles and the rate of CHO utilization required to meet the metabolic demand of exercise. The metabolic effects of CHO ingestion during exercise depend on factors such as the type and intensity of exercise type and timing of CHO ingestion pre- exercise nutritional and training status of the subjects and the magnitude of the

slide 37:

20 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 20 2 max 2 max associated perturbation in insulin secretion. Although endurance training reduces the contribution of endogenous CHO utilization to energy expenditure it does not diminish the exogenous glucose utilization during submaximal exercise 32 pos- sibly because the sensitivity and responsiveness of insulin-stimulated glucose uptake is increased in the trained compared with the untrained human muscle 167. An antecedent CHO-rich diet that elevates resting muscle glycogen con- centrations preserves the ergogenic effect of CHO solutions ingested during high- intensity intermittent running by better maintaining plasma glucose concentrations toward the end of exercise but without affecting muscle glycogen utilization 168. The intensity and/or type of exercise and their effect on blood glucose plasma insulin and catecholamine responses may play a major role in determining the con- tribution of blood glucose and muscle glycogen utilization to energy metabolism when CHO is ingested during exercise. Indeed CHO ingestion during high-intensity cycling 70 V ˙ O results in modest increases in circulating glucose and insulin levels 169 170 whereas during low intensity cycling 30–50 V ˙ O it amplifies the glycemic and insulinemic responses 171 172. Therefore changes in exercise intensity and the associated catecholamine responses may have a profound impact on glycemic responses to exercise which in turn may have important implications for choice of metabolic fuel i.e. endogenous and exogenous CHO during exercise. There are a number of differences in the responses of blood glucose and insulin to oral CHO ingestion between cycling and running the most frequently used exer- cise modes in the study of energy metabolism in humans 160. These apparent differences between cycling and running are likely to result from differences in glucose uptake into active muscle tissue. Although exogenous CHO oxidation rates were reported to be similar between prolonged running and cycling at the same rela- tive exercise intensity 173 in healthy individuals the rate of whole body glucose uptake during physiological hyperinsulinemia maintained by constant infusion of insulin at a fixed rate is greater during running than cycling performed at the same relative intensity 174. In humans skeletal muscle accounts for almost all the glu- cose uptake during exercise performed under euglycemic-hyperinsulinemic condi- tions. Under those conditions the increase in muscle glucose uptake when compared with hyperinsulinemia alone appears to be due to a stimulatory effect of contractile activity and an increase in muscle blood flow and hence glucose delivery 49. Therefore the greater insulin-stimulated glucose disposal during running than cycling might be explained by a higher contractile activity as a result of a greater active muscle mass in the former compared with the latter exercise mode. Alternatively a difference in the pattern of muscle fiber type recruitment and/or glycogen utilization between running and cycling might also explain the difference in glucose disposal between the two exercise modes. Regardless of the mechanism involved exercise mode differences in glucose uptake may have important implica- tions for control of blood glucose concentration and choice of metabolic fuel during exercise performed under hyperinsulinemic conditions i.e. postprandial state in both healthy and diabetic individuals. Carbohydrate ingestion during the hour before the onset of exercise may result in transient hypoglycemia during subsequent exercise. Contrary to popular belief this

slide 38:

21 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 21 transient hypoglycemia which may or may not be accompanied by relevant symptoms does not appear to adversely affect subsequent exercise performance which may actually improve when compared with exercise in the fasting state 175. It should be noted that hypoglycemia is not always observed following CHO inges- tion during the hour before the onset of exercise and some individuals appear to be more prone than others although the factors that determine this susceptibility are not clear 175. Ingestion of CHO-rich meals 3–4 h before exercise also improves endurance per- formance when compared to exercise after an overnight fast 176–178. However large glycemic and insulinemic perturbations are normally associated with such practice which may result in a sharp decline in blood glucose concentration during the early stages of subsequent exercise increased muscle glycogenolysis and reduced plasma FFA availability and oxidation 179 180. The low glucagon-to- insulin ratio during exercise under those conditions is expected to suppress hepatic glucose output. As the effect of insulin and contraction on muscle glucose uptake is synergistic the sharp decline in plasma glucose concentration under those condi- tions may be a reflection of insufficient blood glucose supply in the face of increased muscle glucose uptake. One way to ameliorate such large glycemic and insulinemic perturbations is to consume a meal that consists of low glycemic index GI foods which would pro- voke smaller metabolic disturbances during both the postprandial period and subse- quent exercise as well as result in lower CHO oxidation rates during exercise when compared with a meal consisting of high GI foods 163 181. The lower glycemic and insulinemic responses to low GI meals secondary to slow digestion and absorp- tion of the ingested foods prevent a sharp decline in blood glucose concentration during the early stages of exercise and maintain higher glucagon-to-insulin ratio and plasma FFA availability and fat oxidation rates together with a sparing of muscle glycogen utilization and lower muscle lactate accumulation 163. Despite the profound glycemic and insulinemic perturbations associated with ingestion of high glycemic index GI foods or meals there is no consensus in the literature on whether they adversely affect subsequent exercise performance when compared with low GI meals 175. It is likely that any profound glycemic effects of high GI meals observed early in exercise might be offset by the fact that high GI foods if consumed sufficiently in advance to the start of exercise i.e. 3–4 h confer an advantage in terms of muscle and liver glycogen storage compared to low GI foods 163. 1.9 Summary Exercise exerts a great demand on the capacity of the human body to maintain blood glucose homeostasis. Blood glucose utilization by skeletal muscle increases with increasing intensity and duration of exercise and a decrement in blood glucose concentration is counteracted by a complex and well-coordinated neuroendocrine

slide 39:

22 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 22 response. The liver plays a key role in the maintenance of blood glucose homeostasis during exercise by increasing its glucose production through increased glycogenolysis and gluconeogenesis. An increase in glucagon and a fall in insulin concentrations in the portal vein are important stimulators of hepatic glucose pro- duction during low and moderate intensity exercise whereas catecholamines may play an important role during high-intensity exercise or when the islet hormone responses are disturbed. The normal counterregulatory hormone response to exer- cise is amplified by simultaneous hypoglycemia in nondiabetic individuals. However occurrence of preexercise hypoglycemia is associated with blunted coun- terregulation during subsequent exercise. Conversely prior exercise blunts the counterregulatory response to a subsequent episode of hypoglycemia. The normal counterregulatory response to exercise is also blunted in obese individuals and there is evidence that at least part of the response might be impaired in children although their risk for developing hypoglycemia during prolonged exercise is simi- lar to that of adults. Moderate exercise performed in the postprandial state abolishes the gender difference in substrate utilization normally observed during exercise in the fasting state. However prior exercise performed in the morning can suppress the counterregulatory response to exercise performed in the afternoon in men but not women. Therefore it is possible that antecedent exercise may present a greater risk for developing hypoglycemia during subsequent exercise in men than women. Oral CHO ingestion during prolonged exercise can delay the onset of fatigue in humans by either sparing muscle glycogen utilization or better maintaining blood glucose concentration and CHO oxidation late in exercise. The metabolic effects of CHO ingestion during exercise depend on factors such as the type and intensity of exer- cise type and timing of CHO ingestion preexercise nutritional status and the mag- nitude of the associated perturbation in insulin secretion. Carbohydrate ingestion in the minutes and hours before the onset of exercise is associated with profound gly- cemic and insulinemic perturbations which may result in transient hypoglycemia and increased reliance on muscle glycogen during subsequent exercise. Consumption of low glycemic index foods or meals ameliorates these metabolic perturbations but there is inconclusive evidence on whether they confer an advantage in terms of exercise performance. References 1. Romijn JA Coyle EF Sidossis LS et al. Regulation of endogenous fat and carbohydrate metab- olism in relation to exercise intensity and duration. Am J Physiol. 1993265:E380–91. 2. van Loon LJ Greenhaff PL Constantin-Teodosiu D Saris WH Wagenmakers AJ. The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol. 2001536: 295–304. 3. Hermansen L Hultman E Saltin B. Muscle glycogen during prolonged severe exercise. Acta Physiol Scand. 196771:129–39. 4. Karlsson J Saltin B. Diet muscle glycogen and endurance performance. J Appl Physiol. 197131:203–6.

slide 40:

23 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 23 5. Broberg S Sahlin K. Adenine nucleotide degradation in human skeletal muscle during prolonged exercise. J Appl Physiol. 198967:116–22. 6. Tsintzas K Williams C Constantin-Teodosiu D et al. Phosphocreatine degradation in type I and type II muscle fibres during submaximal exercise in man: effect of carbohydrate ingestion. J Physiol. 2001537:305–11. 7. Ball-Burnett M Green HJ Houston ME. Energy metabolism in human slow and fast twitch fibres during prolonged cycle exercise. J Physiol. 1991437:257–67. 8. Norman B Sollevi A Kaijser L Jansson E. ATP breakdown products in human skeletal mus- cle during prolonged exercise to exhaustion. Clin Physiol. 19877:503–10. 9. Tsintzas OK Williams C Boobis L Greenhaff P. Carbohydrate ingestion and single muscle fiber glycogen metabolism during prolonged running in men. J Appl Physiol. 199681:801–9. 10. Hultman E Bergstrom J Anderson NM. Breakdown and resynthesis of phosphorylcreatine and adenosine triphosphate in connection with muscular work in man. Scand J Clin Lab Invest. 196719:56–66. 11. Sahlin K Soderlund K Tonkonogi M Hirakoba K. Phosphocreatine content in single fibers of human muscle after sustained submaximal exercise. Am J Physiol. 1997273:C172–8. 12. Essen B Jansson E Henriksson J Taylor AW Saltin B. Metabolic characteristics of fibre types in human skeletal muscle. Acta Physiol Scand. 197595:153–65. 13. Schiaffino S Reggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev. 199676:371–423. 14. Gollnick PD Piehl K Saltin B. Selective glycogen depletion pattern in human muscle fibres after exercise of varying intensity and at varying pedalling rates. J Physiol. 1974241:45–57. 15. Tsintzas OK Williams C Boobis L Greenhaff P. Carbohydrate ingestion and glycogen utili- zation in different muscle fibre types in man. J Physiol. 1995489Pt 1:243–50. 16. V ollestad NK Blom PC. Effect of varying exercise intensity on glycogen depletion in human muscle fibres. Acta Physiol Scand. 1985125:395–405. 17. Wahren J Felig P Ahlborg G Jorfeldt L. Glucose metabolism during leg exercise in man. J Clin Invest. 197150:2715–25. 18. Ahlborg G Felig P. Lactate and glucose exchange across the forearm legs and splanchnic bed during and after prolonged leg exercise. J Clin Invest. 198269:45–54. 19. Katz A Broberg S Sahlin K Wahren J. Leg glucose uptake during maximal dynamic exercise in humans. Am J Physiol. 1986251:E65–70. 20. Coggan AR. Plasma glucose metabolism during exercise in humans. Sports Med. 199111: 102–24. 21. Bergeron R Kjaer M Simonsen L Bulow J Galbo H. Glucose production during exercise in humans: a-hv balance and isotopic-tracer measurements compared. J Appl Physiol. 199987: 111–5. 22. Marliss EB Vranic M. Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes. 200251 Suppl 1:S271–83. 23. Coggan AR Coyle EF. Reversal of fatigue during prolonged exercise by carbohydrate infusion or ingestion. J Appl Physiol. 198763:2388–95. 24. Coggan AR Spina RJ Kohrt WM Bier DM Holloszy JO. Plasma glucose kinetics in a well- trained cyclist fed glucose throughout exercise. Int J Sport Nutr. 19911:279–88. 25. Felig P Cherif A Minagawa A Wahren J. Hypoglycemia during prolonged exercise in normal men. N Engl J Med. 1982306:895–900. 26. Petersen KF Price TB Bergeron R. Regulation of net hepatic glycogenolysis and gluconeo- genesis during exercise: impact of type 1 diabetes. J Clin Endocrinol Metab. 200489: 4656–64. 27. Bjorkman O Eriksson LS. Splanchnic glucose metabolism during leg exercise in 60-hour- fasted human subjects. Am J Physiol. 1983245:E443–8. 28. Lavoie C Ducros F Bourque J Langelier H Chiasson JL. Glucose metabolism during exer- cise in man: the role of insulin and glucagon in the regulation of hepatic glucose production and gluconeogenesis. Can J Physiol Pharmacol. 199775:26–35.

slide 41:

24 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 24 29. Richter EA Kiens B Saltin B Christensen NJ Savard G. Skeletal muscle glucose uptake during dynamic exercise in humans: role of muscle mass. Am J Physiol. 1988254:E555–61. 30. Galbo H Holst JJ Christensen NJ. The effect of different diets and of insulin on the hormonal response to prolonged exercise. Acta Physiol Scand. 1979107:19–32. 31. Coggan AR Kohrt WM Spina RJ Bier DM Holloszy JO. Endurance training decreases plasma glucose turnover and oxidation during moderate-intensity exercise in men. J Appl Physiol. 199068:990–6. 32. Jeukendrup AE Mensink M Saris WH Wagenmakers AJ. Exogenous glucose oxidation during exercise in endurance-trained and untrained subjects. J Appl Physiol. 199782: 835–40. 33. Jessen N Goodyear LJ. Contraction signaling to glucose transport in skeletal muscle. J Appl Physiol. 200599:330–7. 34. Lauritzen HP Galbo H Brandauer J Goodyear LJ Ploug T. Large GLUT4 vesicles are sta- tionary while locally and reversibly depleted during transient insulin stimulation of skeletal muscle of living mice: imaging analysis of GLUT4-enhanced green fluorescent protein vesicle dynamics. Diabetes. 200857:315–24. 35. Lauritzen HP Galbo H Toyoda T Goodyear LJ. Kinetics of contraction-induced GLUT4 translocation in skeletal muscle fibers from living mice. Diabetes. 201059:2134–44. 36. Lauritzen HP Ploug T Prats C Tavare JM Galbo H. Imaging of insulin signaling in skeletal muscle of living mice shows major role of T-tubules. Diabetes. 200655:1300–6. 37. Frosig C Roepstorff C Brandt N et al. Reduced malonyl-CoA content in recovery from exer- cise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle. Am J Physiol Endocrinol Metab. 2009296:E787–95. 38. Goodyear LJ Giorgino F Balon TW Condorelli G Smith RJ. Effects of contractile activity on tyrosine phosphoproteins and PI 3-kinase activity in rat skeletal muscle. Am J Physiol. 1995 268:E987–95. 39. Hansen PA Nolte LA Chen MM Holloszy JO. Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol. 1998 85:1218–22. 40. Wojtaszewski JF Hansen BF Gade J et al. 2000 Insulin signaling and insulin sensitivity after exercise in human skeletal muscle. Diabetes 49:325–331 41. Wojtaszewski JF Hansen BF Kiens B Richter EA. Insulin signaling in human skeletal mus- cle: time course and effect of exercise. Diabetes. 199746:1775–81. 42. Treebak JT Taylor EB Witczak CA et al. Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle. Am J Physiol Cell Physiol. 2010298:C377–85. 43. Koh HJ Toyoda T Fujii N et al. Sucrose nonfermenting AMPK-related kinase SNARK mediates contraction-stimulated glucose transport in mouse skeletal muscle. Proc Natl Acad Sci USA. 2010107:15541–6. 44. Witczak CA Jessen N Warro DM et al. CaMKII regulates contraction- but not insulin- induced glucose uptake in mouse skeletal muscle. Am J Physiol Endocrinol Metab. 2010298: E1150–60. 45. Taylor EB An D Kramer HF et al. Discovery of TBC1D1 as an insulin- AICAR- and con- traction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem. 2008283: 9787–96. 46. Toyoda T An D Witczak CA et al. Myo1c regulates glucose uptake in mouse skeletal muscle. J Biol Chem. 2011286:4133–40. 47. DeFronzo RA Ferrannini E Sato Y Felig P Wahren J. Synergistic interaction between exer- cise and insulin on peripheral glucose uptake. J Clin Invest. 198168:1468–74. 48. Wasserman DH Geer RJ Rice DE et al. Interaction of exercise and insulin action in humans. Am J Physiol. 1991260:E37–45. 49. Hespel P Vergauwen L V andenberghe K Richter EA. Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle. Diabetes. 199544:210–5.

slide 42:

25 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 25 50. Newman JM Ross RM Richards SM Clark MG Rattigan S. Insulin and contraction increase nutritive blood flow in rat muscle in vivo determined by microdialysis of L-14Cglucose. J Physiol. 2007585:217–29. 51. Poole DC Copp SW Hirai DM Musch TI. Dynamics of muscle microcirculatory and blood- myocyte O2 flux during contractions. Acta Physiol Oxf. 2011202:293–310. 52. Constantin-Teodosiu D Cederblad G Hultman E. PDC activity and acetyl group accumulation in skeletal muscle during prolonged exercise. J Appl Physiol. 199273:2403–7. 53. Mandarino LJ Consoli A Jain A Kelley DE. Differential regulation of intracellular glucose metabolism by glucose and insulin in human muscle. Am J Physiol. 1993265:E898–905. 54. Mandarino LJ Wright KS Verity LS et al. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase phosphofructokinase and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. J Clin Invest. 198780: 655–63. 55. Tsintzas K Chokkalingam K Jewell K Norton L Macdonald IA Constantin-Teodosiu D. Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A. J Clin Endocrinol Metab. 200792:3967–72. 56. Chokkalingam K Jewell K Norton L et al. High-fat/low-carbohydrate diet reduces insulin- stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: an important role for skeletal muscle pyruvate dehydrogenase kinase 4. J Clin Endocrinol Metab. 200792:284–92. 57. Patel MS Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase com- plexes. FASEB J. 19904:3224–33. 58. Tsintzas K Williams C Constantin-Teodosiu D Hultman E Boobis L Greenhaff P. Carbohydrate ingestion prior to exercise augments the exercise-induced activation of the pyru- vate dehydrogenase complex in human skeletal muscle. Exp Physiol. 200085:581–6. 59. Perseghin G Price TB Petersen KF et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996335:1357–62. 60. Mikines KJ Sonne B Farrell PA Tronier B Galbo H. Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol. 1988254:E248–59. 61. Dela F Mikines KJ Sonne B Galbo H. Effect of training on interaction between insulin and exercise in human muscle. J Appl Physiol. 199476:2386–93. 62. Kraniou GN Cameron-Smith D Hargreaves M. Acute exercise and GLUT4 expression in human skeletal muscle: influence of exercise intensity. J Appl Physiol. 2006101:934–7. 63. Kuo CH Browning KS Ivy JL. Regulation of GLUT4 protein expression and glycogen stor- age after prolonged exercise. Acta Physiol Scand. 1999165:193–201. 64. Greiwe JS Holloszy JO Semenkovich CF. Exercise induces lipoprotein lipase and GLUT-4 protein in muscle independent of adrenergic-receptor signaling. J Appl Physiol. 200089:176–81. 65. Ren JM Semenkovich CF Gulve EA Gao J Holloszy JO. Exercise induces rapid increases in GLUT4 expression glucose transport capacity and insulin-stimulated glycogen storage in muscle. J Biol Chem. 1994269:14396–401. 66. Hansen PA Wang W Marshall BA Holloszy JO Mueckler M. Dissociation of GLUT4 trans- location and insulin-stimulated glucose transport in transgenic mice overexpressing GLUT1 in skeletal muscle. J Biol Chem. 1998273:18173–9. 67. O’Doherty RM Bracy DP Osawa H Wasserman DH Granner DK. Rat skeletal muscle hexokinase II mRNA and activity are increased by a single bout of acute exercise. Am J Physiol. 1994266:E171–8. 68. Koval JA DeFronzo RA O’Doherty RM et al. Regulation of hexokinase II activity and expression in human muscle by moderate exercise. Am J Physiol. 1998274:E304–8. 69. Pilegaard H Osada T Andersen LT Helge JW Saltin B Neufer PD. Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise. Metabolism. 200554:1048–55.

slide 43:

26 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 26 70. Stephens FB Norton L Jewell K Chokkalingam K Parr T Tsintzas K. Basal and insulin- stimulated pyruvate dehydrogenase complex activation glycogen synthesis and metabolic gene expression in human skeletal muscle the day after a single bout of exercise. Exp Physiol. 201095:808–18. 71. Nielsen JN Derave W Kristiansen S Ralston E Ploug T Richter EA. Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen content. J Physiol. 2001531:757–69. 72. Treebak JT Frosig C Pehmoller C et al. Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle. Diabetologia. 200952:891–900. 73. Wende AR Schaeffer PJ Parker GJ et al. A role for the transcriptional coactivator PGC- 1alpha in muscle refueling. J Biol Chem. 2007282:36642–51. 74. Ikeda S Miyazaki H Nakatani T et al. Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training. Biochem Biophys Res Commun. 2002296:395–400. 75. Boonsong T Norton L Chokkalingam K et al. Effect of exercise and insulin on SREBP-1c expression in human skeletal muscle: potential roles for the ERK1/2 and Akt signalling path- ways. Biochem Soc Trans. 200735:1310–1. 76. Burkart EM Sambandam N Han X et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest. 2007 117:3930–9. 77. Hunter WM Sukkar MY . Changes in plasma insulin levels during muscular exercise. J Physiol. 1968196:110P–2. 78. Hartley LH Mason JW Hogan RP et al. Multiple hormonal responses to prolonged exercise in relation to physical training. J Appl Physiol. 197233:607–10. 79. Felig P Wahren J Hendler R Ahlborg G. Plasma glucagon levels in exercising man. N Engl J Med. 1972287:184–5. 80. Ahlborg G Felig P Hagenfeldt L Hendler R Wahren J. Substrate turnover during prolonged exercise in man. Splanchnic and leg metabolism of glucose free fatty acids and amino acids. J Clin Invest. 197453:1080–90. 81. Hermansen L Pruett ED Osnes JB Giere FA. Blood glucose and plasma insulin in response to maximal exercise and glucose infusion. J Appl Physiol. 197029:13–6. 82. Lins PE Wajngot A Adamson U Vranic M Efendic S. Minimal increases in glucagon levels enhance glucose production in man with partial hypoinsulinemia. Diabetes. 198332:633–6. 83. Edgerton DS Cardin S Emshwiller M et al. Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism. Diabetes. 200150:1872–82. 84. Petersen KF Laurent D Rothman DL Cline GW Shulman GI. Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest. 1998101:1203–9. 85. Edgerton DS Ramnanan CJ Grueter CA et al. Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo. Diabetes. 200958:2766–75. 86. Rivera N Ramnanan CJ An Z et al. Insulin-induced hypoglycemia increases hepatic sensitiv- ity to glucagon in dogs. J Clin Invest. 2010120:4425–35. 87. Wasserman DH Spalding JA Lacy DB Colburn CA Goldstein RE Cherrington AD. Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during mus- cular work. Am J Physiol. 1989257:E108–17. 88. Cherrington AD Williams PE Shulman GI Lacy WW. Differential time course of glucagon’s effect on glycogenolysis and gluconeogenesis in the conscious dog. Diabetes. 198130:180–7. 89. Wasserman DH Lickley HL Vranic M. Interactions between glucagon and other counterregu- latory hormones during normoglycemic and hypoglycemic exercise in dogs. J Clin Invest. 198474:1404–13. 90. Miles PD Finegood DT Lickley HL Vranic M. Regulation of glucose turnover at the onset of exercise in the dog. J Appl Physiol. 199272:2487–94. 91. Wasserman DH Williams PE Lacy DB Goldstein RE Cherrington AD. Exercise-induced fall in insulin and hepatic carbohydrate metabolism during muscular work. Am J Physiol. 1989256:E500–9.

slide 44:

27 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 27 92. Wolfe RR Nadel ER Shaw JH Stephenson LA Wolfe MH. Role of changes in insulin and glucagon in glucose homeostasis in exercise. J Clin Invest. 198677:900–7. 93. Hirsch IB Marker JC Smith LJ et al. Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Physiol. 1991260:E695–704. 94. Issekutz Jr B. Effects of glucose infusion on hepatic and muscle glycogenolysis in exercising dogs. Am J Physiol. 1981240:E451–7. 95. Jenkins AB Chisholm DJ James DE Ho KY Kraegen EW. Exercise-induced hepatic glu- cose output is precisely sensitive to the rate of systemic glucose supply. Metabolism. 198534:431–6. 96. Jeukendrup AE Wagenmakers AJ Stegen JH Gijsen AP Brouns F Saris WH. Carbohydrate ingestion can completely suppress endogenous glucose production during exercise. Am J Physiol. 1999276:E672–83. 97. Rojdmark S Bloom G Chou MC Jaspan JB Field JB. Hepatic insulin and glucagon extrac- tion after their augmented secretion in dogs. Am J Physiol. 1978235:E88–96. 98. Wasserman DH Lacy DB Bracy DP. Relationship between arterial and portal vein immuno- reactive glucagon during exercise. J Appl Physiol. 199375:724–9. 99. Camacho RC Pencek RR Lacy DB James FD Wasserman DH. Suppression of endogenous glucose production by mild hyperinsulinemia during exercise is determined predominantly by portal venous insulin. Diabetes. 200453:285–93. 100. Wasserman DH. Regulation of glucose fluxes during exercise in the postabsorptive state. Annu Rev Physiol. 199557:191–218. 101. Coker RH Simonsen L Bulow J Wasserman DH Kjaer M. Stimulation of splanchnic glu- cose production during exercise in humans contains a glucagon-independent component. Am J Physiol Endocrinol Metab. 2001280:E918–27. 102. Coker RH Krishna MG Lacy DB Allen EJ Wasserman DH. Sympathetic drive to liver and nonhepatic splanchnic tissue during heavy exercise. J Appl Physiol. 199782:1244–9. 103. Issekutz Jr B. Role of beta-adrenergic receptors in mobilization of energy sources in exercis- ing dogs. J Appl Physiol. 197844:869–76. 104. Wahrenberg H Engfeldt P Bolinder J Arner P. Acute adaptation in adrenergic control of lipolysis during physical exercise in humans. Am J Physiol. 1987253:E383–90. 105. Wasserman DH Lacy DB Goldstein RE Williams PE Cherrington AD. Exercise-induced fall in insulin and increase in fat metabolism during prolonged muscular work. Diabetes. 198938:484–90. 106. Connolly CC Steiner KE Stevenson RW et al. Regulation of glucose metabolism by norepi- nephrine in conscious dogs. Am J Physiol. 1991261:E764–72. 107. Dufour S Lebon V Shulman GI Petersen KF. Regulation of net hepatic glycogenolysis and gluconeogenesis by epinephrine in humans. Am J Physiol Endocrinol Metab. 2009297:E231–5. 108. Han XX Bonen A. Epinephrine translocates GLUT-4 but inhibits insulin-stimulated glucose transport in rat muscle. Am J Physiol. 1998274:E700–7. 109. Wasserman DH Williams PE Lacy DB Bracy D Cherrington AD. Hepatic nerves are not essential to the increase in hepatic glucose production during muscular work. Am J Physiol. 1990259:E195–203. 110. Simonson DC Koivisto V Sherwin RS et al. Adrenergic blockade alters glucose kinetics during exercise in insulin-dependent diabetics. J Clin Invest. 198473:1648–58. 111. Howlett K Galbo H Lorentsen J et al. Effect of adrenaline on glucose kinetics during exer- cise in adrenalectomised humans. J Physiol. 1999519Pt 3:911–21. 112. Calles J Cunningham JJ Nelson L et al. Glucose turnover during recovery from intensive exercise. Diabetes. 198332:734–8. 113. Marliss EB Simantirakis E Miles PD et al. Glucose turnover and its regulation during intense exercise and recovery in normal male subjects. Clin Invest Med. 199215:406–19. 114. Marliss EB Simantirakis E Miles PD et al. Glucoregulatory and hormonal responses to repeated bouts of intense exercise in normal male subjects. J Appl Physiol. 199171:924–33.

slide 45:

28 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 28 115. Purdon C Brousson M Nyveen SL et al. The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects. J Clin Endocrinol Metab. 199376:566–73. 116. Kreisman SH Halter JB Vranic M Marliss EB. Combined infusion of epinephrine and nor- epinephrine during moderate exercise reproduces the glucoregulatory response of intense exercise. Diabetes. 200352:1347–54. 117. Marker JC Hirsch IB Smith LJ Parvin CA Holloszy JO Cryer PE. Catecholamines in pre- vention of hypoglycemia during exercise in humans. Am J Physiol. 1991260:E705–12. 118. Hartley LH. Growth hormone and catecholamine response to exercise in relation to physical training. Med Sci Sports. 19757:34–6. 119. Bak JF Moller N Schmitz O. Effects of growth hormone on fuel utilization and muscle gly- cogen synthase activity in normal humans. Am J Physiol. 1991260:E736–42. 120. Tsintzas OK Williams C Singh R Wilson W Burrin J. Influence of carbohydrate-electrolyte drinks on marathon running performance. Eur J Appl Physiol Occup Physiol. 199570:154–60. 121. Tsintzas OK Williams C Wilson W Burrin J. Influence of carbohydrate supplementation early in exercise on endurance running capacity. Med Sci Sports Exerc. 199628:1373–9. 122. Galbo H Holst JJ Christensen NJ. Glucagon and plasma catecholamine responses to graded and prolonged exercise in man. J Appl Physiol. 197538:70–6. 123. Deuster PA Singh A Hofmann A Moses FM Chrousos GC. Hormonal responses to ingest- ing water or a carbohydrate beverage during a 2 h run. Med Sci Sports Exerc. 199224:72–9. 124. Fanelli C Pampanelli S Epifano L et al. Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to symptoms of and deterioration of cognitive func- tion in hypoglycaemia in male and female humans. Diabetologia. 199437:797–807. 125. Mitrakou A Ryan C Veneman T et al. Hierarchy of glycemic thresholds for counterregula- tory hormone secretion symptoms and cerebral dysfunction. Am J Physiol. 1991260:E67–74. 126. Heller SR Macdonald IA. The measurement of cognitive function during acute hypoglycae- mia: experimental limitations and their effect on the study of hypoglycaemia unawareness. Diabet Med. 199613:607–15. 127. Sotsky MJ Shilo S Shamoon H. Regulation of counterregulatory hormone secretion in man during exercise and hypoglycemia. J Clin Endocrinol Metab. 198968:9–16. 128. Zinker BA Allison RG Lacy DB Wasserman DH. Interaction of exercise insulin and hypo- glycemia studied using euglycemic and hypoglycemic insulin clamps. Am J Physiol. 1997272:E530–42. 129. Berger CM Sharis PJ Bracy DP Lacy DB Wasserman DH. Sensitivity of exercise-induced increase in hepatic glucose production to glucose supply and demand. Am J Physiol. 1994267:E411–21. 130. Niijima A. Glucose-sensitive afferent nerve fibres in the hepatic branch of the vagus nerve in the guinea-pig. J Physiol. 1982332:315–23. 131. Smith D Pernet A Reid H et al. The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man. Diabetologia. 200245:1416–24. 132. Donovan CM Halter JB Bergman RN. Importance of hepatic glucoreceptors in sympathoa- drenal response to hypoglycemia. Diabetes. 199140:155–8. 133. Davis SN Galassetti P Wasserman DH Tate D. Effects of antecedent hypoglycemia on sub- sequent counterregulatory responses to exercise. Diabetes. 200049:73–81. 134. Galassetti P Mann S Tate D et al. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab. 2001280:E908–17. 135. Davis SN Shavers C Mosqueda-Garcia R Costa F. Effects of differing antecedent hypogly- cemia on subsequent counterregulation in normal humans. Diabetes. 199746:1328–35. 136. Veneman T Mitrakou A Mokan M Cryer P Gerich J. Effect of hyperketonemia and hyper- lacticacidemia on symptoms cognitive dysfunction and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes. 199443:1311–7.

slide 46:

29 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 29 137. V ettor R Macor C Rossi E Piemonte G Federspil G. Impaired counterregulatory hormonal and metabolic response to exhaustive exercise in obese subjects. Acta Diabetol. 199734:61–6. 138. Gustafson AB Farrell PA Kalkhoff RK. Impaired plasma catecholamine response to sub- maximal treadmill exercise in obese women. Metabolism. 199039:410–7. 139. Eliakim A Nemet D Zaldivar F et al. Reduced exercise-associated response of the GH-IGF-I axis and catecholamines in obese children and adolescents. J Appl Physiol. 2006100: 1630–7. 140. Riddell MC. The endocrine response and substrate utilization during exercise in children and adolescents. J Appl Physiol. 2008105:725–33. 141. Martinez LR Haymes EM. Substrate utilization during treadmill running in prepubertal girls and women. Med Sci Sports Exerc. 199224:975–83. 142. Steffensen CH Roepstorff C Madsen M Kiens B. Myocellular triacylglycerol breakdown in females but not in males during exercise. Am J Physiol Endocrinol Metab. 2002282: E634– 42. 143. Tarnopolsky LJ MacDougall JD Atkinson SA Tarnopolsky MA Sutton JR. Gender differ- ences in substrate for endurance exercise. J Appl Physiol. 199068:302–8. 144. Carter SL Rennie C Tarnopolsky MA. Substrate utilization during endurance exercise in men and women after endurance training. Am J Physiol Endocrinol Metab. 2001280:E898–907. 145. Horton TJ Pagliassotti MJ Hobbs K Hill JO. Fuel metabolism in men and women during and after long-duration exercise. J Appl Physiol. 199885:1823–32. 146. M’Kaouar H Peronnet F Massicotte D Lavoie C. Gender difference in the metabolic response to prolonged exercise with 13Cglucose ingestion. Eur J Appl Physiol. 2004 92:462–9. 147. Riddell MC Partington SL Stupka N Armstrong D Rennie C Tarnopolsky MA. Substrate utilization during exercise performed with and without glucose ingestion in female and male endurance trained athletes. Int J Sport Nutr Exerc Metab. 200313:407–21. 148. Leelayuwat N Tsintzas K Patel K Macdonald IA. Metabolic responses to exercise after carbohydrate loads in healthy men and women. Med Sci Sports Exerc. 200537:1721–7. 149. Nuutila P Knuuti MJ Maki M et al. Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes. 199544:31–6. 150. Robertson MD Livesey G Mathers JC. Quantitative kinetics of glucose appearance and dis- posal following a 13C-labelled starch-rich meal: comparison of male and female subjects. Br J Nutr. 200287:569–77. 151. Perseghin G Scifo P Pagliato E et al. Gender factors affect fatty acids-induced insulin resis- tance in nonobese humans: effects of oral steroidal contraception. J Clin Endocrinol Metab. 200186:3188–96. 152. Davis SN Galassetti P Wasserman DH Tate D. Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man. J Clin Endocrinol Metab. 200085:224–30. 153. Galassetti P Mann S Tate D Neill RA Wasserman DH Davis SN. Effect of morning exer- cise on counterregulatory responses to subsequent afternoon exercise. J Appl Physiol. 200191:91–9. 154. Galassetti P Tate D Neill RA Morrey S Wasserman DH Davis SN. Effect of sex on coun- terregulatory responses to exercise after antecedent hypoglycemia in type 1 diabetes. Am J Physiol Endocrinol Metab. 2004287:E16–24. 155. Amiel SA Maran A Powrie JK Umpleby AM Macdonald IA. Gender differences in coun- terregulation to hypoglycaemia. Diabetologia. 199336:460–4. 156. Pruett ED. Glucose and insulin during prolonged work stress in men living on different diets. J Appl Physiol. 197028:199–208. 157. Lambert EV St Clair Gibson A Noakes TD. Complex systems model of fatigue: integrative homoeostatic control of peripheral physiological systems during exercise in humans. Br J Sports Med. 200539:52–62.

slide 47:

30 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 30 158. Nybo L Secher NH. Cerebral perturbations provoked by prolonged exercise. Prog Neurobiol. 200472:223–61. 159. Tsintzas K Liu R Williams C Campbell I Gaitanos G. The effect of carbohydrate ingestion on performance during a 30-km race. Int J Sport Nutr. 19933:127–39. 160. Tsintzas K Williams C. Human muscle glycogen metabolism during exercise. Effect of car- bohydrate supplementation. Sports Med. 199825:7–23. 161. McConell G Fabris S Proietto J Hargreaves M. Effect of carbohydrate ingestion on glucose kinetics during exercise. J Appl Physiol. 199477:1537–41. 162. Tabata I Ogita F Miyachi M Shibayama H. Effect of low blood glucose on plasma CRF ACTH and cortisol during prolonged physical exercise. J Appl Physiol. 199171: 1807–12. 163. Wee SL Williams C Tsintzas K Boobis L. Ingestion of a high-glycemic index meal increases muscle glycogen storage at rest but augments its utilization during subsequent exercise. J Appl Physiol. 200599:707–14. 164. Nicholas CW Tsintzas K Boobis L Williams C. Carbohydrate-electrolyte ingestion during intermittent high-intensity running. Med Sci Sports Exerc. 199931:1280–6. 165. Yaspelkis 3rd BB Patterson JG Anderla PA Ding Z Ivy JL. Carbohydrate supplementation spares muscle glycogen during variable-intensity exercise. J Appl Physiol. 199375: 1477–85. 166. Coyle EF Hagberg JM Hurley BF Martin WH Ehsani AA Holloszy JO. Carbohydrate feeding during prolonged strenuous exercise can delay fatigue. J Appl Physiol. 198355: 230–5. 167. Dela F Mikines KJ von Linstow M Secher NH Galbo H. Effect of training on insulin- mediated glucose uptake in human muscle. Am J Physiol. 1992263:E1134–43. 168. Foskett A Williams C Boobis L Tsintzas K. Carbohydrate availability and muscle energy metabolism during intermittent running. Med Sci Sports Exerc. 200840:96–103. 169. Mitchell JB Costill DL Houmard JA Fink WJ Pascoe DD Pearson DR. Influence of carbo- hydrate dosage on exercise performance and glycogen metabolism. J Appl Physiol. 198967:1843–9. 170. Hargreaves M Briggs CA. Effect of carbohydrate ingestion on exercise metabolism. J Appl Physiol. 198865:1553–5. 171. Yaspelkis 3rd BB Ivy JL. Effect of carbohydrate supplements and water on exercise metabo- lism in the heat. J Appl Physiol. 199171:680–7. 172. Ahlborg G Felig P. Influence of glucose ingestion on fuel-hormone response during pro- longed exercise. J Appl Physiol. 197641:683–8. 173. Pfeiffer B Stellingwerff T Zaltas E Hodgson AB Jeukendrup AE. Carbohydrate oxidation from a drink during running compared with cycling exercise. Med Sci Sports Exerc. 201143:327–34. 174. Tsintzas K Simpson EJ Seevaratnam N Jones S. Effect of exercise mode on blood glucose disposal during physiological hyperinsulinaemia in humans. Eur J Appl Physiol. 200389: 217–20. 175. Jeukendrup AE Killer SC. The myths surrounding pre-exercise carbohydrate feeding. Ann Nutr Metab. 201057 Suppl 2:18–25. 176. Neufer PD Costill DL Flynn MG Kirwan JP Mitchell JB Houmard J. Improvements in exercise performance: effects of carbohydrate feedings and diet. J Appl Physiol. 198762:983–8. 177. Schabort EJ Bosch AN Weltan SM Noakes TD. The effect of a preexercise meal on time to fatigue during prolonged cycling exercise. Med Sci Sports Exerc. 199931:464–71. 178. Sherman WM Brodowicz G Wright DA Allen WK Simonsen J Dernbach A. Effects of 4 h preexercise carbohydrate feedings on cycling performance. Med Sci Sports Exerc. 1989 21:598–604. 179. Coyle EF Jeukendrup AE Wagenmakers AJ Saris WH. Fatty acid oxidation is directly regu- lated by carbohydrate metabolism during exercise. Am J Physiol. 1997273:E268–75.

slide 48:

31 K. Tsintzas and I.A. MacDonald 1 Endocrine and Metabolic Responses to Exercise 31 180. Coyle EF Coggan AR Hemmert MK Lowe RC Walters TJ. Substrate usage during pro- longed exercise following a preexercise meal. J Appl Physiol. 198559:429–33. 181. Wee SL Williams C Gray S Horabin J. Influence of high and low glycemic index meals on endurance running capacity. Med Sci Sports Exerc. 199931:393–9. 182. Wahren J Ekberg K. Splanchnic regulation of glucose production. Annu Rev Nutr. 200727:329–45. 183. Tsintzas K Jewell K Kamran M et al. Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans. J Physiol. 2006575:291–303. 184. Davis SN Fowler S Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes. 200049:65–72.

slide 49:

2 Chapter 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise Michael C. Riddell To Cure Diabetes Naturally Click Here 2.1 Brief Overview of the Normal Endocrine Response to Exercise To provide energy in the form of carbohydrates lipids and protein in the face of increased energy demands during exercise the healthy body must orchestrate a com- plex neuroendocrine response that starts at the onset of the activity. This response is continuously modulated as the duration of the exercise increases and as the intensity of the activity changes. Since one of the main fuels for exercise is carbohydrate glu- cose utilization by the working muscle must be matched equally by glucose provision predominantly by the liver or hypoglycemia will ensue. If the liver cannot keep up with glucose utilization then carbohydrate intake is critical to maintain performance. Glucose homeostasis during prolonged moderate-intensity exercise 40–60 maxi- mal oxygen uptake VO max is primarily regulated by a reduction in insulin secre- tion and an increase in glucagon release from the pancreatic islets which together helps to increase liver glucose production 1. The increase in the glucagon-to-insulin ratio raises the rate of glucose appearance Ra to match almost perfectly the increased rate of peripheral glucose disposal Rd into working muscle Fig. 2.1. Increased hepatic glucose production during exercise occurs primarily through enhanced glycogenolysis and gluconeogenesis with a greater reliance on the latter pathway as the duration of exercise increases 2. Hypoglycemia can occur even in nondiabetic individuals when hepatic glucose production fails to match the ele- vated glucose uptake by working muscle which is particularly pronounced during prolonged exercise usually 3 h of activity if not enough carbohydrate is con- sumed 3. If hepatic glycogen stores are depleted during prolonged exercise M.C. Riddell Ph.D. Physical Activity and Diabetes Unit School of Kinesiology and Health Science Muscle Health Research Centre York University 4700 Keele Street M3J1P3 Toronto ON Canada e-mail: mriddellyorku.ca

slide 50:

I. Gallen ed. Type 1 Diabetes 29 DOI 10.1007/978-0-85729-754-9_2 © Springer-Verlag London Limited 2012

slide 51:

30 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 30 Insulin Glucagon Insulin Euglycemia Hypoglycemia Glucagon or Insulin Hypoglycemia Catecholamines Fig. 2.1 Blood glucose responses to exercise in nondiabetic or ideally controlled patient with type 1 diabetes upper panel overinsulinized patient middle panel and underinsulinized patient or patient performing high-intensity exercise under competition stress lower panel. The thicknesses of the arrows represent glucose flux. In the upper panel hepatic glucose production is balanced with muscle glucose uptake and normal blood glucose levels are maintained. In the middle panel high circulating insulin levels reduce hepatic glucose production and increase muscle glucose uptake thereby resulting in hypoglycemia. In the lower panel low circulating insulin levels and/ or elevated counterregulatory hormones increase hepatic glucose production and decrease muscle glucose uptake resulting in hyperglycemia Reprinted by permission of the publisher from Chu et al. 94 JTE Multimedia gluconeogenesis alone is unable to provide adequate glucose to supply the working muscles. To help reduce the reliance on endogenous carbohydrate as a fuel source reductions in insulin levels and increases in growth hormone along with increases in sympathoadrenal activity and other factors help promote increased lipid provi- sion for oxidation by muscle 4. Even with very prolonged exercise when reliance on lipid as a primary fuel source is maximal carbohydrate provision either by the liver through gluconeogenesis or by oral ingestion is essential to prevent hypogly- cemia even in nondiabetics 5.

slide 52:

31 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 31 In healthy individuals several glucose counterregulatory mechanisms i.e. anti- hypoglycemic actions exist to help limit hypoglycemia both when fasting occurs at rest and when prolonged exercise is performed. For example 6 a slight decrease in glycemia from normal normal being 90 mg/dL or 5 mmol/L lowers insulin secretion and activates the release of various counterregulatory hormones including glucagon catecholamines growth hormone and cortisol in a stepwise and hierar- chical fashion 7. During exercise other humoral and muscle factors also likely help augment glucose production 100. All of these hormones act to increase hepatic glucose production and lower peripheral glucose disposal thereby defend- ing against ensuing hypoglycemia. As such several safeguards need to be breached before hypoglycemia occurs in nondiabetic individuals. Interestingly heavy aerobic exercise 80 VO also generates a complex 2 max neuroendocrine response similar to that of acute stress perhaps as a means of ele- vating glucose provision for “fight or flight”. In intense exercise glucose is the exclusive muscle fuel and it must be mobilized from muscle and liver glycogen in the fed and fasted state. This process is largely governed by increases in cate- cholamines which facilitate glucose production but limit glucose uptake. As such in healthy individuals insulin secretion actually increases post-exercise to help nor- malize this transient hyperglycemia caused by intense exercise 8. This complex neurohormonal regulation during exercise performed at a wide range of differing intensities and durations and at different environmental conditions makes it nearly impossible to mimic in the patient with type 1 diabetes. 2.2 Abnormalities in the Endocrine Responses to Acute Exercise in Type 1 Diabetes The blood glucose response to exercise in patients with type 1 diabetes varies con- siderably both between and within individuals likely depending on several factors including the type and intensity of exercise performed the duration of the activity and the level of circulating “on board” insulin during and after the exercise. Even if all of these variables are taken into consideration the blood glucose response differs markedly between individuals but has some reproducibility within an individual 9. One of the key determinates of the glycemic response to exercise is the general clas- sification of the exercise i.e. aerobic vs. anaerobic. 2.2.1 Aerobic Exercise Aerobic exercise may be defined as any activity that uses large muscle groups at relatively low rates of muscular contraction. This type of activity can be maintained continuously or rhythmically for prolonged periods minutes to hours through oxidative metabolism of various fuel sources including carbohydrates fats and some protein. Moderate-intensity aerobic exercise generally involves continuous

slide 53:

32 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 32 2 aerobic activity between 40 and 59 of VO max or 55–69 of maximal heart rate HRmax 10. Examples of moderate-intensity exercise include continuous aerobic activities such as jogging cycling and swimming. Typically this type of exercise promotes a lowering of blood glucose concentration both during and after the end of the activity and thus requires nutritional intervention and/or adjustments in insulin dosages to limit hypoglycemia. The physiological mechanisms by which aerobic exercise causes undesirable alterations in glycemia in individuals with type 1 diabetes are detailed below and highlighted in Fig. 2.1. 2.2.1.1 Hypoglycemia For individuals with type 1 diabetes the inability to reduce exogenous insulin levels during aerobic exercise is a key factor that contributes to an increased risk of exercise-induced hypoglycemia 11. As discussed above insulin levels in the portal circulation normally drop after the onset of aerobic exercise and this drop helps to sensitize the liver to increasing glucagon concentrations 2 12. Since in the insulin-dependent type 1 patient exercise is often performed in a 0–4-h time frame post-insulin injection concentrations of insulin typically do not decrease during exercise and may actually increase just because of the kinetics of peak insulin action 13 14. A second related factor that increases the risk of hyperin- sulinemia and hypoglycemia is the accelerated absorption of insulin from subcu- taneous tissues once it has been injected or infused 15. Even if no bolus insulin has been injected or infused in the hours preceding exercise it is still possible but less likely to have hypoglycemia because of elevated basal insulin concentrations compared to nondiabetics who are exercising 13. Relative hyperinsulinemia during exercise in the patient with type 1 diabetes limits the effect of glucagon on hepatic glucose production and promotes insulin-induced peripheral glucose uptake further decreasing blood glucose levels. A third factor that may contribute to an increased risk for exercise-associated hypoglycemia in patients with type 1 diabetes may be the loss in glucagon response to developing hypoglycemia 16 or an impaired stimulation of hepatic glucose output in response to glucagon secretion 17. Although it has been established that the glucagon response to exercise may be intact in people with type 1 diabetes if they are not hypoglyce- mic 18 there may be deficiencies in the glucagon response during exercise if the patients were previously exposed to hypoglycemia 19 or perhaps if they are in fact exercising while hypoglycemic. Moreover there may also be impaired adren- ergic responses to exercise in patients with type 1 diabetes under hypoglycemic conditions 18. Finally other factors such as a low level of hepatic glycogen content in poorly controlled diabetes 20 and/or reduced gluconeogenesis and/or increased peripheral glucose disposal in the face of hyperinsulinemia 21 may contribute to exercise-induced hypoglycemia in patients with type 1 diabetes. A summary of the factors that may predispose the patient to hypoglycemia during aerobic exercise is shown in Table 2.1.

slide 54:

33 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 33 Table 2.1 Factors that can affect changes in blood glucose levels during exercise Drop in blood glucose Blood glucose unchanged Increase in blood glucose Hyperinsulinemia due to usual insulin injection or infusion prior to exercise and increased insulin absorption kinetics and action Prolonged aerobic type activity with no carbohydrate intake or without a reduction in insulin administration Pre-exercise insulin adjusted appropriately Appropriate consumption of carbohydrate before and during exercise Hypoinsulinemia and ketoacidosis prior to exercise Prolonged pump disconnect Unfamiliarity with the activity Very vigorous aerobic exercise 80 of maximal oxygen consumption Defective glucose counterregula- tion to hypoglycemia and/or exercise Repeated or intermittent anaerobic exercise Excessive carbohydrate consumption Post-exercise when glucose production or carbohydrate feeding exceeds disposal 2.2.1.2 Hyperglycemia Although aerobic exercise is typically associated with an increased risk for hypo- glycemia certain types of activity may promote hyperglycemia. Specifically high- intensity aerobic exercise i.e. above the lactate threshold tends to increase blood glucose levels because insulin levels do not rise in the portal circulation of the patient with diabetes to compensate for the normal increase in circulating cate- cholamine levels. It is well established that heavy aerobic exercise short- and middle-distance running short track cycling some other individual and team sports etc. induce increases in catecholamines that increase hepatic glucose production and limit peripheral disposal Fig. 2.1. In individuals who do not have diabetes the increase in catecholamines and hyperglycemia is compensated for by increases in insulin secretion usually at the end of the activity. If hyperglycemia occurs post-exercise this phenomenon is usually transient in the individual with diabetes lasting for 1–2 h in recovery. No current guidelines are available on the amount of insulin to administer in the presence of hyperglycemia after high-intensity exercise for patients with type 1 diabetes. Although some limited experimental data suggests that a doubling in insulin levels relative to when the vigorous exercise was performed may be needed to counter this transient hyperglycemia 22. Patients and caregivers should be aware of the potential for a rise in blood glu- cose before “stressful” competition. Even if blood glucose levels are normal in the hours before exercise anticipatory stress increases counterregulatory hormones and hyperglycemia can occur. Typically this “stress-related” increase in glycemia at the

slide 55:

34 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 34 onset of exercise does not need to be corrected for since the increased glucose utilization rate during the activity as long as it is aerobic in nature will often lower blood glucose levels. However frequent self-monitoring of blood glucose is needed to make sure that any pre-exercise hyperglycemia is not worsened during the exer- cise to which continuous glucose monitoring CGM may be an asset. In situations of prolonged and severe hypoinsulinemia missed insulin injections blocked insulin pump illness etc. patients may have elevations in circulating and urinary ketone bodies. In these situations vigorous exercise may cause further increases in hyperglycemia and ketoacidosis particularly if elevated blood ketones are present at the time of exercise. In these situations hepatic glucose production continues to rise while glucose utilization remains impaired and glycemic control deteriorates even further. For these reasons it is recommended to delay exercise if blood glucose is higher than 14 mmol/L and if blood or urinary ketones are also elevated 23 24. A summary of the possible reasons for exercise-associated hyper- glycemia during sport is shown in Table 2.1. For patients on insulin pump devices with hyperglycemia and elevated ketone levels infusion sets should be changed and individuals may need to temporarily change to needles with rapid-acting insulin injected until glucose is restored. Hyperglycemia and ketoacidosis may cause dehydration and decrease blood pH resulting in impaired performance and severe illness. Rapid ketone production can precipitate ketoacidotic abdominal pain and vomiting. In these situations patients are advised to seek emergency care for intravenous insulin and rehydration protocols. 2.2.2 Anaerobic Exercise Anaerobic activities are characterized by high rates of intense muscular contraction. With purely anaerobic exercise muscle contractions are sustained by the phospha- gen and anaerobic glycolytic systems to produce lactic acid and energy in the form of adenosine triphosphate ATP. Anaerobic activities include sprinting power lift- ing hockey and some motions during basketball and racquet sports. In reality how- ever most of the sports and physical activities that athletes perform are a mix of both anaerobic and aerobic actions soccer basketball mountain biking squash football etc.. Anaerobic fitness refers to the ability to work at a very high level during these activities for relatively short periods 5–30 s. With anaerobic exercise lactate production within the muscle rises dramatically. This lactate which is a glycolytic end product can either be used within the cells of formation or transported through the interstitium and vasculature to adjacent and ana- tomically distributed cells for utilization by other tissues 25. Elevations in lactate and catecholamines during anaerobic exercise are known to lower the uptake of plasma glucose and free fatty acids into skeletal muscle 26 and increase hepatic glucose production 27 thereby increasing the likelihood of hyperglycemia in patients with type 1 diabetes. Moreover anaerobic flux of muscle glycogen also lowers

slide 56:

35 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 35 skeletal muscle glucose uptake 26 which could contribute to hyperglycemia in persons with diabetes if hepatic glucose production is elevated. Interestingly just a 10-s high-intensity anaerobic sprint has been shown to help prevent early post-exercise hypoglycemia in persons with type 1 diabetes 28 29. In addition performing weight training before the onset of aerobic exercise may also attenuate the drop in blood glucose levels in patients with type 1 diabetes 30. Similarly performing intermittent high-intensity exercise with repeated anaerobic work may be superior over continuous moderate-intensity aerobic exercise for gly- cemic stability particularly in early and late recovery 31 32. 2.2.3 Early Post-exercise Hyperglycemia Just after the end of either vigorous aerobic or anaerobic work individuals with type 1 diabetes may experience increases in blood glucose levels through a number of mechanisms. First any reduction in insulin dosage prior to exercise might promote hyperglycemia once the activity is finished since glucose disposal will eventually return toward pre-exercise levels but glucose production will remain elevated because of the reduction in circulating insulin concentration. If the individual wears an insulin infusion device insulin pump and has removed the pump altogether then circulating insulin levels may be very low by the end of prolonged exercise and hyperglycemia is likely 33. In addition some individuals may be motivated to consume carbohydrates early in recovery which may drive up blood glucose levels. In addition as mentioned above very vigorous aerobic exercise with a heavy anaer- obic producing catecholamines and lactate component will increase glycemia for 1–2 h in recovery 8. In these situations it may be necessary or desirable to lower glycemia by injecting rapid-acting insulin analogs or by increasing the basal infu- sion rates to normal or slightly above normal early in recovery. 2.2.4 Late Post-exercise Hypoglycemia Post-exercise late-onset hypoglycemia has long been a complaint of patients with type 1 diabetes 34. If patients develop hypoglycemia during sleep it may go unno- ticed. If patients perform just 45 min of moderate-intensity exercise during the day then the risk of nocturnal hypoglycemia may be as high as 30–40 in the evening following exercise 35–39. An investigation in children with type 1 diabetes indi- cates that increased insulin sensitivity occurs immediately after exercise and again 7–11 h later 40 which may further elevate their risk for late-onset post-exercise nocturnal hypoglycemia. This is particularly problematic as patients may not perceive hypoglycemia dur- ing sleep and the hypoglycemic duration may last for just a few minutes or for several hours. In these situations a reduction in bedtime basal insulin by 20 is

slide 57:

36 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 36 recommended with a reduction in basal infusion rate from bedtime to 4 AM if on a pump 35. Otherwise a complex carbohydrate snack with some protein is advised either without an insulin bolus at all or with a drastically reduced bolus dose. 2.3 Abnormalities in Fuel Utilization During Exercise in Type 1 Diabetes A number of subtle alterations in fuel metabolism during exercise have been noted in persons with type 1 diabetes 41–45. In patients deprived of insulin for 12–24 h prolonged moderate-intensity exercise is associated with a lower respiratory exchange ratio and thus a reduced rate of carbohydrate oxidation than that shown in control subjects at the same exercise intensity 42 46. As such it would appear that a patient with type 1 diabetes who is underinsulinized would have a greater reli- ance on lipid oxidation during exercise compared to when they have elevated insulin levels. When insulin is administered to the patient to levels somewhat representa- tive of nondiabetics the overall ratio of carbohydrate to lipid utilization during exer- cise performed in the postprandial state looks remarkably normal 43 44 47 48. Indeed in a study conducted by Francescato et al. 44 which was conducted at various time intervals after insulin injection and with different amounts of glucose ingested fat oxidation and CHO oxidation were not significantly different from those observed in control subjects. The ingestion of fast-acting carbohydrate during exercise clearly helps to limit the hypoglycemic effect of endurance type exercise in individuals with type 1 dia- betes 49 50. Largely the oxidation of orally ingested carbohydrate is normal in those with diabetes if the circulating insulin levels are elevated although the rate of oxidation may be initially slightly impaired 41 43 45. Moreover rates of plasma glucose disappearance during exercise in patients with diabetes are comparable to control subjects 11 51–53 or just slightly impaired 48. Although total fat and carbohydrate oxidation rates may be normal during exer- cise in persons with type 1 diabetes who are well insulinized some evidence does exist to suggest that muscle glycogen utilization rates may be higher and plasma glucose oxidation rates lower during prolonged exercise than in nondiabetic indi- viduals 21. Unfortunately a greater reliance on limited endogenous muscle fuels i.e. muscle glycogen may put the individual at risk of early fatigue. A recent study has shown that a low-glycemic-index carbohydrate and reduced insulin dose administered 30 min before running maintains control of both pre- and post-exercise blood glucose responses in type 1 diabetes 54. The amount of car- bohydrate needed to limit hypoglycemia is at least partly related to the proximity of the last insulin injection 44. As such anywhere from 1.0 to 1.5 g of carbohy- drate per kilogram body mass per hour of exercise is required when the exercise is within 1–2 h of insulin administration 24 but this amount drops to about 0.2 g/ kg by about 5.5 h postinjection 44. Estimating glucose utilization rates during exercise either via respiratory exchange ratio or via heart rate appears to be an

slide 58:

37 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 37 2 2 2 effective means for determining the appropriate carbohydrate feeding regimen to help prevent hypoglycemia 50 55. 2.4 Effects of Type 1 Diabetes on Performance Normally insulin therapy is rapidly initiated at the time of diagnosis in patients with type 1 diabetes and dramatic metabolic improvements are achievable within a fairly short time frame days to weeks after the initiation of treatment 56. However clini- cal diagnosis may be delayed and the overall management in youth with the disease is usually suboptimal for a variety of physiological and psychosocial reasons 57. It should also be noted that normal restoration in glucose homeostasis is nearly impos- sible in type 1 diabetes since the sophisticated control system is no longer in place that maintains a small but critical amount of blood glucose constant 2. As such a number of physiological challenges in substrate metabolism exist that places the individual with type 1 diabetes at risk for suboptimal exercise performance. Overall aerobic capacity can be impaired significantly in young patients with type 1 particularly if they are in suboptimal glycemic control. For example in one large study of healthy and diabetic adolescents/young adults matched similarly in age weight height and body composition aerobic capacity was shown to be about 20 lower in those with type 1 diabetes 58. Several cardiovascular muscular and metabolic impairments in type 1 diabetes might help to explain their potential dec- rement in aerobic and anaerobic performance. A number of studies report reduced physical work capacity or maximal aerobic capacity VO max in young patients with type 1 diabetes despite insulin therapy when compared to their nondiabetic peers 58–64. Both end diastolic volume and left ventricular ejection fraction fail to increase normally during exercise in young adults with type 1 diabetes compared with controls 65. In contrast Nugent and colleagues 66 report no difference in VO peak during a progressive incremental exercise test in adults with long-stand- ing diabetes while Veves et al. 67 found that only inactive adults with demon- strated neuropathic complications had reduced VO max. Taken together these studies suggest that if one is physically active with type 1 diabetes then aerobic capacity can be normal at least if neuropathy has not yet developed. Impairments in physical work capacity in those with type 1 diabetes if observed appear to be related to the level of glycemic control in the patient. For example Poortmans et al. 64 and Huttunen et al. 61 both reported that physical capacities were inversely related to the level of metabolic control as measured by HbA1c. It is unclear however if a reduced work capacity in youth with type 1 diabetes is a result of poorer oxygenation of muscle 68 a lower amount of muscle capillarization 69 or if poorer metabolic control is a function of lower amounts of habitual physi- cal activity 70. In an experimentally induced murine model of diabetes there is altered expression of several genes involved in angiogenesis and reduced muscle capillarization which could not be normalized even by high-volume endurance exercise training 69.

slide 59:

38 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 38 Studies investigating muscular strength and endurance in individuals with type 1 diabetes have shown mixed results although a recent review by Krause and col- leagues has indicated that a myopathy may exist in type 1 diabetes 71. A number of investigators report decrements in strength 72–77 while others have shown no strength deficit but slower rates of muscular recruitment during isometric contrac- tion 78. Although fatigue is a common complaint of patients with diabetes 79 80 the effect of type 1 diabetes on endurance capacity during exercise is not well docu- mented. Compared to controls patients with type 1 diabetes have been reported to have both impaired 78 and enhanced 74 capacity during relatively brief bouts of intense exercise. Ratings of perceived exertion during prolonged exercise have been reported to be higher in boys with type 1 diabetes compared to age weight and aero- bic fitness matched controls 81. Also during prolonged exercise those with type 1 diabetes who are under good glycemic control have a higher glycolytic flux 82 and tend to rely considerably more on muscle glycogen utilization as an energy source 45 which might reduce endurance capacity although this hypothesis has yet to be tested. Moreover exercising while hyperglycemic has been shown to increase reli- ance on muscle glycogen compared to exercising while euglycemic 83 and the individual who is exercising while hypoinsulinemic/hyperglycemic would be expected to be prone to early dehydration and acidosis 84 all factors that might promote early fatigue. Moreover increasing blood glucose levels to 16 mmol/L has been shown to reduce isometric muscle strength but not maximal isokinetic muscle strength compared with strength measured at glycemia clamped at 5 mmol/L in patients with type 1 diabetes 85. This reduction in isometric strength might play a role in the development of early fatigue during certain types of resistance exercise. If individuals with type 1 diabetes are actively engaged in regular exercise they can clearly achieve a normal or even an elite level of sport performance. In one German study of ten middle-aged long-distance triathletes with type 1 diabetes studied over 3 years overall endurance performance was said to be “normal” despite documented hyperglycemia during the early part of a race then hypoglycemia dur- ing the marathon leg 86. The degree to which acute changes in blood glucose levels influence sports performance remains somewhat unclear however. Unfortunately very few studies have been conducted in which exercise performance is examined during differing levels of blood glucose concentrations in those with type 1 diabetes. Circumstantial evidence suggests that an increase in plasma glucose availability might improve the exercise capacity perhaps because more fuel is read- ily available for muscle contraction. However this hypothesis has not been sup- ported by one study that “clamped” nondiabetic cyclists at hyperglycemia and euglycemia and found no difference in endurance performance 87. Similarly in one study of prepubertal boys with type 1 diabetes n 16 lowering the insulin dose prior to exercise to reduce the likelihood of hypoglycemia did not influence aerobic capacity during cycling compared to the usual insulin dose 88. In eight endurance-trained adults with type 1 diabetes elevating blood glucose levels from 5.3 ± 0.6 mmol/L to 12.4 ± 2.1 mmol/L via hyperinsulinemic glucose clamp tech- nique also failed to change peak power output or other physiological endpoints such as lactate heart rate or respiratory exchange ratio 89.

slide 60:

39 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 39 In contrast to mild hyperglycemia mild hypoglycemia probably lowers exercise capacity and sport performance in individuals with type 1 diabetes. For example capacity was reduced and ratings of perceived exertion increased with hypoglycemia in a group of youth with type 1 diabetes 50 81 although the exercise was always stopped by the research investigators rather than the subjects for safety reasons. In a recent sports camp field study of 28 youth with type 1 diabetes Kelly et al. 90 found that the ability to carry out fundamental sports skills was markedly reduced by mild hypoglycemia compared with either eugly- cemia or hyperglycemia. Importantly this finding of significantly impaired sports performance with hypoglycemia appeared universally across nearly all subjects and is similar to the well-documented detrimental effects of hypoglycemia on cognitive processing 91. Profound or sustained hyperglycemia also likely impairs endurance performance in those with type 1 diabetes although the evidence for this statement is somewhat limited. Prolonged hypoinsulinemia/hyperglycemia would be expected to lower muscle glycogen levels reduce muscle strength and predispose the individual to dehydration and electrolyte imbalance 92. As mentioned above exercising while hyperglycemic has been shown to increase the reliance on muscle glycogen as a fuel source and limit the capacity to switch from carbohydrate to lipid energy sources 83. Importantly substrate oxidation during prolonged endurance exercise can be similar to what is observed in nondiabetics if diabetic subjects are clamped eugly- cemic 83. Taken together it is likely that there is an inverted-U shape relationship between glycemia and exercise/sport performance with the best performance in the euglycemic range. 2.5 Adaptations to Exercise Training in Type 1 Diabetes Individuals with type 1 diabetes appear to respond normally to both endurance- and resistance type training from an adaptive point of view particularly if they are in good glycemic control. Endurance training in humans normally results in numerous beneficial adapta- tions in skeletal muscles including an increase in GLUT4 expression and glucose transport capacity resulting in increased insulin sensitivity 93. Paradoxically however despite these adaptations improvements in glycemic control are not always observed with regular exercise in this patient population 94. The physio- logical adaptations to regular exercise are clearly beneficial for patients even if glycemic control is not improved. For example in response to endurance training children with type 1 diabetes have improved vascular function 95 and an improved cardiovascular risk profile 96 which will likely enhance long-term health. Interval sprint training has been shown to reduce metabolic acidosis and enhance oxidative capacity and fitness 97. Some have even speculated that regular exercise may attenuate the autoimmune event that causes beta cell death 98. Overall life expec- tancy appears to increase with regular activity in this patient population 99.

slide 61:

40 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 40 2.6 Summary In summary a number of neuroendocrine disturbances can influence glucose regulation during exercise making the management of glycemia challenging for the patient and caregiver. In general aerobic exercise promotes a reduction in blood glucose concen- tration while anaerobic exercise can promote transient hyperglycemia. Although indi- viduals with type 1 diabetes can achieve excellence in sport rigorous glycemic control and the appropriate insulin modifications on exercise days and appropriate nutritional intake is likely critical for maximizing individual performance. Overall improve- ments in various health metrics clearly indicate that regular exercise should remain at the cornerstone of clinical care for patients with type 1 diabetes. References 1. Wasserman DH. Regulation of glucose fluxes during exercise in the postabsorptive state. Annu Rev Physiol. 199557:191–218. 2. Wasserman DH. Berson award lecture 2008 four grams of glucose. Am J Physiol Endocrinol Metab. 20092961:E11–21. 3. Levine SA Gordon B Derick CL. Some changes in the chemical constituents of the blood following a marathon race: with special reference to the development of hypoglycemia. J Am Med Assoc. 19248222:1778–9. 4. Frayn KN. Fat as a fuel: emerging understanding of the adipose tissue-skeletal muscle axis. Acta Physiol Oxf. 20101994:509–18. 5. Dennis SC Noakes TD Hawley JA. Nutritional strategies to minimize fatigue during pro- longed exercise: fluid electrolyte and energy replacement. J Sports Sci. 1997153:305–13. 6. Cryer PE. Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract. 2008146:750–6. 7. Cryer PE. Hierarchy of physiological responses to hypoglycemia: relevance to clinical hypo- glycemia in type I insulin dependent diabetes mellitus. Horm Metab Res. 1997293:92–6. 8. Marliss EB Vranic M. Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes. 200251 Suppl 1:S271–83. 9. Temple MY Bar-Or O Riddell MC. The reliability and repeatability of the blood glucose response to prolonged exercise in adolescent boys with IDDM. Diabetes Care. 1995183:326–32. 10. Warburton DE Nicol CW Bredin SS. Prescribing exercise as preventive therapy. CMAJ. 20061747:961–74. 11. Zinman B Murray FT Vranic M Albisser AM Leibel BS Mc Clean PA et al. Glucoregulation during moderate exercise in insulin treated diabetics. J Clin Endocrinol Metab. 1977454:641–52. 12. Camacho RC Galassetti P Davis SN Wasserman DH. Glucoregulation during and after exer- cise in health and insulin-dependent diabetes. Exerc Sport Sci Rev. 2005331:17–23. 13. Tuominen JA Karonen SL Melamies L Bolli G Koivisto V A. Exercise-induced hypoglycae- mia in IDDM patients treated with a short-acting insulin analogue. Diabetologia. 1995381:106–11. 14. Rabasa-Lhoret R Bourque J Ducros F Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen ultralente-lispro. Diabetes Care. 2001244:625–30.

slide 62:

41 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 41 15. Berger M Halban PA Assal JP Offord RE Vranic M Renold AE. Pharmacokinetics of sub- cutaneously injected tritiated insulin: effects of exercise. Diabetes. 197928 Suppl 1:53–7. 16. Gerich JE Langlois M Noacco C Karam JH Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973182108:171–3. 17. Orskov L Alberti KG Mengel A Moller N Pedersen O Rasmussen O et al. Decreased hepatic glucagon responses in type 1 insulin-dependent diabetes mellitus. Diabetologia. 1991347:521–6. 18. Schneider SH Vitug A Ananthakrishnan R Khachadurian AK. Impaired adrenergic response to prolonged exercise in type I diabetes. Metabolism. 19914011:1219–25. 19. Galassetti P Tate D Neill RA Morrey S Wasserman DH Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes. 2003527:1761–9. 20. Cline GW Rothman DL Magnusson I Katz LD Shulman GI. 13C-nuclear magnetic reso- nance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. J Clin Invest. 1994946:2369–76. 21. Chokkalingam K Tsintzas K Snaar JE Norton L Solanky B Leverton E et al. Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 dia- betes: a magnetic resonance spectroscopy study. Diabetologia. 2007509:1921–9. 22. Sigal RJ Purdon C Fisher SJ Halter JB Vranic M Marliss EB. Hyperinsulinemia prevents prolonged hyperglycemia after intense exercise in insulin-dependent diabetic subjects. J Clin Endocrinol Metab. 1994794:1049–57. 23. Sigal R Kenny G Oh P Perkins BA Plotnikoff RC Prud’homme D et al. Physical activity and diabetes. Canadian diabetes association clinical practice guidelines expert committee. Canadian diabetes association 2008 clinical practice guidelines for the prevention and man- agement of diabetes in Canada. Can J Diabetes. 2008321:S37–9. 24. Robertson K Adolfsson P Scheiner G Hanas R Riddell MC. Exercise in children and adoles- cents with diabetes. Pediatr Diabetes. 200910 Suppl 12:154–68. 25. Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009587Pt 23:5591–600. 26. Lee AD Hansen PA Schluter J Gulve EA Gao J Holloszy JO. Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle. Am J Physiol. 19972733 Pt 1:C1082–7. 27. Purdon C Brousson M Nyveen SL Miles PD Halter JB Vranic M et al. The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects. J Clin Endocrinol Metab. 1993763:566–73. 28. Bussau V A Ferreira LD Jones TW Fournier PA. A 10-s sprint performed prior to moderate- intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Diabetologia. 2007509:1815–8. 29. Bussau V A Ferreira LD Jones TW Fournier PA. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care. 2006293:601–6. 30. Yardley JE Sigal RJ Perkins BA Riddell M. Performing resistance exercise before aerobic exercise reduces the risk of hypoglycemia in type 1 diabetes: a study using continuous glucose monitoring. Can J Diabetes. 2010343:247. 31. Guelfi KJ Ratnam N Smythe GA Jones TW Fournier PA. Effect of intermittent high-inten- sity compared with continuous moderate exercise on glucose production and utilization in individuals with type 1 diabetes. Am J Physiol Endocrinol Metab. 20072923:E865–70. 32. Iscoe KE Riddell MC. Continuous moderate-intensity exercise with or without intermittent high-intensity work: effects on acute and late glycaemia in athletes with type 1 diabetes mel- litus. Diabet Med. 2011287:824–32. 33. Delvecchio M Zecchino C Salzano G Faienza MF Cavallo L De Luca F et al. Effects of moderate-severe exercise on blood glucose in type 1 diabetic adolescents treated with insulin pump or glargine insulin. J Endocrinol Invest. 2009326:519–24.

slide 63:

42 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 42 34. MacDonald MJ. Post-exercise late-onset hypoglycemia in insulin-dependent diabetic patients. Diabetes Care. 1987105:584–8. 35. Taplin CE Cobry E Messer L McFann K Chase HP Fiallo-Scharer R. Preventing post-exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr. 20101575:784–8.e1. 36. Iscoe KE Campbell JE Jamnik V Perkins BA Riddell MC. Efficacy of continuous real-time blood glucose monitoring during and after prolonged high-intensity cycling exercise: spinning with a continuous glucose monitoring system. Diabetes Technol Ther. 200686:627–35. 37. Iscoe KE Corcoran M Riddell MC. High rates of nocturnal hypoglycemia in a unique sports camp for athletes with type 1 diabetes: lessons learned from continuous glucose monitoring. Can J Diabetes. 2008323:182–9. 38. Tsalikian E Mauras N Beck RW Tamborlane WV Janz KF Chase HP et al. Impact of exer- cise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 20051474:528–34. 39. Maran A Pavan P Bonsembiante B Brugin E Ermolao A Avogaro A et al. Continuous glu- cose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther. 20101210:763–8. 40. McMahon SK Ferreira LD Ratnam N Davey RJ Youngs LM Davis EA et al. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adoles- cents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab. 2007923:963–8. 41. Krzentowski G Pirnay F Pallikarakis N Luyckx AS Lacroix M Mosora F et al. Glucose utilization during exercise in normal and diabetic subjects. The role of insulin. Diabetes. 19813012:983–9. 42. Ramires PR Forjaz CL Strunz CM Silva ME Diament J Nicolau W et al. Oral glucose ingestion increases endurance capacity in normal and diabetic type I humans. J Appl Physiol. 1997832:608–14. 43. Riddell MC Bar-Or O Hollidge-Horvat M Schwarcz HP Heigenhauser GJ. Glucose inges- tion and substrate utilization during exercise in boys with IDDM. J Appl Physiol. 2000884:1239–46. 44. Francescato MP Geat M Fusi S Stupar G Noacco C Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism. 2004539:1126–30. 45. Robitaille M Dube MC Weisnagel SJ Prud’homme D Massicotte D Peronnet F et al. Substrate source utilization during moderate intensity exercise with glucose ingestion in type 1 diabetic patients. J Appl Physiol. 20071031:119–24. 46. Wahren J Hagenfeldt L Felig P. Splanchnic and leg exchange of glucose amino acids and free fatty acids during exercise in diabetes mellitus. J Clin Invest. 1975556:1303–14. 47. Murray FT Zinman B McClean PA Denoga A Albisser AM Leibel BS et al. The metabolic response to moderate exercise in diabetic man receiving intravenous and subcutaneous insulin. J Clin Endocrinol Metab. 1977444:708–20. 48. Raguso CA Coggan AR Gastaldelli A Sidossis LS Bastyr 3rd EJ Wolfe RR. Lipid and carbohydrate metabolism in IDDM during moderate and intense exercise. Diabetes. 1995449:1066–74. 49. Nathan DM Madnek SF Delahanty L. Programming pre-exercise snacks to prevent post- exercise hypoglycemia in intensively treated insulin-dependent diabetics. Ann Intern Med. 19851024:483–6. 50. Riddell MC Bar-Or O Ayub BV Calvert RE Heigenhauser GJ. Glucose ingestion matched with total carbohydrate utilization attenuates hypoglycemia during exercise in adolescents with IDDM. Int J Sport Nutr. 199991:24–34. 51. Shilo S Shamoon H. Abnormal growth hormone responses to hypoglycemia and exercise in adults with type I diabetes. Isr J Med Sci. 1990263:136–41. 52. Shilo S Sotsky M Shamoon H. Islet hormonal regulation of glucose turnover during exercise in type 1 diabetes. J Clin Endocrinol Metab. 1990701:162–72.

slide 64:

43 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 43 53. Simonson DC Koivisto V Sherwin RS Ferrannini E Hendler R Juhlin-Dannfelt A et al. Adrenergic blockade alters glucose kinetics during exercise in insulin-dependent diabetics. J Clin Invest. 1984736:1648–58. 54. West DJ Stephens JW Bain SC Kilduff LP Luzio S Still R et al. A combined insulin reduc- tion and carbohydrate feeding strategy 30 min before running best preserves blood glucose concentration after exercise through improved fuel oxidation in type 1 diabetes mellitus. J Sports Sci. 2011293:279–89. 55. Francescato MP Carrato S. Management of exercise-induced glycemic imbalances in type 1 diabetes. Curr Diabetes Rev. 201174:253–63. 56. Chase HP Lockspeiser T Peery B Shepherd M MacKenzie T Anderson J et al. The impact of the diabetes control and complications trial and humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes. Diabetes Care. 2001243:430–4. 57. Hamilton J Daneman D. Deteriorating diabetes control during adolescence: physiological or psychosocial J Pediatr Endocrinol Metab. 2002152:115–26. 58. Komatsu WR Gabbay MA Castro ML Saraiva GL Chacra AR de Barros Neto TL et al. Aerobic exercise capacity in normal adolescents and those with type 1 diabetes mellitus. Pediatr Diabetes. 200563:145–9. 59. Baraldi E Monciotti C Filippone M Santuz P Magagnin G Zanconato S et al. Gas exchange during exercise in diabetic children. Pediatr Pulmonol. 1992133:155–60. 60. Gusso S Hofman P Lalande S Cutfield W Robinson E Baldi JC. Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus. Diabetologia. 2008517:1317–20. 61. Huttunen NP Kaar ML Knip M Mustonen A Puukka R Akerblom HK. Physical fitness of chil- dren and adolescents with insulin-dependent diabetes mellitus. Ann Clin Res. 1984161:1–5. 62. Larsson Y Persson B Sterky G Thoren C. Functional adaptation to rigorous training and exercise in diabetic and nondiabetic adolescents. J Appl Physiol. 196419:629–35. 63. Larsson YA Sterky GC Ekengren KE Moller TG. Physical fitness and the influence of train- ing in diabetic adolescent girls. Diabetes. 196211:109–17. 64. Poortmans JR Saerens P Edelman R Vertongen F Dorchy H. Influence of the degree of meta- bolic control on physical fitness in type I diabetic adolescents. Int J Sports Med. 198674:232–5. 65. Larsen S Brynjolf I Birch K Munck O Sestoft L. The effect of continuous subcutaneous insulin infusion on cardiac performance during exercise in insulin-dependent diabetics. Scand J Clin Lab Invest. 1984448:683–91. 66. Nugent AM Steele IC al-Modaris F Vallely S Moore A Campbell NP et al. Exercise responses in patients with IDDM. Diabetes Care. 19972012:1814–21. 67. Veves A Saouaf R Donaghue VM Mullooly CA Kistler JA Giurini JM et al. Aerobic exer- cise capacity remains normal despite impaired endothelial function in the micro- and macro- circulation of physically active IDDM patients. Diabetes. 19974611:1846–52. 68. Ditzel J Standl E. The problem of tissue oxygenation in diabetes mellitus. Acta Med Scand Suppl. 1975578:59–68. 69. Kivela R Silvennoinen M Touvra AM Lehti TM Kainulainen H Vihko V . Effects of experi- mental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. FASEB J. 2006209:1570–2. 70. Valerio G Spagnuolo MI Lombardi F Spadaro R Siano M Franzese A. Physical activity and sports participation in children and adolescents with type 1 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2007175:376–82. 71. Krause MP Riddell MC Hawke TJ. Effects of type 1 diabetes mellitus on skeletal muscle: clini- cal observations and physiological mechanisms. Pediatr Diabetes. 2011124 Pt 1:345–64. 72. Andersen H Gadeberg PC Brock B Jakobsen J. Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study. Diabetologia. 1997409:1062–9. 73. Andersen H Stalberg E Gjerstad MD Jakobsen J. Association of muscle strength and electro- physiological measures of reinnervation in diabetic neuropathy. Muscle Nerve. 19982112:1647–54.

slide 65:

44 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 44 74. Andersen H. Muscular endurance in long-term IDDM patients. Diabetes Care. 1998214:604–9. 75. Andersen H Gjerstad MD Jakobsen J. Atrophy of foot muscles: a measure of diabetic neu- ropathy. Diabetes Care. 20042710:2382–5. 76. Andreassen CS Jakobsen J Ringgaard S Ejskjaer N Andersen H. Accelerated atrophy of lower leg and foot muscles–a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging MRI. Diabetologia. 2009526:1182–91. 77. Andreassen CS Jakobsen J Flyvbjerg A Andersen H. Expression of neurotrophic factors in diabetic muscle–relation to neuropathy and muscle strength. Brain. 2009132Pt 10:2724–33. 78. Almeida S Riddell MC Cafarelli E. Slower conduction velocity and motor unit discharge frequency are associated with muscle fatigue during isometric exercise in type 1 diabetes mel- litus. Muscle Nerve. 2008372:231–40. 79. Surridge DH Erdahl DL Lawson JS Donald MW Monga TN Bird CE et al. Psychiatric aspects of diabetes mellitus. Br J Psychiatry. 1984145:269–76. 80. Van der Does FE De Neeling JN Snoek FJ Kostense PJ Grootenhuis PA Bouter LM et al. Symptoms and well-being in relation to glycemic control in type II diabetes. Diabetes Care. 1996193:204–10. 81. Riddell MC Bar-Or O Gerstein HC Heigenhauser GJ. Perceived exertion with glucose inges- tion in adolescent males with IDDM. Med Sci Sports Exerc. 2000321:167–73. 82. Crowther GJ Milstein JM Jubrias SA Kushmerick MJ Gronka RK Conley KE. Altered energetic properties in skeletal muscle of men with well-controlled insulin-dependent type 1 diabetes. Am J Physiol Endocrinol Metab. 20032844:E655–62. 83. Jenni S Oetliker C Allemann S Ith M Tappy L Wuerth S et al. Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus–a pro- spective single-blinded randomised crossover trial. Diabetologia. 2008518:1457–65. 84. Magee MF Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin. 2001171:75–106. 85. Andersen H Schmitz O Nielsen S. Decreased isometric muscle strength after acute hypergly- caemia in type 1 diabetic patients. Diabet Med. 20052210:1401–7. 86. Boehncke S Poettgen K Maser-Gluth C Reusch J Boehncke WH Badenhoop K. Endurance capabilities of triathlon competitors with type 1 diabetes mellitus. Dtsch Med Wochenschr. 200913414:677–82. 87. Bosch AN Kirkman MC. Maintenance of hyperglycaemia does not improve performance in a 100 km cycling time trial. S Afr J Sports Med. 2007193:94–8. 88. Heyman E Briard D Dekerdanet M Gratas-Delamarche A Delamarche P. Accuracy of physi- cal working capacity 170 to estimate aerobic fitness in prepubertal diabetic boys and in 2 insulin dose conditions. J Sports Med Phys Fitness. 2006462:315–21. 89. Stettler C Jenni S Allemann S Steiner R Hoppeler H Trepp R et al. Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia. Diabetes Metab Res Rev. 2006224:300–6. 90. Kelly D Hamilton JK Riddell MC. Blood glucose levels and performance in a sports camp for adolescents with type 1 diabetes mellitus: a field study. Int J Pediatr. 20102010. doi:10.1155/2010/216167. 216167. Epub 2010 Aug 2. 91. Gonder-Frederick LA Zrebiec JF Bauchowitz AU Ritterband LM Magee JC Cox DJ et al. Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study. Diabetes Care. 2009326:1001–6. 92. Jimenez CC Corcoran MH Crawley JT Guyton Hornsby W Peer KS Philbin RD et al. National athletic trainers’ association position statement: management of the athlete with type 1 diabetes mellitus. J Athl Train. 2007424:536–45. 93. Goodyear LJ Kahn BB. Exercise glucose transport and insulin sensitivity. Annu Rev Med. 199849:235–61. 94. Chu L Hamilton J Riddell MC. Clinical management of the physically active patient with type 1 diabetes. Phys Sportsmed. 2011392:64–77.

slide 66:

45 M.C. Riddell 2 The Impact of Type 1 Diabetes on the Physiological Responses to Exercise 45 95. Seeger JP Thijssen DH Noordam K Cranen ME Hopman MT Nijhuis-van der Sanden MW. Exercise training improves physical fitness and vascular function in children with type 1 diabetes. Diabetes Obes Metab. 2011134:382–4. 96. Heyman E Toutain C Delamarche P Berthon P Briard D Youssef H et al. Exercise training and cardiovascular risk factors in type 1 diabetic adolescent girls. Pediatr Exerc Sci. 2007194:408–19. 97. Harmer AR Chisholm DJ McKenna MJ Hunter SK Ruell PA Naylor JM et al. Sprint training increases muscle oxidative metabolism during high-intensity exercise in patients with type 1 diabetes. Diabetes Care. 20083111:2097–102. 98. Krause Mda S de Bittencourt Jr PI. Type 1 diabetes: can exercise impair the autoimmune event The L-arginine/glutamine coupling hypothesis. Cell Biochem Funct. 2008264:406–33. 99. Moy CS Songer TJ LaPorte RE Dorman JS Kriska AM Orchard TJ et al. Insulin- dependent diabetes mellitus physical activity and death. Am J Epidemiol. 19931371:74–81. 100. Coker RH Kjaer M. Glucoregulation during exercise: the role of the neuroendocrine system. Sports Med. 2005357:575–83.

slide 67:

Chapter 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual Richard M. Bracken Daniel J. West and Stephen C. Bain To Get Rid Of Diabetes Permanently Click Here 3.1 Characteristics of Physical Exercise Physical exercise is a potent stressor that causes large increases in the metabolic rate of the type 1 diabetes T1DM individual. The magnitude of the increase in fuel use above resting values is dependent on factors such as the duration intensity and type of exer- cise. Somewhat simplistically an ability to perform exercise is dependent on the amount and rate of supply of carbohydrate and lipid fuel to facilitate completion of exercise. Deficiencies in carbohydrate availability will cause fatigue but from the viewpoint of the person with T1DM aid the development of hypoglycemia. Carbohydrate and fat represent the most abundant and available stores for the exercising type 1 athlete. Liver 80–110 g for a 70-kg male and skeletal muscle 300– 350 g stores represent the main sites of endogenous carbohydrate. The meager amount of circulating glucose of 10–15 g represents the balance between glucose appearance into the circulation released from the liver and uptake by bodily tissues. With resting rates of whole-body carbohydrate use of 0.25 g·min −1 1 day of starva- tion can significantly reduce carbohydrate stores excepting for the body’s ability to R.M. Bracken B.Sc. M.Sc. PGCert Ph.D. Health and Sport Science College of Engineering Swansea University Singleton Park Swansea SA2 8PP UK e-mail: r.m.brackenswansea.ac.uk D.J. West B.Sc. Ph.D. Department of Sport and Exercise Northumbria University Northumberland Street Newcastle upon Tyne Tyne and Wear NE1 8ST UK e-mail: d.j.westnorthumbria.ac.uk S.C. Bain M.A. M.D. FRCP Institute of Life Sciences College of Medicine Swansea University Singleton Park Swansea Wales SA2 8PP UK e-mail: s.c.bainswansea.ac.uk

slide 68:

I. Gallen ed. Type 1 Diabetes 47 DOI 10.1007/978-0-85729-754-9_3 © Springer-Verlag London Limited 2012

slide 69:

48 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 48 2 2 minimize this loss through the manufacture of new glucose from e.g. amino acids keto acids or lactate. Adipose tissue and skeletal muscle fat stores are more plentiful so for a 70-kg male with an estimated 10 body fat i.e. 7 kg an energy density of 37.7 kJ per gram of fat provides an estimated potential energy store of 264 MJ – enough to run more than 20 marathons Fats are used heavily in low-intensity exer- cise but are rate limited to 60–65 VO peak. An ability to increase exercise intensity relies on an increased combustion of carbohydrate in muscle. Clearly the exercising T1DM has a choice of fuels to use dependent on the amount of exercise i.e. duration intensity and its type. Knowledge of how stores of liver and muscle of carbohydrate are used or preserved by preferential use of fat determines how blood glucose levels respond to exercise. Furthermore different exercise models evoke dif- ferent patterns of change in energy stores that also complicate an understanding of the blood glucose response to exercise. Understanding variation in metabolic changes in T1DM individuals is a first step towards understanding the efficacy of pre-exercise alterations in insulin and/or carbohydrate supplementation. 3.2 Exercise-Induced Hypoglycemia with Different Exercise Types To Kill Diabetes Forever Click Here 3.2.1 Endurance Exercise Endurance exercise-induced hypoglycemia is a frequent occurrence in T1DM indi- viduals and represents a challenge to good glycemic control 1–3 when compared with sprinting or intermittent exercise patterns mimicking games activities 4–6. In response to a single bout of continuous endurance exercise evidence has demon- strated patients with T1DM may develop a hypoglycemic episode 2 3 7. For example Campaigne et al. 2 investigated the effects of different diets and insulin adjustments prior to a 45-min bout of steady state cycling that was performed at 60 of VO peak. Six out of the nine patients experienced hypoglycemic episodes within 5 h of completing the exercise which was independent of prior insulin dosage or post-exercise feeding. The authors suggested the findings might reflect an enhanced glucose uptake following the reduction in muscle glycogen stores due to exercise. Moreover in a study by Tsalikian et al. 3 hypoglycemia developed over- night more frequently in T1DM children after performance of continuous exercise that day four 15-min periods of walking at a heart rate of 140 bpm compared to nights when daily exercise was not performed. The results showed that plasma glu- cose concentrations decreased by at least 25 during or immediately after the exer- cise period in 41 subjects with 11 demonstrating blood glucose concentrations of £ 60 mg/dL during or immediately after walking. Thus it appears that the incidence of developing a post-exercise hypoglycemic episode following continuous endur-

slide 70:

49 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 49 ance exercise is significant and ranges from 15 to 66 in T1DM patients across studies 1–3.

slide 71:

50 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 50 2 2 3.2.2 Sprint Exercise The performance of a short sprint before or after continuous moderate-intensity exercise can reduce the degree of hypoglycemia following exercise in T1DM patients 4 8. In these two separate studies 7 T1DM males were recruited to com- plete 20 min of cycle ergometry at an exercise intensity equivalent to 40 VO peak with a 10-s sprint performed before 8 or after 4 the low-intensity cycling. The control trial in each study was 20-min cycling at 40 VO peak with no sprinting. In both studies the 20-min bout of cycling resulted in a significant fall in blood glucose values 2 h after exercise however the addition of a 10-s sprint placed before or after the endurance exercise significantly attenuated the drop in blood glucose concentration. The mechanisms explaining the improved post-exercise glycemia were not clear but the authors suggested that there was an increased hepatic glucose release in response to the sprint due to greater counter-regulatory hormones and/or greater circulating lactate after exercise which may have contributed to liver gluco- neogenesis and/or restoration of reduced muscle carbohydrate stores. 3.2.3 Intermittent Exercise Sport and recreational activities vary greatly in terms of muscular recruitment tech- nical requirements exercise intensity and duration. In contrast to endurance-based activities such as constant pace running cycling or swimming where energy sup- ply is more evenly matched to the energy demands of the activity most sporting activities are intermittent in nature. Examples of this type of exercise pattern can be seen in field games football rugby and hockey racquet sports tennis squash and badminton and court games basketball volleyball and netball. In recent years there has been an increase in the number of studies employing exercise protocols that attempt to replicate typical patterns of intermittent activities while remaining well controlled within a laboratory environment. Research has demonstrated that the performance of intermittent high-intensity sprints INT 11 × 4-s cycle sprints every 2 min for 20 min did not increase the risk of developing hypoglycemia during and for 60 min post-exercise when compared to a resting control trial 5. The researchers demonstrated blood glucose levels fell by 4 mmol·l −1 during INT com- pared to 2 mmol·l −1 during the control trial. Interestingly blood glucose did not continue to fall following exercise resulting in similar glucose levels by 50 min in post-INT exercise and control trials. Moreover intermittent high-intensity INT exercise has been shown to preserve blood glucose concentrations more than con- tinuous CON exercise and reduce the risk of hypoglycemia during and after exer- cise 6 9. In a study by Guelfi et al. 6 blood glucose responses to both continuous and intermittent exercise were compared. Participants performed 30 min of cycling at 40 VO peak CON or 30 min of cycling at 40 VO peak with 4 s maximal 2 2 sprints interspersed every 2 min INT. Blood glucose responses revealed a smaller

slide 72:

51 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 51 2 1c decline during INT exercise despite performing more work. Moreover blood glucose remained stable for 60 min post-exercise whereas they continued to decline under CON. The preserved blood glucose concentrations were suggested to be related to the stimulatory effects of catecholamines and growth hormone on liver glycogenolysis. It is interesting to note that none of the aforementioned research that utilized high-intensity exercise protocols employed pre-exercise rapid-acting insulin reductions unlike the apparent common practice in endurance exercise see Sect. 3.4.1. This may be because of the greater likelihood of post-exercise hyperg- lycemia in INT exercise from the combined effects of a small amount of circulating insulin-reducing glucose uptake and an increased counter-regulatory hormone- stimulated effect on hepatic glucose release. On the other hand the potential to avoid hypoglycemia or at least improve the stability of post-exercise blood glucose concentrations may be worthy of investigation. At present the literature examining different exercise factors affecting blood glu- cose responses within T1DM individuals has employed cycling exercise 2 4–6 8 10–19. Cycling is a primarily concentric form of exercise i.e. the muscle shortens as it contracts. However in many daily activity patterns including non-body-weight- supported exercises such as walking jogging or running there is a significant pro- portion of eccentric muscle action where the muscle lengthens in the performance of the movement. Eccentric muscle actions have been demonstrated to hinder insulin action and glucose uptake for many hours following exercise 20 21. Such data sug- gest an additional layer of complexity to the understanding of post-exercise glycemia in response to different patterns of exercise in the T1DM individual. From a practical point of view although much more work is needed to explore glycemic responses to real-life sports and exercise patterns “in the field” the speci- ficity of submaximal endurance exercise as the “exercise of choice” for some T1DM cohorts is clear. In research studies examining the glycemic responses to high-inten- sity exercise participant mean age was young i.e. 21–22 years old 4 6 8. It is less likely that older T1DM individuals are inclined to perform high-intensity inter- mittent exercise as a method to preserve blood glucose after exercise as the risk of injury may be more significant 22. Additionally although high-intensity 90– 100 VO max exercise will increase cardiovascular fitness more so than lower intensity exercise 23 research suggests that when lower intensity exercise exceeds 35 min there are similar gains in cardiovascular fitness when compared with short- duration high-intensity training 22. For these reasons methods to help preserve glycemia during and after submaximal endurance exercise should continue to be explored. 3.2.4 Resistance Exercise Resistance exercise is important in the glycemic control of T2DM individuals 24 25 however its effect on glycemic control within T1DM is unclear with research demonstrating no change in HbA after a resistance training program 26 27.

slide 73:

52 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 52 Additionally data on the acute effects of a single session of resistance exercise on glycemia and metabolism are sparse. A single resistance exercise session did not affect post-exercise insulin sensitiv- ity in T1DM individuals 28. In this study 2 groups of 7 T1DM individuals were placed under a euglycemic-hyperinsulinemic clamp before resting control or per- forming 5 sets of 6 repetitions at 80 of 1 repetition maximum of a combined lower leg extension and flexion movement i.e. quadriceps extension and hamstring curl. The clamp procedure was repeated at 12 and 36 h following the resistance and control protocol. After exercise insulin sensitivity did not differ from baseline at 12 and 36 h post-exercise moreover there were no differences when compared to the control group. However caution should be taken when interpreting this data. There is a large contribution from muscle glycogen during resistance exercise 29–31 and its depletion is a key factor in exercise-induced increases in insulin sensitivity 32–34. Furthermore there is a rapid-replenishment of muscle glycogen stores within the first 2 h of completing a resistance exercise session 30. Potentially within the study of Jiminez et al. 28 differences in insulin sensitivity and blood glucose concentrations may have been more likely to occur in a shorter time frame after completion of the resistance protocol. In addition the exercise protocol con- sisted of concentric-only muscle contractions whereas free or machine-assisted resistance exercises consist of both eccentric and concentric muscle contractions. As previously mentioned eccentric contractions hinder insulin action and glucose uptake within skeletal muscle for many hours following exercise 20 21. Resistance exercise is a potent stimulator of counter-regulatory hormones such as catecholamines growth hormone and cortisol in people that do not have diabetes 35–38. Blood glucose increases in response to a single resistance exercise session 36 with a 1.8 mmol·l −1 increase in blood glucose after 6 sets of 10 repetition back squats at 80 of 1 repetition maximum in nondiabetes participants. Increases in blood glucose were related to increases in adrenaline r 0.6 and noradrenaline r 0.9 concentrations respectively. Thus available data suggest potential for resistance exercise to promote hyperglycemia but to date there is limited data to demonstrate this in T1DM individuals. The limited literature on the acute metabolic responses to resistance exercise in T1DM individuals warrants future research to develop more comprehensive blood glucose management strategies across all types of exercise. 3.3 Strategies for Preventing and/or Minimizing Post-exercise Hypoglycemia In light of the aforementioned potential for hypoglycemia following some forms of exercise strategies that help combat hypoglycemia have received considerable attention within the literature 2 6 12 13 15 18 39–41. An important aspect of the research focuses on reducing the pre-exercise rapid-acting insulin dose 2 15 18.

slide 74:

53 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 53 2 3.3.1 The Efficacy of Pre-exercise Insulin Dose Reduction on Post-exercise Glycemia The type of insulin is important to consider when examining its consequent effects on blood glucose concentrations. Currently many T1DM individuals are treated with modern insulin analogues in a basal-bolus regimen these rDNA insulins e.g. insulin glargine/detemir and aspart/lispro/glulisine offer very different more favor- able action-time profiles and less variability than longer established insulins such as regular human insulin and NPH insulin 19 42 43. In recent years research that has begun to emerge that has examined the effectiveness of pre-exercise rapid-act- ing insulin reductions employed in a basal-bolus insulin routine 18 44–47. 3.3.1.1 Basal Insulins The choice of basal insulin may influence the potential for hypoglycemia. In a mul- tinational randomized 3-year crossover trial T1DM individuals managed with basal insulin detemir glargine or neutral protamine Hagedorn NPH performed 30 min of exercise and were monitored over 150 min of recovery 48. During exercise 18 38 of 51 participants on glargine developed hypoglycemia compared with 5 11 and 6 12 participants on detemir and NPH respectively. Furthermore incidence of hypoglycemia in those participants on glargine was greater than detemir and NPH 19 vs. 14 and 11 P 0.001. Thus insulin detemir was associated with less hypoglycemia than insulin glargine but not NPH insulin during and after exercise. Interestingly compared to rapid-acting insulin 49 the effect of exercise appears minimal on absorption kinetics of some basal insulins. In one study in T1DM individuals cycling 30 min 65 VO max did not influence glargine absorption rate and produced similar declines in plasma glucose and insulin compared to a non- cycling condition 17. So reductions to modern long-lasting insulins in a basal- bolus routine have the potential to influence circulating glucose concentrations however its manipulation before acute exercise may be impractical given the need for dose alterations for many hours prior to the exercise session. Finally there is little research that has examined the effects of manipulations of basal insulins in T1DM individuals that are engaged in regular exercise training. 3.3.1.2 Rapid-Acting Insulins Within the existing literature examining pre-exercise rapid-acting insulin reduc- tions recommendations have varied from 10 to 40 39 50 2 10 to 50 40 50 to 90 15 and 50 to 75 18 Table 3.1. Some of the variation in the recommended reduction can be accounted for by differences in the insulin type used by participants and the exercise model employed Table 3.1.

slide 75:

2 2 2 2 2 2 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 53 Table 3.1 Summary of literature investigating the effects of reducing pre-exercise insulin dose on the maintenance of glycemia Participant insulin Reference Participants regimen Insulin reduction Exercise Findings Campaigne et al. 2 9 T1DM males 2 daily – premixed A – 50 ↓ of interme- 45 min continuous Hypoglycemia occurred despite Rabasa-Lhoret et al. 18 NPH and soluble 8 T1DM males Basal ultralente with prandial lispro diate insulin B – 50 ↓ of soluble insulin C – No change No change 50 or 75 ↓ in all exercise protocols cycling at 60 VO max Cycling at A – 25 VO max for 1 h B – 50 VO max for 30 and 60 min C – 75 VO max for reductions. ↑ Nocturnal hypoglycemia under C. Hypoglycemia occurred despite insulin reductions No insulin reduction ↑ chance of hypoglycemia at all intensities. Appropriate adjustments maintain glycemia during and after exercise Mauvais-Jarvis et al. 15 12 T1DM males NPH and regular insulin twice n 6 or three times n 6 daily 50 ↓ for subjects on twice-daily regimen 90 ↓ for three times daily 30 min 1-h continuous cycling at 70 VO max No reduction ↑ chance of hypogly- cemia. 50–90 reductions depending on insulin regimen can maintain glycemia during and after exercise West et al. 45 7 T1DM 6 males 1 female Basal insulin glargine with prandial insulin lispro or aspart Administered normal 75 50 or 25 of rapid-acting insulin dose 2 h prior to exercise 45-min continuous running at 70 VO max 25 dose preserved blood glucose the most for 24 h post-exercise despite consuming fewer carbohydrates. Severe rapid- acting insulin reductions do not increase the risk of developing hyperketonemia or ketoacidosis

slide 76:

54 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 54 2 2 2 2 2 An early study by Campaigne et al. 2 Table 3.1 examined blood glucose responses during and after 45 min of cycling at 60 VO max in 9 T1DM males who were treated with a twice-daily intermediate/short-acting insulin mix. Despite 50 reductions in the intermediate or the soluble insulin prior to exercise hypoglycemia still occurred in 6 of the 9 subjects at some point during or after exercise mainly dur- ing the night of the trial day. Additionally Mauvais-Jarvis et al. 15 Table 3.1 examined pre-exercise insulin reductions during and for 2 h after exercise within 12 T1DM individuals. Six of the participants were treated with regular insulin in the morning and at noon and NPH before bed while the other six participants were treated with bi-daily mixed insulin regimen of 30 regular insulin combined with 70 NPH insulin. Participants performed 60 min of cycling at 70 VO max 90 min after a set meal where participants administered an unaltered insulin dose or a 90 insulin reduction participants on 3 daily injections/50 insulin reduction bi-daily mixed regimen. Eight participants had to receive an oral glucose solution during the no insulin reduction condition due to rapidly falling plasma glucose concentrations. Plasma glucose levels were consistently higher during and for 2 h after exercise within the insulin reduction trial. It was concluded that a 50–90 reduction in insulin dose depending on their insulin regimen allowed T1DM individuals to engage in endurance exercise without causing hypoglycemia 15. A limitation of the research of Campaigne et al. 2 and Mauvais-Jarvis et al. 15 was the lack of specific guidelines for pre-exercise insulin dose adjustments taking into consideration exercise intensity and duration. In addition the duration of moni- toring blood glucose was just 2–12 h but hypoglycemia may develop up to 24 h after exercise 1 3 so a larger window of examination would allow determination of the effectiveness of the degree of insulin reduction. Finally with the increased prescription of a basal-bolus regimen to treat many T1DM individuals dose adjust- ments specific to this kind of treatment as opposed to the use of mixed insulins in the studies above is worthy of more exploration. Research by Rabasa-Lhoret et al. 18 Table 3.1 strengthened the area by addressing some of the above-mentioned issues by examining alterations in rapid- acting insulin as part of a basal-bolus regimen Ultralente with prandial insulin lis- pro while also taking into consideration exercise intensity and duration. Participants performed 60 min cycling at 25 VO max 30 and 60 min at 50 VO max and 2 2 30 min at 75 VO max. Blood glucose concentrations were monitored during and for an hour after exercise. All trials were performed following administration of a full insulin dose Full a 50 reduction 50 and after a 75 reduction 25. The researchers demonstrated that the drop in blood glucose that occurs with exer- cise at 25 VO max for 60 min did not differ between Full and 50 but higher pre- exercise glucose concentrations resulted in a safer glycemic profile following exercise. Plasma glucose at the end of exercise was D − 2.9 ± 1.1 mmol·l −1 below baseline after Full compared with D − 0.6 ± 0.9 mmol·l −1 after 50. This trend fol- lowed during exercise at 50 VO max for 30 min the decrease in plasma glucose relative to rest at the end of exercise was less under 50 D − 0.4 ± 1.3 mmol·l −1 compared with Full D − 2.1 ± 0.7 mmol·l −1 and resulted in greater plasma glucose concentrations during and for 1 h after exercise. Plasma glucose responses revealed

slide 77:

55 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 55 2 2 2 that the greatest preservation of post-exercise glycemia occurred after a 75 insulin reduction when exercising at 50 VO max for an hour and 75 VO max for 30 min. The 75 reduction trial resulted in a better maintenance of glycemia during and after exercise 7–10 mmol·l −1 with less chance of developing hypoglycemia compared to just a 50 reduced dose which elicited post-exercise concentrations of 4.5–7 mmol·l −1 . Large reductions to pre-exercise insulin lispro or aspart resulted in better preser- vation of blood glucose during and after running in T1DM individuals Fig. 3.1 45. In this study effects of pre-exercise insulin reductions on consequent meta- bolic and dietary patterns for 24 h after running were examined in individuals with type 1 diabetes. Participants administered their full rapid-acting insulin dose or 75 50 or 25 of it immediately before consuming a carbohydrate rich meal. After 2 h participants completed 45 min of running at 70 VO peak. Pre-exercise peak insulin concentrations were greatest with the Full dose and consequently elic- ited the lowest blood glucose concentrations. Blood glucose decreased under all conditions with exercise with the fall in the full dose greater than with 25 insulin. Blood glucose at 3 h post-exercise was greatest with the 25 dose. Interestingly over the next 21 h self-recorded blood glucose area under the curve was greater with the 25 dose compared with all other trials despite consuming less energy and fewer carbohydrates. Thus a 75 reduction to pre-exercise insulin resulted in the greatest preservation of blood glucose and a reduced dietary intake for 24 h after running in individuals with type 1 diabetes. 3.3.2 The Safety of Strategies Employing Reductions to Rapid-Acting Insulin Dose Exogenous insulin treatment reduces blood glucose which prevents hyperglycemia and risk of ketosis 50. Under normal physiological conditions ketones acetoac- etate bbeta-hydroxybutyrate and acetone are produced through hepatic fatty acid metabolism during periods of low carbohydrate availability. Ketogenesis allows fat- derived energy to be generated in the liver and used by other organs such as the brain heart kidney cortex and skeletal muscle 51. However reduction or omis- sion in insulin dose is a significant factor in the development of diabetic ketoacido- sis accounting for 13–45 of reported DKA cases 52. The formation of ketone bodies above nonphysiological levels 1 mmol·l −1 has been shown to increase oxygen radical formation and cause lipid peroxidation 53–55 as well as induce metabolic acidosis 51. Diabetic ketoacidosis is characterized by an absolute or relative deficiency of circulating insulin and combined increases in counter-regula- tory hormones catecholamines glucagon cortisol growth hormone particularly glucagon and adrenaline hyperglycemia and metabolic acidosis 52. Furthermore physical exercise increases ketone body formation 56 alters acid-base balance and increases counter-regulatory hormones. Therefore the potential for a combined effect of a pre-exercise insulin reduction strategy and performance of exercise

slide 78:

56 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 56 Delta baseline serum insulin pmol.l –1 Delta baseline BG mmol.l –1 140 a 120 100 80 60 40 20 Full 75 50 25 0 10.0 b 7.5 5.0 2.5 0.0 −2.0 −5.0 R 30 60 90 120 0 5 15 Sample point 30 60 120 180 Fig. 3.1 Serum insulin and blood glucose responses to progressive reductions in rapid-acting insulin at rest and during and after 45 min of aerobic running Reprinted with permission of the publisher from West et al. 45 Taylor Francis

slide 79:

57 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 57 2 might exacerbate ketogenesis and result in hyperketonemia 1.0 mmol·l −1 or development of ketoacidosis 3.0 mmol·l −1 51. However reductions in pre- exercise rapid-acting insulin dose were not found to influence ketogenesis following running 44. In this study 7 T1DM participants attended the laboratory four times each time consuming a 1.12 MJ wheat biscuit and peach meal 60 g carbohydrate 2 g fat 2 g protein with Full 7.3 ± 0.2 units 75 5.4 ± 0.1 units 50 3.7 ± 0.1 units or 25 1.8 ± 0.1 units of their rapid-acting insulin lispro or aspart. After a 2-h rest participants completed 45-min running at 70 ± 1 VO peak. Resting ketoacids b-O-hydroxybutyrate gradually decreased over 2-h rest with similar post-exercise peak b-OHB at 3 h. This preparatory strategy preserved blood glucose and posed no greater risk to exercising T1DM individuals in exercise- induced ketone body formation. 3.3.3 Current Recommendations for Carbohydrate Intake and Exercise in T1DM The importance of carbohydrate for the exercising person with T1DM is in the pro- vision of fuel for exercise as well as the avoidance of hypoglycemia during or after exercise. From a clinical exercise physiology perspective both are of utmost impor- tance in ensuring the individual adapts safely to exercise. Carbohydrates come in a variety of forms with very different functional characteristics. The simplest forms of carbohydrates are the monosaccharides commonly referred to as “simple sugars” which include pentoses e.g. arabinose ribose xylose and hexoses e.g. fructose galactose glucose mannose. Disaccharides e.g. lactose maltose sucrose isomaltulose are comprised of pairs of monosaccharides linked together while polysaccharides e.g. glycogen or starches like amylin and amylopectin are com- prised of long chains of glucose molecules. Important characteristics of carbohydrate such as the amount and concentration determine the rate of gastric emptying due to the resultant increase in volume and potential for intestinal feedback. The bolus temperature pH osmolality viscos- ity multiple carbohydrate content and hypo- or hyperglycemic state also influence the rate of gastric emptying 57–59. Thereafter the entry of carbohydrate into the bloodstream from the small intestine is determined to a large degree by the type of carbohydrate. Glucose and galactose are transported into enterocytes in the small intestine by sodium/glucose co-transporter 1 SGLT1 while fructose is trans- ported into enterocytes by GLUT5 transporters. This has distinct implications for the resultant appearance of carbohydrate from ingestion to circulatory appearance. The transport of glucose by SGLT1 is saturable and somewhat independent of the ingested glucose load so its entry into the bloodstream is rate-limited. However the ingestion of multiple carbohydrates by involving more than one transport system can increase the carbohydrate transport rate into the bloodstream e.g. by an increase in GLUT5-mediated transport of fructose. Therefore the type of carbohydrate i.e. mono- di- or polysaccharide can influence the rate of appearance in the circulation.

slide 80:

58 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 58 2 For example hydrolysis of isomaltulose by a sucrose-isomaltase complex into glucose and fructose in the jejunum of the small intestine results in a slower carbohydrate transport rate into the portal vein circulation 60. Indeed reported values from several studies suggest exogenously ingested carbohydrates demonstrate a wide range in maximum circulatory appearance rates due to several of the above- mentioned factors 61. However an important observation from this research is a maximum appearance rate of carbohydrate into the bloodstream of 1.0–1.1 g·min −1 . This suggests a maximum of 60–66 grams of ingested carbohydrate may contribute to the maintenance of blood glucose levels per hour of exercise. There has been a wide range of recommendations for carbohydrate consumption before or during exercise in T1DM individuals that have condensed to three main strands namely a amounts based on pre-exercise blood glucose concentration 5.6 or 6.7 mM 39 62 b amounts based on exercise duration 20–60 g every 30 min 63 60 g·h −1 64 or c amounts based on body mass 1–2 g·kg −1 BM 65 66. One criticism of blood glucose measurement before exercise is the lack of knowledge of blood glucose changes in the hours prior to measurement. Potentially a single blood glucose reading may appear euglycemic but could be declining from previous values in which case exercise might accelerate the decline in circulating glucose to hypoglycemic levels. Although there appears strong support for carbohydrate consumption before dur- ing and after exercise the primary question for the T1DM individual is what amount of carbohydrate to consume. Hernandez et al. 13 Table 3.2 suggested that 60–120 g of carbohydrates should be consumed in equal bolus before during and after exercise to prevent late-onset hypoglycemia. Iafusco recommended consumption of 15 g of “simple carbohydrates” immediately before exercise and consumption of a hypotonic sports drink e.g. Gatorade ® 4 sucrose 2 fructose during exercise 41. Dubé et al. 12 recommended a beverage containing 35 g of glucose should be consumed imme- diately before exercise to maintain blood glucose during 60 min of moderate-intensity exercise. During the exercise bout 7 of 9 individuals required glucose infusion under a no-added carbohydrate trial 0 g 4 of 9 participants required glucose infusion under the 15 g trial and 3 under the 30 g condition. Therefore it appears glucose ingestion up to an upper limit of 1 g.min -1 of exercise may facilitate optimal glucose appearance rates and preserve glycemia reducing the occurrence of hypoglycemia. Carbohydrate drink concentration is another important characteristic to consider in the avoidance of low blood glucose. Some research has recommended T1DM individuals consume a 10 carbohydrate solution before and during exercise to maintain glycemia Table 3.2 16. Participants cycled at 55–60 VO max for 60 min consuming either an 8 or a 10 carbohydrate solution before and during exercise. Throughout the duration of the trial blood glucose concentrations were lower under the 8 solution and four individuals experienced hypoglycemia under this condition. Furthermore blood glucose concentrations dropped 1.8 mmol·l −1 in the hour post-exercise whereas concentrations remained stable under the 10 con- dition. Additionally to quickly correct falling blood glucose during exercise Gallen 67 recommended consumption of a 15 carbohydrate solution. Drinks with a high carbohydrate concentration ranging from 6 to 20 have been shown to

slide 81:

2 2 2 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 59 Table 3.2 Summary of current literature examining carbohydrate consumption in order to prevent hypoglycemia during and after exercise Reference Participants Participant insulin regimen Protocol Exercise Findings Hernandez et al. 13 7 T1DM 6 males 1 female Bovine/porcine ultralente with regular human Water 0 g CHO whole milk 40 g skim milk 66 g sports drink A 60-min cycling at 60 VO max. After 30 2 min a 10-min rest No trial completely prevented hypoglyce- mia. Milk trials had ↓ pre-bed BG concentrations. During milk trials no insulin 121 g and sports drink B 74 g consumed in thirds immediately before during and after exercise. BG monitored 12 h post-exercise period was carried out for fluid ingestion early morning incidents of hypoglyce- mia there was 1 incident under sports drink B. Authors conclude CHO beverage must be consumed before during and after exercise. Amount may depend on level of glycogen depletion across participants Dubé et al. 9 T1DM 6 males Bi-daily NPH and 3 h after a standardized 60-min continuous 30 g delayed the time before glucose 12 3 females prandial insulin breakfast 8 kcal·kg −1 cycling at needed to be infused more than 15 g. Perrone et al. 16 16 T1DM 10 males 6 females lispro Intermediate or ultra-long insulin participants consumed either 0 15 or 30 g of glucose immediately before exercise Participants consumed an 8 5.4 g glucose 2.6 g fructose per 100 mL or 10 6.7 g glucose 3.3 g fructose per 100 mL before and during exercise 50 VO max 60-min continuous cycling at 55–60 VO max 7 of 9 needed glucose infusion under 0 g 4 of 9 under 15 g and 3 under 30 g. Authors estimate a beverage of 35 g of glucose is required to maintain BG for 60 min of moderate exercise 4 incidents of hypoglycemia during exercise under 8 and none under 10. 60-min post-exercise BG ↓ under 8 but ↔ under 10. Authors recommend a 10 carbohydrate solution to avoid hypoglycemia during exercise West et al. 47 7 T1DM males Basal insulin glargine with prandial insulin lispro or aspart 75 g of isomaltulose with a 75 reduced insulin dose 120 90 60 and 30 min pre-exercise 45-min continuous running at 70 VO max 5 out of 7 experienced post-exercise hypoglycemia after 120-min ingestion time. 30-min ingestion time completely prevented hypoglycemia and increased lipid oxidation during exercise

slide 82:

60 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 60 1c reduce gastric emptying rates in non-T1DM individuals 68–70. Similarly Schvarcz et al. 59 demonstrated a slowing of gastric emptying in T1DM individuals when blood glucose concentrations were clamped at 8 compared to 4 mmol·l −1 . In addi- tion gastric emptying rates are also negatively influenced by long-term poor glyce- mic control 71. Conversely low blood glucose concentrations increase gastric emptying rates in non-T1DM individuals 58. Therefore blood glucose concentra- tions and long-term glycemic control may be contributing factors to understanding the large inter-individual variability in blood glucose responses that exist after ingestion of carbohydrate. None of the above-mentioned research in T1DM individuals employed a pre- exercise insulin reduction. Doing so could result in different carbohydrate require- ments. Research is needed to examine the weight of insulin reduction against carbohydrate consumption on post-exercise glycemia. 3.3.4 Carbohydrate Type: The Glycemic Index The glycemic index GI is a method of classifying carbohydrate-containing foods according to blood glucose responses following ingestion 72. For example carbo- hydrates with a high GI such as white bread will induce a rapid increase in blood glucose concentrations after ingestion 73. Conversely carbohydrates with a low GI such as peaches will induce more gradual increases with lower peaks in blood glucose 73. From a diabetes management perspective this classification of foodstuffs is use- ful as patients can include low GI LGI carbohydrates in their diet and in doing so benefit from greater feelings of satiety 73 improved insulin sensitivity and blood lipid profiles 74 lower daily mean blood glucose concentrations 75 and reduced incidence of hypoglycemia and reductions in HbA 76–78. In one dietary study consumption of LGI foodstuffs such as peaches kidney beans or brown rice resulted in continuously monitored glucose concentrations being within a target range of 3.9–9.9 mmol·l −1 more of the time than under a high GI HGI trial 67 vs. 47. Furthermore participants elicited a lower mean blood glucose concentra- tion LGI 7.6 ± 2.0 vs. HGI 10.1 ± 2.6 mmol·l −1 and required less bolus insulin per 10 g of ingested CHO. Based on the existing literature in nondiabetic individuals consumption of LGI carbohydrates increases blood glucose concentration less than equivalent amounts of high glycemic carbohydrate 79 80. Additionally LGI carbohydrates may sup- press fat oxidation less during exercise sparing both endogenous and exogenous carbohydrate use resulting in better preservation of blood glucose during exercise and in the recovery period 81. Only recently has research begun to emerge that has examined the metabolic responses to exercise after ingestion of different GI carbo- hydrates within T1DM in combination with insulin dose reductions. West et al. Fig. 3.2 compared the alterations in metabolism and fuel oxidation in 8 T1DM individuals after pre-exercise ingestion of 75 g 10 solution of either LGI

slide 83:

61 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 61 Delta baseline blood glucose mmol.l –1 10.0 7.5 5.0 2.5 0.0 −2.5 REST 30 60 90 120 0 5 15 30 60 Sample point DEX ISO 120 180 Fig. 3.2 Blood glucose responses to ingestion of high and low glycemic index carbohydrates at rest and during and after 45 min of aerobic running 46. Hollow symbols indicate significant change from rest with each CHO condition. indicates significant difference between CHO conditions at this time point Reprinted with permission of the publisher from West et al. 46 Wolters Kluwer Health carbohydrate isomaltulose ISO GI 32 or dextrose DEX GI 96 2 h before a 45-min treadmill run 46. Blood glucose increased half as much in the isomaltulose trial compared to dextrose over the rest period D + 4.5 ± 0.4 vs. D + 9.1 ± 0.6 mmol·l −1 P 0.01 and remained 21 lower for 3-h recovery. Additionally during the later stages of exercise there was a lower carbohydrate ISO 2.85 ± 0.07 vs. DEX 3.18 ± 0.08 g·min −1 P 0.05 and greater lipid ISO 0.33 ± 0.03 vs. DEX 0.20 ± 0.03 g·min −1 P 0.05 oxidation rate under the isomaltulose trial. Thus con- sumption of a low GI carbohydrate improved blood glucose responses and sup- ported continued use of lipid in spite of carbohydrate ingestion. 3.3.5 Pre-exercise Timing of Carbohydrate Consumption and Insulin Administration The advice regarding timing of pre-exercise carbohydrate consumption and insulin administration is largely dependent upon the insulin type and the altered uptake kinetics that are associated with exercise 11 19 82. Research has demonstrated that exercise can result in greater peaks in insulin as well as increasing absorption rates and ultimately increasing the risk of hypoglycemia 11 19. The altered rates of absorption are likely due to a combination of increases in exercise-induced blood flow 83–85 and temperature 86 87. Regular human insulin and animal preparations interact differently with exer- cise. Fernqvist et al. 82 demonstrated that the exercise-induced peak in insulin

slide 84:

62 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 62 2 concentrations was less with regular human insulin as opposed to porcine insulin. Moreover Tuominen et al. 19 demonstrated that rDNA insulins human insulin and the analogue insulin lispro also interact differently with exercise with consid- eration of pre-exercise timing particularly important in subsequent insulin and blood glucose responses. Tuominen and colleagues identified that when exercise was per- formed 40 min after insulin administration insulin lispro induced an earlier and 56 greater peak in insulin concentrations resulting in a greater drop in blood glu- cose with exercise when compared to regular human insulin. Moreover when exer- cising this close to administration the exercise bout was associated with a 2.2-fold greater risk of hypoglycemia. However when exercising 3 h after insulin adminis- tration the drop in blood glucose was less under insulin lispro and the risk of hypo- glycemia was reduced by 46 compared to regular human insulin. This research highlights pre-exercise timing as an important factor to consider as the intense rise and peak in insulin that is elicited soon after administration of rapid-acting insulin results in marked increases in the risk of hypoglycemia during exercise. The lower variability and more favorable action-time profiles of the rapid-acting insulins 19 42 make these analogues of insulin ideal for prandial use and have been shown to improve glycemic control within T1DM individuals without increas- ing the risk of hypoglycemia 88. However the rapid rise in insulin concentrations peaking 45–60 min after administration 89 means that it is currently recom- mended to avoid administration of rapid-acting insulin within 90–120 min of exercise due to the risk of over-insulinization of the active musculature during exer- cise 39 90 as demonstrated by the early work of Tuominen et al. 19. Thus at present it is recommended that insulin dose should be reduced before performing exercise regardless of the insulin type or time before exercise 2 15 18. However there is limited literature that examined pre-exercise timing as a factor to consider in subsequent blood glucose responses. Specifically there are limited data available on the absorption kinetics of the insulin analogues when administered in reduced doses with the carbohydrate meal at different times prior to exercise. Within the study of Tuominen et al. 19 participants administered 6.3 IU of insulin how- ever if employing a heavy insulin reduction as recommended by Rabasa-Lhoret et al. 18 pre-exercise insulin dose could be as little as 3 IU. Therefore there is potential that administering such small doses of insulin closer to exercise may not increase the risk of hypoglycemia. The study of West et al. 47 aimed to examine the influence of alterations in the timing of a 75 reduction in insulin administra- tion and ingestion of a 10 low GI carbohydrate solution on glycemic and fuel oxidation responses prior to endurance running in T1DM individuals. Participants rested for 30 30MIN 60 60MIN 90 90MIN or 120 min 120MIN before completing 45 min of running at 70 VO peak. Pre-exercise blood glucose concen- trations were lower for 30MIN compared with 120MIN P 0.05. Exercising car- bohydrate and lipid oxidation rates were lower and greater respectively for 30MIN compared with 120MIN P 0.05. The drop in blood glucose during exercise was less for 30MIN −3.7 ± 0.4 mmol·l −1 compared with 120MIN −6.4 ± 0.3 mmol·l −1 . During the first 60 min of the 3-h recovery blood glucose concentrations were higher for 30MIN compared with 120MIN P 0.05. In addition there were no cases of hypoglycemia in 30MIN one case in 60MIN two in 90MIN and five in the

slide 85:

63 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 63 2 120MIN condition. Therefore a strategy involving heavy reductions to rapid-acting insulin and use of a low glycemic index carbohydrate administered 30 min before running improves pre- and post-exercise blood glucose responses in type 1 diabetes through subtle alterations in fuel metabolism promoting lipid combustion. 3.3.6 Preparatory Insulin and Carbohydrate Strategies and Exercise Performance Carbohydrate consumption has the potential to alter endurance exercise perfor- mance in T1DM individuals. In a study by Ramires et al. 65 withholding neutral protamine Hagedorn porcine insulin for 12 h prior to exercise followed by adminis- tration of 1 g·kg −1 BM of dextrose 30 min before cycling at 55–60 VO max to exhaustion resulted in a 12 improvement in cycling performance compared to a carbohydrate-free solution in participants with well-controlled T1DM. Preservation of carbohydrate stores through combustion of endogenous lipid use is conducive to an improvement in endurance capacity. However although studies have demon- strated the importance of a carbohydrates glycemic index in influencing exercise capacity in nondiabetic individuals by such mechanisms 91 results have been equivocal 92. Furthermore scant research has addressed the relationship between carbohydrate type and endurance performance in T1DM individuals. This is sur- prising since the functional capacity of T1DM individuals is often lower than in matched individuals without diabetes and as an example in the above-mentioned study by Ramires et al. 65 cycling performance to exhaustion was 62 lower 77 ± 6 vs. 125 ± 7 min P 0.05. However it may be inappropriate to employ an endurance “exercise to exhaus- tion” model to determine functional capacity in T1DM individuals given the risk of progressively lowering blood glucose concentrations to potentially hypoglycemic levels. Alternative exercise models in cycling ergometry advocating completion of an amount of work have been shown to reduce intra-subject variation compared to endurance capacity models 93. Thus the use of time or distance trials using a nonmotorized treadmill or cycling-based protocols to retain ecological validity of “real-life” movement patterns under controlled laboratory conditions might facili- tate a deeper insight into the metabolic and performance effects of insulin reduction/ carbohydrate administration strategies that avoid placing the T1DM individual at risk of hypoglycemia. In one study seven T1DM individuals consumed isomaltulose or dextrose alongside a 50 reduction in rapid-acting insulin 2 h before an incre- mental run test followed by a 10-min distance trial where the objective was to cover as much distance as possible. There was a 50 lower peak blood glucose concentra- tion before running after consumption of isomaltulose compared with dextrose. However running performance was maintained during the high-intensity run per- formance in T1DM individuals 94. Thus consumption of a low GI carbohydrate improved glycemia and maintained run performance similar to that elicited using high GI carbohydrates. Some preliminary findings from our laboratory suggest some carbohydrates may confer a positive impact on exercise performance. We

slide 86:

64 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 64 examined the influence of ingestion of a high molecular mass carbohydrate waxy barley starch WBS GI 98 on glycemia and endurance performance in T1DM compared with dextrose. WBS carbohydrates have been shown to improve high- intensity exercise performance capacity in individuals without diabetes 95. In a similar protocol to that employed by Bracken et al. 94 preliminary data from our laboratory demonstrated similar glycemic responses to ingestion of high WBS and low DEX molecular weight carbohydrates in T1DM individuals however dis- tance in the last quarter of a 10-min performance run was significantly greater after ingestion of WBS compared with DEX WBS 323 ± 21 vs. dextrose 301 ± 20 m P 0.001 96 unpublished data. Thus it appears more research is warranted into the functional characteristics of carbohydrates and exercise performance. 3.4 Practical Advice The principles of rapid-acting insulin reduction and carbohydrate ingestion form an important strategy in the daily glycemic management of those with T1DM wishing to be physically active. A schematic to improve blood glucose responses to exercise that takes into account these and other factors is graphically illustrated in Fig. 3.3. Many of these factors are already supported by the ADA/ACSM or IDF guidelines for those T1DM individuals wishing to exercise safely. It is important to state that there is no one strategy that fits all T1DM individuals and a degree of trial and error at least initially is involved to minimize the risk of hypoglycemia before or after beginning regular physical activity. Internet websites like www.runsweet.com or those of diabetes charities support the contributions from physically active or ath- letic individuals and allow more confidence to refine generic components of strate- gies to preserve blood glucose concentrations. The main factors involved in safe participation of T1DM individuals in exercise are comprised of: 3.4.1 Monitoring of Blood Glucose Before Physical Activity Use caution if blood glucose concentrations are 17 mM 300 mg·dL −1 and no ketones are present. However avoid exercising if blood glucose levels are 14 mM 250 mg·dL −1 and ketosis is present. If glucose levels are 5.5 mM 100 mg·dL −1 carbohydrate ingestion will be required before exercise begins. 3.4.2 Ingestion of Carbohydrate Carbohydrate ingestion is dependent on the pre-exercise blood glucose concentrations and knowledge of the volume and type of exercise. Aim to consume carbohydrates based on a maximum intake of 60 g·h −1 of exercise. Low glycemic index carbohydrates

slide 87:

65 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 65 Intensity Blood glucose mM Monitor blood Glucose Carbohydrate Amount Concentration Type Insulin Basal or bolus reduction Time before exercise Duration 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Post-exercise Fig. 3.3 Schematic of the important components of good blood glucose management prior to physical activity may be recommended before exercise with the aim of stabilizing glucose during and after physical activity. If glucose levels are low consumption of high GI carbohy- drates like dextrose tablets may help restore glucose to euglycemic levels. 3.4.3 Reduction of Rapid-Acting Insulin Research is available to support the use of rapid-acting insulin reduction with extended exercise sessions. Through trial and error more knowledge of the exercise type and volume will allow refinement of the exact degree of the rapid-acting insu- lin reduction in each individual. 3.4.4 Awareness of Time of Insulin Reduction: Carbohydrate Ingestion Before Exercise Although research suggests not administering insulin 1–2 h before exercise more recent research suggests reduced rapid-acting insulin dose in conjunction with low

slide 88:

66 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 66 GI carbohydrate consumption allows a shorter period of time before exercise i.e. 30 min with better maintenance of post-exercise glycemia. 3.4.5 Knowledge of Exercise V olume and Type A single sprint has very different metabolic responses to prolonged aerobic exer- cise. Therefore knowledge of the athlete’s individual responses to these forms of exercise alongside an understanding of the metabolic effects of increased intensity or volume in one specific exercise will aid in combative strategies to counter low blood glucose. 3.4.6 Blood Glucose Monitoring Post-exercise Low blood glucose has the potential to occur many hours after exercise. Therefore regular post-exercise monitoring of glucose may prevent late-onset hypoglycemia. 3.5 Future Research Although it has been shown to be beneficial to reduce pre-exercise rapid-acting insu- lin and/or consume carbohydrates in response to certain exercise types much work remains in optimizing these and other factors to safely preserve blood glucose during and after different volumes of one exercise e.g. aerobic exercise or specific to dif- ferent forms of exercise e.g. sprint or resistance exercise. From an aerobic-endur- ance exercise point of view research to examine “fat-burning” strategies to preserve limited carbohydrate stores in an attempt to improve glycemic control and increase performance is an attractive area to pursue. At the other end of the exercise spectrum more knowledge of the metabolic effects of resistance exercise in T1DM individuals is needed. Continued examination of the metabolic effects of modification of exog- enous insulin and/or carbohydrate consumption has two modest but important aims namely to improve performances of T1DM individuals in their chosen sport and increase the numbers of those with T1DM safely participating in physical activity. 3.6 Conclusions Pre-exercise reductions in exogenous insulin and/or carbohydrate consumption improve glycemia and may improve performance during some forms of exercise. However the exact weighting of the determinants of the insulin reduction – carbohydrate

slide 89:

67 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 67 consumption strategy – specific to the type and volume of exercise remains to be deter- mined. Additionally due to the complexity of the interrelated components of physical exercise i.e. duration intensity mode and frequency the strategy may be specific to the model of exercise employed e.g. endurance vs. sprint exercise. Nonetheless the existing research examining manipulation of pre-exercise insulin and carbohydrates offers some suggestions to the physically active T1DM individual the majority of whom use basal-bolus routines and many of whom have better knowledge of “carbo- hydrate counting.” With continued research development of exercise-specific strate- gies with a little trial and error may allow each T1DM individual to safely engage in all forms of physical activity. References 1. MacDonald MJ. Postexercise late-onset hypoglycaemia in insulin-dependent diabetic patients. Diabetes Care. 198710:584–8. 2. Campaigne BN Wallberg-Henriksson H Gunnarsson R. Glucose and insulin responses in relation to insulin dose and caloric intake 12 h after acute physical exercise in men with IDDM. Diabetes Care. 198710:716–21. 3. Tsalikian E Maurus N Beck RW Janz KF Chase HP et al. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Paediatr. 2005147:528–34. 4. Bussau V A Ferreira LD Jones TW Fournier PA. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care. 200629:601–6. 5. Guelfi KJ Jones TW Fournier PA. Intermittent high-intensity exercise does not increase the risk of early post-exercise hypoglycaemia in individuals with type 1 diabetes. Diabetes Care. 2005282:416–8. 6. Guelfi KJ Jones TW Fournier PA. The decline in blood glucose levels is less with intermittent high-intensity compared with moderate exercise in individuals with type 1 diabetes. Diabetes Care. 2005286:1289–94. 7. Iscoe KR Riddell MC. Continuous moderate-intensity exercise with or without intermittent high-intensity work: effects on acute and late glycaemia in athletes with type 1 diabetes mel- litus. Diabet Med. 2011287:824–32. 8. Bussau V A Ferreira LD Jones TW Fournier PA. A 10-s sprint performed prior to moderate- intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Diabetologia. 2007509:1815–8. 9. Maran A Pavan P Bonsembiante B Brugin E Ermolao A Avogaro A Zaccaria M. Continuous glucose monitoring reveals delayed nocturnal hypoglycaemia after intermittent high-intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther. 2010. doi:10.1089/ dia.2010.0038. 10. Chokkalingam K Tsintzas K Norton L Jewell K Macdonald IA Mansell PI. Exercise under hyperinsulinaemic conditions increases whole-body glucose disposal without affecting muscle glycogen utilisation in type 1 diabetes. Diabetologia. 200750:414–21. 11. Dandona P Hooke D Bell J. Exercise and insulin absorption from subcutaneous injection site. Br Med J. 1980280:479–80. 12. Dubé MC Weisnagel J Homme DP Lavoie C. Exercise and newer insulins: how much glu- cose supplement to avoid hypoglycemia. Med Sci Sports Exerc. 200537:1276–82. 13. Hernandez JM Moccia T Fluckey JD Ulbrecht JS Farrell PA. Fluid snacks to help persons with type 1 diabetes avoid late onset post-exercise hypoglycemia. Med Sci Sports Exerc. 200032:904–10.

slide 90:

68 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 68 2 14. Jenni S Oetliker S Allemann M. Fuel metabolism during exercise in euglycaemia and hyper- glycaemia in patients with type 1 diabetes mellitus – a prospective single-blinded randomised crossover trial. Diabetologia. 200851:1457–65. 15. Mauvais-Jarvis F Sobngwi E Porcher R Garnier JP Vexiau P Duvallet A Gautier JF. Glucose response to intense aerobic exercise in type 1 diabetes. Diabetes Care. 200326:1316–7. 16. Perrone C Laitano O Mayer F. Effect of carbohydrate ingestion on the glycemic response to type 1 diabetic adolescents during exercise. Diabetes Care. 200528:2537–8. 17. Peter R Luzio SD Dunseath G Miles A Hare B Backx K Pauvaday V Owens DR. Effects of exercise on the absorption of insulin glargine in patients with type 1 diabetes. Diabetes Care. 200528:560–5. 18. Rabasa-Lhoret R Bourque J Ducros F Chiasson J. Guidelines for premeal insulin dose reduc- tion for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen ultralente-lispro. Diabetes Care. 200124:625–30. 19. Tuominen JA Karonen SL Melamies L Bolli G Koivisto V A. Exercise-induced hypoglycae- mia in IDDM patients treated with a short-acting insulin analogue. Diabetologia. 1995 38:106–11. 20. Asp S Daugaard JR Richter EA. Eccentric exercise decreases glucose transporter GLUT4 protein in human skeletal muscle. J Physiol. 1995482:705–12. 21. Asp S Daugaard JR Kristiansen S Kiens B Richter EA. Eccentric exercise decreases maxi- mal insulin action in humans. J Physiol. 1996494:891–8. 22. Wenger HW Bell GJ. The interactions of intensity frequency and duration of exercise training in alerting cardiorespiratory fitness. Sports Med. 19863:345–56. 23. Tabata I Nishimura K Kouzaki M Hirai Y Ogita F Miyachi M Yamamoto K. Effects of moderate-intensity endurance and high-intensity intermittent training on anaerobic capacity and VO max. Med Sci Sports Exerc. 199628:1327–30. 24. Sigal RJ Kenny GP Boule NG Wells GA Prudhomme D Fortier M Reid RD Tulloch H Coyle D Phillips P Jennings A Faffey J. Effects of aerobic training resistance training or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med. 2007 147:357–69. 25. Jorge ML de Oliveira VN Resende NM Paraiso LF Calixto A Diniz AL Resende ES Ropelle ER Carvalheira JB Espindola FS Jorge PT Geloneze B. The effects of aerobic resistance and combined exercise on metabolic control inflammatroy markers adipocytok- ines and muscle insulin signalling in patients with type 2 diabetes mellitus. Metabolism. 2011609:1244–52. doi:10.1016/j.metabol.2011.01.006. 26. Durak EP Jovanovic-Peterson L Peterson CM. Randomized crossover study of effect of resis- tance training on glycemic control muscular strength and cholesterol in type 1 diabetic men. Diabetes Care. 199013:1039–43. 27. Ramalho AC de Lourdes Lima M Nunes F Cambuí Z Barbosa C Andrade A Viana A Martins M Abrantes V Aragão C Temístocles M. The effect of resistance versus aerobic training on metabolic control in patients with type-1 diabetes mellitus. Diabetes Res Clin Pract. 200672:271–6. 28. Jiminez C Santiago M Sitler M Boden G Homko C. Insulin-sensitivity responses to a single bout of resistive exercise in type 1 diabetes mellitus. J Sport Rehabil. 200918:564–71. 29. Essen-Gustavsson B Tesch PA. Glycogen and triglyceride utilization in relation to muscle metabolic characteristics in men performing heavy-resistance exercise. Eur J Appl Physiol Occup Physiol. 199061:5–10. 30. Robergs RA Pearson DR Costill DL Pascoe DD Benedict MA Lambert CP Zachwieja JJ. Muscle glycogenolysis during differing intensities of weight-resistance exercise. J Appl Physiol. 199170:1700–6. 31. Tesch PA Ploutz-Snyder LL Ystrom L Castro MJ Dudley GA. Skeletal muscle glycogen loss evoked by resistance exercise. J Strength Cond Res. 199812:67–73. 32. Bogardus C Thuillez P Ravussin E Vasquez B Narimiga M Azhar S. Effect of muscle gly- cogen depletion in vivo in insulin action in man. J Clin Invest. 198372:1605–10.

slide 91:

69 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 69 33. Munger R Temler E Jallut D Haesler E Felber JP. Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human musclebiopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown. Metabolism. 199342:36–43. 34. Zachwieja JJ Costill DL Beard GC Robergs RA Pascoe DD Anderson DE. The effects of a carbonated carbohydrate drink on gastric emptying gastro-intestinal distress and exercise per- formance. Int J Sports Nutr. 19922:229–38. 35. Fry AC Kraemer WJ Stone MH Warren BJ Fleck SJ Kearney JT Gordon SE. Endocrine responses to overreaching before and after 1 year of weightlifting. Can J Appl Physiol. 199419:400–10. 36. French DN Kraemer WJ V olek JS Spiering BA Judelson DA Hoffman JR Maresh CM. Anticipatory responses of catecholamines on muscle force production. J Appl Physiol. 20071021:94–102. 37. Matsuse H Nago T Takano Y Shiba N. Plasma growth hormone is elevated immediately after resistance exercise with electrical stimulation and voluntary muscle contraction. Tohoku J Exp Med. 2010222:69–75. 38. Leite RD Prestes J Rosa C De Salles BF Major A Miranda H Simao R. Acute effect of resistance training volume on hormonal responses in trained men. J Sports Med Phys Fitness. 201151:322–8. 39. De Feo P Di Loreto C Ranchelli A Fatone C Gam-belunghe G Lucidi P Santeusanio F. Exercise and diabetes. Acta Biomedica. 200677:14–7. 40. Grimm JJ. Exercise in type 1 diabetes. In: Nagi D editor. Exercise and sport in diabetes. Hoboken: Wiley 2005. p. 25–43. 41. Iafusco D. Diet and physical activity in patients with type 1 diabetes. Acta Biomedica. 200677:41–6. 42. Brange J V ølund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 199935:307–35. 43. Leopore M Pampanelli S Fanelli C Porcellatim F Bartocci L Di Vincenzo A. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analogue glargine NPH insulin and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 200049:2142–8. 44. Bracken RM West D Stephens JW Kilduff L Luzio S Bain SC. Impact of pre-exercise rapid- acting insulin reductions on ketogenesis following running in type 1 diabetes. Diabet Med. 2011282:218–22. 45. West DJ Morton RD Bain SC Stephens JW Bracken RM. Blood glucose responses to reduc- tions in pre-exercise rapid-acting insulin for 24 h after running in individuals with type 1 dia- betes. J Sports Sci. 2010287:781–8. 46. West DJ Morton RD Stephens JW Bain SC Kilduff LP Luzio S Still R Bracken RM. Isomaltulose improves post-exercise glycemia by reducing CHO oxidation in T1DM. Med Sci Sports Exerc. 2011432:204–10. 47. West DJ Stephens JW Bain SC Kilduff LP Luzio S Still R Bracken RM. A combined insu- lin reduction and carbohydrate feeding strategy 30 min before running best preserves blood glucose concentration after exercise through improved fuel oxidation in type 1 diabetes mel- litus. J Sports Sci. 2011293:279–89. 48. Arutchelvam V Heise T Dellweg S Elbroend B Minns I Home PD. Plasma glucose and hypoglycaemia following exercise in people with type 1 diabetes: a comparison of three basal insulins. Diabet Med. 20092610:1027–32. 49. Koivisto V A Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Ann Intern Med. 1980921:59–61. 50. Cryer PE. The prevention and correction of hypoglycaemia. In: Jefferson LS Cherrington AD editors. The endocrine pancreas and regulation of metabolism. New York: Oxford University Press 2001. p. 45–56. 51. Laffel L. Ketone bodies: a review of physiology pathophysiology and application of monitor- ing to diabetes. Diabetes Metab Res Rev. 199915:412–26.

slide 92:

70 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 70 52. Wallace TM Matthews DR. Recent advances in the monitoring and management of diabetic ketoacidosis. Q J Med. 200497:773–80. 53. Jain SK McVie R Jaramillo JJ Chen Y . Hyperketonemia acetoacetate increases oxidizabil- ity of LDL + VLDL in type-1 diabetic patients. Free Radic Biol Med. 199824:175–81. 54. Jain SK McVie R. Hyperketonemia can increase lipid peroxidation and lower glutathione lev- els in human erythrocytes in vitro and in type 1 diabetic patients. Diabetes. 199948:1850–5. 55. Jain SK McVie R Jackson R Levine SN Lim G. Effect of hyperketonemia on plasma lipid peroxidation levels in diabetic patients. Diabetes Care. 199922:1171–5. 56. Køeslag JH Noakes TD Sloan AW. Post-exercise ketosis. J Physiol Lond. 1980301: 79–90. 57. Leiper JB Aulin KP Söderlund K. Improved gastric emptying rate in humans of a unique glucose polymer with gel-forming properties. Scand J Gastroenterol. 20003511:1143–9. 58. Schvarcz E Palmer M Aman J Lindkvist B Beckman KW. Hypoglycaemia increases the gastric emptying rate in patients with type 1 diabetes mellitus. Diabet Med. 199310:660–3. 59. Schvarcz E Palmer M Aman J Horowitz M Stridsberg M Berne C. Physiological hypergly- caemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology. 1997113:60–6. 60. Lina BAR Jonker D Kozianowski G. Isomaltulose Palatinose®: a review of biological and toxicological studies. Food Chem Toxicol. 200240:1375–81. 61. Jeukendrup AE Jentjens RL. Oxidation of carbohydrate feedings during prolonged exercise: current thoughts guidelines and directions for future research. Sports Med. 2000296:407–24. 62. Steppel JH Horton ES. Exercise in the management of type 1 diabetes mellitus. Rev Endocr Metab Disord. 20034:355–60. 63. Diabetes mellitus and exercise. American Diabetes Association. Diabetes Care. 19972012: 1908–12. 64. Gallen I. Exercise in type 1 diabetes. Diabet Med. 200320:1–17. 65. Ramires PR Forjaz CL Strunz CM Silva ME Diament J Nicolau W Liberman B Negrão CE. Oral glucose ingestion increases endurance capacity in normal and diabetic type I humans. J Appl Physiol. 1997832:608–14. 66. Riddell MC Iscoe K. Physical activity sport and pediatric diabetes. Pediatr Diabetes. 200671:60–70. 67. Gallen I. The management of insulin treated diabetes and sport. Pract Diab Int. 2005 22:307–12. 68. Davis JM Burgess WA Slentz CA Bartoli WP. Fluid availability and sports drinks differing in carbohydrate type and concentration. Am J Clin Nutr. 199051:1054–7. 69. Maughan RJ Leiper JB. Limitations to fluid replacement during exercise. Can J Appl Physiol. 199924:173–87. 70. Murray R Bartoli WP Eddy DE Horn MK. Gastric emptying and plasma deuterium accumu- lation following ingestion of water and two carbohydrate-electrolyte beverages. Int J Sports Nutr. 19977:144–53. 71. Jing M Rayner CK Jones KL Horowitz M. Diabetic gastroparesis: diagnosis and manage- ment. Drugs. 200969:971–86. 72. Wolever TM Jenkins DJ Jenkins AL Josse RG. The glycemic index: methodology and clini- cal implications. Am Soc Clin Nutr. 199154:846–54. 73. Foster-Powell K Holt SHA Brand-Miller JC. International table of glycaemic index and gly- cemic load values. Am J Clin Nutr. 200276:5–56. 74. Jenkins DJ Wolever TM Kalmusky J Giudici S Giordano C Wong GS Bird JN Patten R Hall M Buckley G. Low glycemic index carbohydrate foods in the management of hyperlipi- demia. Am J Clin Nutr. 198542:604–17. 75. Nansel TR Gellar L McGill A. Effect of varying glycemic index meals on blood glucose control assessed with continuous glucose monitoring in youth with type 1 diabetes on basal- bolus insulin regimens. Diabetes Care. 200831:695–7.

slide 93:

71 R.M. Bracken et al. 3 Pre-exercise Insulin and Carbohydrate Strategies in the Exercising T1DM Individual 71 76. Brand JC Colagiuri S Crossman S Allen A Truswell AS. Low glycaemic index carbohydrate foods improve glucose control in non-insulin dependent diabetes mellitus NIDDM. Diabetes Care. 199114:95–101. 77. Gilbertson HR Brand-Miller JC Thorburn AW Evans S Chondros P Wether GA. The effect of flexible low glycemic index dietary advice versus measured carbohydrate diets on glycemic control in children with type 1 diabetes. Diabetes Care. 200134:1137–43. 78. Thomas DE Elliott EJ Baur L. Low glycemic index or low glycemic load diets for overweight and obesity. Cochrane Database Syst Rev. 200718:1–38. 79. DeMarco H Sucher KP Cisar CJ Butterfield GE. Pre-exercise carbohydrate meals: applica- tion of glycemic index. Med Sci Sports Exerc. 199931:164–70. 80. Achten J Jentjens RL Brouns F Jeukendrup AE. Exogenous oxidation of isomaltulose is lower than that of sucrose during exercise in men. J Nutr. 2007137:1143–8. 81. Stevenson EJ Williams C Mash LE Phillips B Nute ML. Influence of high-carbohydrate mixed meals with different glycemic indexes on substrate utilisation during subsequent exer- cise in women. Am J Clin Nutr. 200684:354–60. 82. Fernqvist E Linde B Ostman J Gunnarsson R. Effects of physical exercise on insulin absorp- tion in insulin-dependent diabetics. A comparison between human and porcine insulin. Clin Physiol. 19866:489–97. 83. Lauritzen T Binder C Faber OK. Importance of insulin absorption subcutaneous blood flow and residual beta-cell function in insulin therapy. Acta Paediatr Scand. 1980283:81–5. 84. Linde B Gunnarsson R. Influence of aprotinin on insulin absorption and subcutaneous blood flow in type 1 insulin-dependent diabetes. Diabetologia. 198528:645–8. 85. V ora JP Burch A Peters JR Owens DR. Absorption of radiolabelled soluble insulin in type 1 insulin dependent diabetes: influence of subcutaneous blood flow and anthropometry. Diabet Med. 199310:736–43. 86. Koivisto V A. Sauna-induced acceleration in insulin absorption from subcutaneous injection site. Br Med J. 1980280:1411–3. 87. Koivisto V A Fortney S Hendler R Felig P. A rise in ambient temperature augments insulin absorption in diabetic patients. Metabolism. 198130:402–5. 88. Tamás GY Marre M Astorga R Dedov I Jacobsen J Lindholm A. Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study. Diabetes Res Clin Pract. 200154:105–14. 89. Plank J Wutte A Brunner G Siebenhofer A Semlitsch B Sommer R Hirschberger S Pieber T. A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. Diabetes Care. 200225:2053–7. 90. Perry E Gallen IW. Guidelines on the current best practice for the management of type 1 dia- betes sport and exercise. Pract Diab Int. 200926:116–23. 91. Moore LJ Midgley AW Thomas G Thurlow S McNaughton LR. The effects of low- and high- glycemic index meals on time trial performance. Int J Sports Physiol Perform. 2009 43:331–44. 92. Wong SH Chen YJ Fung WM Morris JG. Effect of glycemic index meals on recovery and subsequent endurance capacity. Int J Sports Med. 20093012:898–905. 93. Jeukendrup A Saris WH Brouns F Kester AD. A new validated endurance performance test. Med Sci Sports Exerc. 1996282:266–70. 94. Bracken RM Page R Gray B Kilduff LP West DJ Stephens JW Bain SC. Isomaltulose improves glycaemia and maintains run performance in type 1 diabetes. Med Sci Sports Exerc. 2011 Epub ahead of print doi: 10.1249/MSS.0b013e31823f6557. 95. Stephens FB Roig M Armstrong G Greenhaff PL. Post-exercise ingestion of a unique high molecular weight glucose polymer solution improves performance during a subsequent bout of cycling exercise. J Sports Sci. 2008262:149–54. 96. Bracken RM Page R Gray B West D Kilduff L Stephens JW Bain SC. Waxy barley starch improves high intensity run performance in type 1 diabetes. 2012. Paper in preparation.

slide 94:

Chapter 4 Physical Activity in Childhood Diabetes Krystyna A. Matyka and S. Francesca Annan 4.1 Introduction Physical activity is an important part of childhood. It is important for normal child- hood development to maintain healthy bones and body composition and is useful in developing and maintaining social contacts. Physical activity is no less important for children and young people with diabetes. It is actively encouraged but presents signifi- cant challenges for diabetes management for the child family and the diabetes team. Physical activity can lead to fluctuations in blood glucose levels that can be difficult to manage or to avoid. In this chapter we will provide some background to the develop- mental aspects of physical activity in children and young people and suggest some strategies for managing type I diabetes during periods of physical activity. 4.2 Definitions Physical activity is defined as any force exerted by skeletal muscle that results in energy expenditure above resting level. Exercise is defined as a subset of physical activity that is volitional planned structured repetitive and aimed at improvement or maintenance of any aspect of fitness or health. Sport is a subset of physical K.A. Matyka M.B.B.S. M.D. M.R.C.P.C.H.

slide 95:

Division of Metabolic and Vascular Health Warwick Medical School Clinical Sciences Research Laboratories University Hospital Clifford Bridge Road Coventry CV2 2DX UK e-mail: k.a.matykawarwick.ac.uk S.F. Annan B.Sc. Hons PGCert Department of Nutrition and Dietetics Alder Hey Children’s NHS Foundation Trust Eaton Road West Derby Liverpool Merseyside L12 2AP UK e-mail: francesca.annannhs.net I. Gallen ed. Type 1 Diabetes 73 DOI 10.1007/978-0-85729-754-9_4 © Springer-Verlag London Limited 2012

slide 96:

74 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 74 activity that involves structured competitive situations governed by rules. Physical fitness is a set of attributes that people have or achieve that relates to the ability to perform physical activity 1. 4.3 Developmental Changes and Physical Activity There are quite marked variations in patterns of physical activity throughout child- hood as a result of childhood development. These changes will be a reflection of the dramatic changes in stature body composition and neuromuscular development that occur. There will be improvements in strength and coordination and hence physical ability and these will change constantly throughout childhood and into young adult life 1. Changes in cognitive ability of children will allow them to participate in more structured and organized events involving either exercise or sporting activities. There are also significant differences between boys and girls throughout the period of development with boys being more active than girls even in the early years. This period of development will depend not only on the physical attributes of the child but also on the opportunities provided both within the environment and also by adult carers: data suggest that children are more likely to be active if their parents are active and encourage physical activity 2. It is beyond the scope of this chapter to go into the developmental changes which will influence physical activity in child- hood in any detail. However there are changes in muscle strength pulmonary func- tion cardiovascular function and aerobic fitness throughout childhood and into early adult life 1. Some of these changes occur as a result of developmental changes in stature and body composition: it is well described that boys will develop more muscle mass going through puberty and girls will predominantly accrue more fat mass 1. Yet some of these changes will also be mediated by physical activity itself which will influence body composition. Thus some of the differences between children of similar age and developmental stage may be explained by their access to opportunities to be physically active 3. Infants less than 1 year of age will be doing little in the form of vigorous move- ment as they are yet to develop the necessary skills to be active with any degree of confidence. This changes quickly over the first few years of life as the young child learns to crawl shuffle walk run climb stairs and so on. As the skills increase the intensity of the activity is likely to increase along with the complexity. Preschool children are likely to be active through play involving a mixture of activity and social interaction 4. Primary school children will start to participate in more structured activity or exercise within PE lessons although it is likely that they will participate in unstructured activity in the playground at break times. Once young people go to secondary school the nature of physical activity may change again and become more structured and potentially become restricted to organized events or sports. Data suggest that along with these changes in type of activity there are also changes in the amount of physical activity that is performed. It is well described that

slide 97:

75 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 75 activity levels decrease as children get older and become adolescents 5. The reasons for this are likely to be multifactorial and include both physiological rapid growth and pubertal changes as well as environmental and societal factors. The increased emphasis on academic achievement is likely to be a significant barrier to regular physical activity for a number of teenage pupils. As already mentioned data also highlight gender differences throughout the life course with girls performing significantly less physical activity than boys. Again the reason for this is likely to be complex. It is plausible that there are physiological factors which mediate the decrease in physical activity which is particularly pronounced in teenage girls. However it is also well described that boys use physical activity as a method of socializing with their peer group while girls are more likely to have other methods for social interactions which do not include physical activity 6. These developmental changes will have significant implications to the manage- ment of diabetes in children of different ages. Physical activity improves physical fit- ness which in turn improves insulin sensitivity: those children who are most physically active are likely to need lower doses of insulin compared to those who are more sed- entary 7. Assessing both the quantity and intensity of physical activity performed by children and young people with diabetes is likely to be as important as assessing nutri- tional intake yet in the clinical setting it is a hugely challenging exercise. 4.4 Assessing Physical Activity in Childhood There are significant difficulties in the accurate objective measurement or assess- ment of physical activity particularly in childhood. There are a number of different methods of assessment ranging from questionnaires to more objective measures involving monitoring of movement or heart rate 8 9. Questionnaires create the greatest concern. Data can be recorded either prospectively or retrospectively and both methods have significant flaws. Retrospective data collection may be imprecise and challenging with children who lack the cognitive ability to accurately recall details of activity patterns and report them without bias 10. Studies suggest that children younger than 9 years old will have problems reliably reporting physical activity patterns 11. On the other hand prospective data collection is labor inten- sive as it requires detailed documentation of all physical activity performed in pre- defined time blocks sometimes as short as 15 min. Again this can be very difficult for young children but is also a challenge for older children and young people who will easily tire of the intensity of this procedure 10. Questionnaires are often used as part of research studies where large number of subjects are to be studied yet they are likely to have significant limitations within a clinical context 8 9. More objective measures of assessing physical activity using either heart rate or activity monitors are likely to provide better quality data with respect to the amount of activity performed 8 9. However they do not provide information on the type of activity performed. Activity monitors can measure either heart rate or physical activity or a combination of the two. Measurement of heart rate only has limitations

slide 98:

76 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 76 in that a number of other physiological variables can lead to an increase in heart rate other than physical activity. For example stress excitement or an increased tem- perature can all lead to an increase in heart rate. On the other hand measurement of activity with a movement sensor such as an accelerometer also causes problems particularly with movement artifacts leading to erroneously high levels of activity. In addition some types of physical activity are not captured very well with an accel- erometer worn on the waistband activities such as cycling are examples of this. Many activity monitors are also not waterproof and so water-based activities are not included as part of the assessment. More recent activity monitors provide a combination of both heart rate measurement and accelerometry and are thought to be a more robust assessment of patterns of physical activity in both children and adults 12. Using standardized metabolic equations many of these monitors can provide estimates of energy expenditure although some of the physiological assumptions used in these calculations have not been validated in studies of children 13. Many of these monitors are reasonably expensive so their use in large com- munity-based studies can be unfeasible. Familiarity with their use is necessary if they are to be valuable within a clinical setting. A combination of an objective measurement of physical activity using an activity monitor in combination with an activity diary is likely to provide the best informa- tion with respect to both type and frequency of physical activity 8 9. Most coun- tries will have national recommendations for levels of physical activity in children and young people. It does appear that the majority of these recommendations sug- gest at least 60 min of moderate to vigorous physical activity activity which leads to an increase in heart rate or feelings of sweatiness per day 14. 4.5 Patterns of Physical Activity in Children with Diabetes Click Here For Best Diabetes Treatment A number of studies have been performed to examine patterns of physical activity in children with diabetes 15–19. These studies on the whole have used question- naires to collect data on levels of activity. The results from these studies have been rather variable with studies suggesting both increased and decreased levels of activ- ity when compared to children who are otherwise healthy. A study in 2010 from North America has examined physical activity and electronic media use in young people with both type I and type II diabetes 15. The study examined compliance with the physical activity recommendations for children and young people which was either 30 min per day of vigorous physical activity or 60 min per day of moder- ate to vigorous physical activity for adolescents. The study found that 81 of ado- lescents with type I diabetes met these target criteria compared to 80 of healthy controls. Only 68 of adolescents with type II diabetes met these national guide- lines 15. Another study from Italy examined computer use free time activities and metabolic control in 115 patients aged 10–35 years 16. The authors found that in the group as a whole the mean time spent playing sports was 2 ½ h per week with a range from 0 to 8 h. Twenty five subjects i.e. 29 did not practice any kind

slide 99:

77 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 77 of physical activity at all 16. A much larger study from Norway evaluated physical activity patterns of 723 children with type I diabetes aged from 6 to 19 years using a questionnaire that could estimate total amount of time spent on inactivity and light moderate and vigorous activity 17. The study found that 54 of the partici- pants did not fulfill the international recommendations of 60 min of moderate to vigorous activity per day. Not surprisingly girls were less active than boys in child- hood and in adolescents. Worryingly 43 of the participants watched TV for more than 2 h a day: TV viewing was found to be related to overweight in children and adolescents with type I diabetes. The study found no statistical differences in physi- cal activity between the different intensified insulin regimens and pump patients were not less active than other patients with diabetes 17. A study of heart rate monitoring in 127 children with diabetes and 200 controls in France showed that schoolchildren with diabetes were significantly more active than healthy peers when considering moderate activity 18. In addition teenagers with diabetes were also significantly more active when considering moderate and vigorous activity. Furthermore there was a negative correlation between the most recent glycated hemoglobin and the time spent in light activities in schoolchildren 18. Another study from Sweden of 26 adolescent girls with type I diabetes and 49 controls using accelerometers showed that there was a tendency toward a lower total amount of physical activity in the diabetes group but the difference between the study groups did not reach statistical significance 19. 4.6 Beneficial Effects of Physical Activity 4.6.1 Well-being In the nondiabetic population there is now fairly strong evidence of a positive asso- ciation between physical activity and psychological well-being. A Cochrane review from 2004 found that physical activity is associated with reduction in depression anxiety and stress and with increased self-esteem although it was felt there were few data available on which to make this assumption 20. Physical activity is encouraged in the majority of patients with chronic illnesses who are able to be physically active in a safe and pain-free manner. There are a number of reasons why physical activity may be important for psy- chological well-being in patients with type I diabetes. The incidence of depression is significantly higher in patients with diabetes than in the healthy population: chil- dren with type I diabetes have a two- to threefold increased incidence of depression compared to healthy controls 21. There have been few studies which have specifically examined psychological well-being and physical activity in children with type I diabetes. A study by Edmunds at al from the United Kingdom studied 36 participants aged between 9 and 15 years with a mean duration of type I diabetes of almost 6 years 22. The participants filled in a number of questionnaires including the Quality of Life for

slide 100:

78 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 78 Youths questionnaire the Self-Efficacy for Diabetes scale and the Physical Self- Perception Profile for Children. Physical activity was assessed using heart rate mon- itoring for 2 weeks and 2 weekend days. This small study found that 16 47 of children participated in at least 60 min per day of moderate to vigorous physical activity. Twenty-six 76 engaged in at least 30 min of moderate to vigorous phys- ical activity per day. Again boys reported higher levels of both moderate to vigor- ous physical activity and vigorous physical activity compared to girls. Boys reported higher self-esteem than females but self-efficacy with respect to diabetes manage- ment was higher in females than males. Self-reported quality of life was above the median value for this scale and males reported better quality of life than females in all subscales. Correlation analysis revealed no significant associations between moderate to vigorous physical activity and self-esteem self-efficacy quality of life or glycemic control 22. The authors concluded that the role of physical activity as part of disease management may reduce the extent to which physical activity is seen as fun. They also felt that there might be a significant element of worry involved that blood glucose levels will be affected by physical activity both in the short term and later on that night which would impact on the psychological benefits of physical activity 22. Emotional concerns have also been described by parents who have been asked about their experiences of learning to cope with a diagnosis of diabetes in one of their offspring. Feelings of sadness and guilt resurfaced at times when their child’s diabetes is brought to the forefront: for example at times of physical activity when a child may have to stop playing a sport because they start to feel low 23. Studies have shown that parental support is essential to promote physical activity in healthy populations of children 2. Studies of families of children with diabetes have shown that parental conflict around physical activity was related to decreased activity in children with type I diabetes. The authors suggested that nag- ging and criticism as well as arguing about physical activity make a child less likely to engage 24. However other parents report the importance of fostering normality by allowing their children to be physically active with other children 25. In this study parents reported that they did what they had to do so that their child with diabetes could do anything they wanted to do. Planning and vigilance was espe- cially evident for parents of children with diabetes reflecting the difficult negotia- tions necessary to maintain good blood glucose control around periods of activity 25. Schools also play an important role in encouraging children to be active. In a qualitative study of how children with chronic disease and their parents manage physical activity one child with asthma reported “one of the PE teachers used to treat me as if I was about to die that’s so annoying” 25. In a report from the Hvidoere Study Group on childhood diabetes a large group of just over 2000 adolescents with an average age of 14 ½ years were asked to complete three questionnaires: the Diabetes Quality of Life – Short Form questions on psycho- logical well-being and health perception from the Health Behaviour in School Children WHO project HBSC and five questions on physical activity and sedentary lifestyle from the HBSC survey 2001 26. Questions on physical activity focused on the number of days during the last week being moderately physically active for more than 60 min per day. The average HbA1c of the whole sample was 8.2 ± 1.4. Boys

slide 101:

79 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 79 reported not only being more physically active but also doing less school homework and spending more time on the computer than girls. Older respondents were less physically active but did more school homework and spent more time on the com- puter. Physical activity was also positively correlated with nearly all markers of psy- chological health with more activity associated with greater well-being fewer symptoms less worry greater perception of health and general quality of life 26. 4.6.2 Cardiovascular Benefits Regular physical activity which leads to improvement in physical fitness has signifi- cant cardiovascular and metabolic benefits in both children and adults 27. Type I diabetes is associated with a significantly increased risk of cardiovascular disease and so physical activity is important to this group of patients 28. There have been few studies examining cardiovascular risk factors with respect to physical activity in children with type I diabetes. Reduced heart rate variability is an independent predictor of heart disease and risk of heart disease in healthy populations of adults 29 30. Heart rate variability in 93 children with type I diabetes aged 8–12 years was compared to 107 matched healthy control children 31. Level of physical activity was assessed using a questionnaire which could divide activity levels into low mod- erate or high. This study showed that children with type I diabetes who had low levels of activity had significantly lower heart rate variability at rest when compared to healthy controls 31. Aerobic fitness has also been examined in some studies. One study has examined physical activity levels using an accelerometer and cardio- respiratory fitness by a treadmill test in children with three different chronic diseases and compared them to healthy controls 32. Forty-five obese children 31 children with juvenile idiopathic arthritis 48 children with type I diabetes and 85 healthy children took part in the study. This study showed that 60 of healthy controls met the recommended daily 60 min of moderate to vigorous physical activity but only 39 of children with type I diabetes met these criteria. In the group as a whole lower cardiorespiratory fitness was associated with female gender and low daily physical activity. This study did not find any significant differences in cardiorespira- tory fitness in children with diabetes 32. Other studies confirm these findings: using an incremental exercise test on a bicycle ergometer in late pubertal adolescent girls with diabetes there were no differences in aerobic power compared to healthy siblings 33. In another study significant differences in aerobic capacity were found between in people with type I diabetes and healthy controls 34. The study also used an incremental treadmill test and found that subjects with type I diabetes had lower maximal heart rates and lower time to exhaustion compared to healthy con- trols however there was a wide variation in the age range and probably pubertal status of both cohorts and it is difficult to assess the robustness of the data 34. The beneficial effects of physical activity on cardiovascular risk profiles have been examined in young people with diabetes. A multicenter study of over

slide 102:

80 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 80 23000 patients attending 209 centers in Germany and Austria examined lipid profiles blood pressure glycated hemoglobin and body mass index and compared them to levels of physical activity as assessed by questionnaire 35. The group was divided into 10392 patients who performed no physical activity outside of school per week 8607 who performed 1–2 episodes of at least 30 min per week and 4252 who performed at least 30 min of physical activity more than three times a week. With increasing frequency of physical activity the percentage of patients with dys- lipidemia decreased from 41 in the physically inactive group to 34 in the most active group. There was no difference in systolic or diastolic blood pressure among the groups but there was a lower glycated hemoglobin in patients with a higher frequency of physical activity p 0.00001 and this effect was found in both sexes and in all age groups 35. A study examining noninvasive markers of atherosclero- sis using flow-mediated dilation and intima-media thickness with high-resolution ultrasonography found that patients n 32 with type I diabetes had higher intima- media thickness and reduced flow-mediated dilation compared to control subjects n 42 36. When children with diabetes were assessed based on their level of daily physical activity those children who did 60 or more minutes of moderate to vigorous physical activity were found to have higher flow-mediated dilation com- pared to the inactive group and similar differences were found when comparing inactive and active healthy subjects. Again the group studied was of a wide age range from 6 to 17 years and it does not appear that pubertal status was controlled for although it was assessed 36. 4.7 Effects on Glucose and Glycemic Control Exercise increases the risk of hypoglycemia in type I diabetes and this risk is both acute and delayed. A very elegant study has examined glucose requirements during moderate-intensity afternoon exercise in adolescents with type I diabetes 37. Nine adolescents with a mean age of 16 years and duration of diabetes of approximately 8 years were studied using exercise clamp studies. The aim of the study was to maintain glucose levels in the euglycemic range using an infusion of a fixed dose of insulin but variable doses of intravenous dextrose. A standardized “dose” of exer- cise was performed at 16:00 hours with 45 min of cycling on a cycle ergometer at an intensity of approximately 55 of their peak aerobic capacity. A second eugly- cemic clamp study was performed at rest with no periods of exercise. This study shows that glucose infusion rates to maintain stable glucose levels were increased during and shortly after exercise and again from 7 to 11 h after exercise. Counterregulatory hormone levels were measured and were similar between exer- cise and rest days although there was a peak immediately after exercise 37. This study suggests that patients are risk of hypoglycemia during and shortly after exer- cise and again from 7 to 11 h after exercise. If exercise is performed late in the day this risk of delayed hypoglycemia will occur during sleep. In addition the peak in counterregulatory hormone responses immediately after exercise can cause blood

slide 103:

81 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 81 glucose levels to rise for a while after exercise. This means that patients need less insulin during activity but then may need extra insulin straight after exercise which is often when they are checking their blood glucose level 37. This response to physical activity does appear to be reproducible within patients. Nine adolescent boys with type I diabetes were tested using six 10-min cycling bouts at moderate intensity separated by a 5-min rest period on two separate occasions 5–17 days apart. Plasma glucose levels for each time period from the beginning of exercise to the end of the recovery period were unchanged between the two sessions 38. Carbohydrate intake insulin injections exercise bouts and their timing were identi- cal in both sessions. This does suggest that patients who can monitor themselves intensively around periods of activity can learn a great deal with respect to making adjustments to their diabetes regimen to keep glucose levels at acceptable values during exercise 38. Another study has examined the effect of physical activity in 50 subjects with type I diabetes aged 11–17 years. Blood glucose was frequently sampled on a day of physical activity a standardized afternoon exercise session on a treadmill compared to a day of inactivity 39. Current guidelines from the American Diabetes Association for the management of exercise for patients with type I diabetes were used to try to avoid hypoglycemia during exercise 40. Despite this 11 22 of patients developed hypoglycemia during exercise. In addition the mean glucose concentration overnight was lower on the exercise day than on a rest day. Hypoglycemia was more frequent on exercise nights occurring in 13 26 of nights 39. Studies have also examined the effects of physical activity on long-term glyce- mic control. Two large epidemiological studies have found rather conflicting results. The Hvidoere Study Group found that physical activity as assessed by question- naires based on retrospective reporting of amounts of physical activity has shown no link with glycemic control as judged by glycated hemoglobin levels 26. Furthermore there were also no associations with reported frequency of severe hypoglycemia or diabetic ketoacidosis 26. In contrast a study using cross-sec- tional analysis of data from 19000 patients with type I diabetes aged 3–20 years showed that regular physical activity is a major factor influencing glycemic control 41. Again physical activity data were collected using questionnaires and subjects were divided based on the frequency of physical activity bouts of greater than 30 min per week. No association was noted between the frequency of physical activity and episodes of severe hypoglycemia. Data on episodes of mild hypoglyce- mia were not collected 41. Neither of these studies was designed to look at a link between physical activity and glycemic control. One study of 81 youth with type I diabetes aged 11–16 years who were randomized either to usual care or personal trainer intervention found that glycated hemoglobin levels increased in the control group by 0.3 whereas there was a decrease in the intervention group of 0.39 over a 2-year period 42. Another study examined the impact of preexisting glyce- mic control on the beneficial effects of physical activity on glycated hemoglobin. Twenty-four adolescents with type I diabetes with glycated hemoglobin levels either higher or lower than 9 participated in 12 weeks of supervised exercise

slide 104:

82 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 82 followed by 12 weeks of unsupervised training 43. The study found no improve- ments in HbA1c in those who are either poorly controlled or well controlled 43. 4.8 Managing Diabetes During Physical Activity Want To Diabetes Free Life Click Here 4.8.1 Insulin Adjustment Management of type I diabetes around the times of physical activity is fraught with problems particularly among children and young people. However it is also a sig- nificant concern to adults in whom fear of hypoglycemia is the most significant barrier to physical activity 44. There has been surprisingly little research into the management of activity in childhood diabetes. The American Diabetes Association has provided guidelines to the management of diabetes and exercise however this is very much a consensus statement rather than an evidence-based document 40. ISPAD has also produced some guidelines 45. These guidelines assume that episodes of activity are planned and that the level of physical activity can be reasonably well predicted. This may be possible in young people and adults but becomes more problematic when considering young children and toddlers. As mentioned earlier young children are less likely to have planned episodes of physical activity or exercise and data suggest that they are more likely to have multiple short bouts of potentially intense activity 46. Planning for this kind of physical activity is almost impossible to do with any degree of accu- racy. If parents are aware that their child may have opportunity for physical activity during the day at school they may plan to make reductions in insulin doses during the day or a range for extra snacks but the weather or whim of the child could turn these plans upside down. A few studies have examined the management of physical activity with particular emphasis on hypoglycemia avoidance. The DirecNet study group has studied a group of 49 children with type I diabetes aged 8–17 years of age 47. All children were on insulin pump therapy and were studied on 2 days during which time they had struc- tured exercise sessions. On one day basal insulin was stopped during exercise and on the second day basal insulin was continued. The standardized exercise sessions con- sisted of four 15-min treadmill cycles at a target heart rate of 140 beats per minute. The study found that hypoglycemia during exercise occurred less frequently when the basal insulin was discontinued p 0.003. Post-exercise hyperglycemia was more fre- quent when basal insulin had been discontinued 47. Another study of ten adoles- cents using a similar study design found no difference between having a pump off and the pump on during exercise 48. This study did find that delayed hypoglycemia was more common than hypoglycemia during exercise suggesting that even though it may be possible to avoid hypoglycemia during planned exercise delayed hypoglycemia which often occurs at night time is more problematic to avoid 48. In an attempt to avoid post-exercise nocturnal hypoglycemia Taplin et al. stud- ied 16 adolescents on insulin pump therapy using a 60-min exercise session followed

slide 105:

83 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 83 by an overnight reduction in basal rates by 20 for 6 h or oral terbutaline at a dose of 2.5 mg 49. Terbutaline did result in an avoidance of hypoglycemia overnight however there were significantly more episodes of hyperglycemia compared to basal rate reduction blood glucose greater than 13.8 mmol/l. Blood glucose pro- files were better overnight with a basal rate reduction but there was still more hyperglycemia than was clinically acceptable 49. There are pragmatic adjustments that have been suggested in terms of insulin dosing around the time of planned episodes of physical activity 50. If exercise is to be taken within 2 h of a mealtime bolus of rapid-acting insulin the dose needs to be reduced to avoid exercise-induced hypoglycemia. If the exercise is of moderate to high intensity a premeal reduction of 50 is recommended. If exercise is to be taken greater than 2 h after a mealtime bolus there does not need to be a reduction in insulin dose. If the exercise is anaerobic or in hot conditions or at a time of com- petition stress then an increase in insulin dose may be needed. Those patients on insulin pump therapy will be able to make reductions in their basal rates both during and after physical activity. It is likely that different types of physical activity as well as different intensities of activity are likely to need varying adjustments to basal rates at these times. It would be very useful for children young people and their parents to do much more rigorous monitoring of physical activity nutrition and blood glucose levels around the time of physical activity. It may then be possible for the diabetes team to work closely with families to develop plans for diabetes man- agement that are personalized. 4.9 Nutrition and Exercise Nutrition advice is another strategy that can be used to achieve glycemic control during exercise. Nutritional aspects of glycemic control and prevention of long- term complications are summarized in the 2009 International Society for Pediatric and Adolescent Diabetes ISPAD consensus guidelines 51. Where nutrition is used to manage blood glucose levels it should not compromise the diets of young people with diabetes. Information about what young people with type 1 diabetes eat demonstrates that often they fail to achieve the recommendations made for health 52 53. Management of exercise and physical activity needs to balance health benefits with hypoglycemia risk. 4.10 Unplanned or Spontaneous Physical Activity Nutrition advice for unplanned and spontaneous physical activity usually focuses on hypoglycemia prevention. Where exercise is unplanned the usual nutritional advice is to consume additional carbohydrate to prevent hypoglycemia. This carbo- hydrate should not contribute to an increased intake of saturated fats or disrupt

slide 106:

84 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 84 Table 4.1 Estimated average energy requirements for children 7–18 years in the UK Sex and age years Boys Estimated average requirement for energy a kcal/day 7–10 1970 11–14 2220 15–18 2750 Girls 7–10 1740 11–14 1845 15–18 2110 a Values taken from UK dietary reference values 1991 62 energy balance and encourage weight gain. Children and families will benefit from guidance on the suitable carbohydrate-containing foods to use in these situations. 4.11 Management of Regular Physical Activity and Exercise Regular and planned activities such as games lessons in schools attendance at sports clubs and activity trips require nutrition advice appropriate to the level of participation in the sport/activity. Advice for individual children needs to consider energy balance glycemic control and insulin adjustment strategies. Nutritional advice for hypoglyce- mia prevention should not increase overall energy intake and contribute to weight gain. Individual advice plans will depend on insulin treatment regimens. Conventional twice-daily biphasic insulin regimens provide fewer options for insulin adjustment to manage blood glucose levels during activity especially activities performed in the afternoon in schools/clubs. The use of intensive therapy increases the options avail- able insulin doses can be adjusted at meals before and after activity and back- ground/basal insulin adjustments can also be made. For many this may be a more appropriate strategy to prevent excess energy intake and weight gain. Children and young people with diabetes have the same energy requirements as their peers. Dietary reference values DRVs for populations usually summarize energy recommendations across population groups estimated average requirements EAR meet the needs of 50 of a population group. In the UK DRVs published by the Department of Health in 1991 give a summary of EAR for energy across age groups based on weight and average activity levels Table 4.1. By contrast the 2006 Australia and New Zealand nutrient reference values give estimated energy expenditure values based on average weight age and physical activity factors Table 4.2 and do not present this data averaged across age ranges. Advice to manage the hypoglycemia risks associated with exercise should not increase energy intake beyond expenditure and care is needed when interpreting energy require- ments from DRV to ensure that estimated average values apply to the individual. Energy expenditure and carbohydrate needs to prevent hypoglycemia will vary with age and weight. For most young people undertaking regular physical activity of moderate intensity lasting up to 60 min per day broad guidelines on exercise

slide 107:

85 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 85 Table 4.2 Calculated energy requirement for age and physical Sex and age Calculated average energy requirements Light activity Moderate activity Vigorous activity activity level in Australia and NZ years Boys PAL 1.6 PAL 1.8 PAL 2.2 7 1670 1866 2272 11 2105 2368 2870 15 2679 3014 3684 Girls 7 1555 1746 2129 11 1913 2153 2631 15 2248 2535 3086 Values for energy requirements for light moderate and vigorous activity levels taken from nutrient reference values for Australia and New Zealand 61 Table 4.3 Summary of exercise management strategies for regular planned activity Management advice Exercise within peak insulin action Anaerobic activities e.g. basketball athletic field events sprint events Consider decreasing pre-exercise insulin food bolus by up to 50 If exercise is aerobic or duration greater than 45 min consume carbohydrate 1 g/kg/h at 20-min intervals to maintain blood glucose levels Check blood glucose levels before during and after activity. If blood glucose is below 4 mmol/l delay exercise until blood glucose level is normal If blood glucose level is 10 mmol/l delay carbohydrate intake until 20 min into activity If blood glucose level is 15 mmol/l check for ketones and manage high blood glucose levels before exercise commences Consume adequate fluids Check blood glucose levels to assess responses to exercise If activity last longer than 45 min consume carbohydrate during exercise for fuel Consume meal or snack within 1 h of finishing exercise to reduce risk of post-exercise hypoglycemia Aerobic activities Consume additional carbohydrate and/or adjust insulin when exercise lasts 45 min or longer Team sports Monitor blood glucose levels during and after activity If within peak action of insulin consider reducing insulin doses Consume snack and fluid at half time if competition stress increases blood glucose levels consider small corrective dose of insulin Post-exercise Consume carbohydrate snack or meal with fluids after exercise If blood glucose levels raised post-exercise treat with caution Consume pre-bed snack whenever exercise duration is 60 min or longer management can be used and adapted according to blood glucose responses. These broad guidelines should cover blood glucose level type and duration of activity timing of activity appropriate amounts and type of carbohydrate needed and post- exercise hypoglycemia prevention 45. Key characteristics of advice for regular activity are summarized in Table 4.3.

slide 108:

86 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 86 If more detailed advice about nutrition and sport is needed then the information and guidance for training and competition nutrition can be adapted to meet the needs of the individual based on estimation of energy and carbohydrate needs. 4.12 Management of Training/Competitive Sports Young athletes require adequate nutrition to grow to develop and to fuel perfor- mance 54 55. A healthy diet is an essential part of training for sports performance. As with diabetes most recommendations are extrapolated from adult guidelines. Nutritional considerations for young athletes include growth and development as well as health and performance. Meyer in 2007 56 and Jeukendrup and Cronin in 2011 57 summarize an appropriate nutritional intake as one that will support train- ing and recovery as well as limiting problems that may occur due to nutritional deficiency and injury. While diabetes disrupts glucose homeostasis it does not alter the nutritional requirements associated with sport. Managing diabetes and achiev- ing an appropriate nutritional intake can present the athlete family and health-care professionals with a number of challenges. This section will discuss how best to advise young athletes to maximize performance ability through good nutrition. Education and counseling of young athletes with type 1 diabetes needs to consider all the factors that influence food choice and the impact of diabetes management. Neumark-Sztainer et al. summarize the influencing factors as hunger food cravings appeal of food time considerations convenience food availability peer influence parental influence health beliefs mood body image habit cost and media 58. 4.12.1 Practice Tips • In clinical practice a diet history is the usual method of assessing dietary intake food intake checklists and 24-h recalls of food intake are useful tools in young athletes. • Asking young athletes about goals for their sport helps to provide effective behavioral strategies for each individual. 4.13 Energy Balance Energy requirements vary with age growth and activity levels. Achieving an appropri- ate energy intake is of paramount importance to ensure that the demands of training do not have a negative impact on growth and maturation. In the general population energy requirements based on age and average activity levels and weight are available through dietary reference values. Energy requirements given in dietary reference tables are unlikely to meet the needs of young athletes undertaking regular training and daily energy needs will be influenced by the volume of training being undertaken.

slide 109:

87 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 87 4.14 Assessment of Energy Requirements Energy requirements can be calculated using predictive equations and energy costs of particular exercise types. Predictive formulas include Schofield’s age- mass- and gen- der-specific equation Harrell’s age- gender- and pubertal-specific equation and WHO/FAO/UNU equation 59. Within pediatric population subgroups each predic- tive equation has varying agreement with calorimetry dependent on the population characteristics. A comparison by Rodriguez et al. in 2000 recommends the use of Schofield’s height and weight equation for estimation of resting energy expenditure REE 60. The Schofield height and weight equation is used in the Australian dietary reference values whereas UK DRVs use the WHO/FAO/UNU equation 61 62. Once REE is calculated information about the energy costs of exercise or activ- ity is required to estimate total daily energy expenditure TEE. Estimation of TEE can be made using either physical activity factors to estimate daily energy require- ments or use of activity diaries to calculate the energy expenditure associated with sports. Data on the energy costs of activity in young athletes are limited use of adapted tables of metabolic equivalents METs allows some attempt to quantify energy costs of exercise 63. Use of adult physical activity data to estimate energy costs of exercise may underestimate the actual energy requirements due to the decrease in energy cost per unit of body weight with age. Recent work to develop a compendium of energy expenditures in youth has been published by Ridley et al. 64 65. The MET data from these compendium tables can be used to assess energy expenditure during exercise see Box 1. Anthropometric assessment including monitoring of height and weight on centile charts skinfold and circumferences should be used to assess body composition and growth. In practice assessment of energy requirements is a key first step in providing sports nutrition advice as the recommendations for protein carbohydrate and fat intake are all based on the energy needs of the athlete. 4.14.1 Practice Tips • A detailed history of activity and training is needed to calculate energy requirements. Box 1: Example Use of MET Data to Calculate Energy Expenditure Example A boy who weighs 45 kg and is 150 cm tall doing 60 min basketball has a REE of 1452 kcal/24 h using Schofield HW equation. Energy expenditure per min 1.0 kcal/min Basketball light effort has a MET of 7.2 Energy expenditure for 60 min basketball 1.0 × 7.2 × 60 435 kcal/h

slide 110:

88 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 88 • Activity diaries can be used but may not be completed accurately adequate time is needed in the consultation to take a detailed activity history. • Energy requirements should be calculated for each individual. 4.15 Carbohydrate Energy metabolism in young athletes differs through the ages and stages of develop- ment younger prepubertal athletes generally have a greater dependence on fat rather than carbohydrate as fuel source compared to postpubertal and adult athletes. However despite these differences in energy metabolism carbohydrate remains the main dietary fuel source for young people. Carbohydrate intake in adults has been well studied and the benefits of ingestion of carbohydrate pre- and post-exercise are well documented 66. 4.15.1 Type of Exercise Adult recommendations consider the carbohydrate needs of athletes according to the type of sport being undertaken. Detailed information about the carbohydrate needs of endurance versus strength/power sports is available. There is little informa- tion available about specific sports types and the younger competitor. For all sports types the key consideration is achieving the appropriate intake for growth and mat- uration. The type of exercise will impact on blood glucose responses as strength and power sports are predominantly anaerobic and therefore likely to raise blood glu- cose levels. Appropriate adjustments in insulin should be made to achieve blood glucose targets rather than adjustments in food intake which may be detrimental to overall energy balance. 4.15.2 Timing of Carbohydrate Ingestion with Exercise Studies on the ingestion of carbohydrate before and during exercise in children have shown equivocal results. In adults it is accepted practice that carbohydrate should be consumed 1–3 h prior to exercise bouts during exercise bouts of greater than 60–90 min duration and within 1–2 h of completing exercise to maximize muscle recovery. Despite the limited body of available evidence about performance benefits of carbohydrate ingestion for younger athletes it is appropriate to recommend that carbohydrate is ingested before and after exercise and for the young athlete with diabetes carbohydrate should be consumed during any exercise where the duration of the activity is 60 min or longer.

slide 111:

4 Physical Activity in Childhood Diabetes 89 89 K.A. Matyka and S.F. Annan 4.15.3 Pre-exercise Meal/Snack Suggestions Fruit and low fat milk or yogurt Sandwich with low fat filling Low fat cereal bars Jacket potato with filling Breakfast cereals with low fat milk Pasta with tomato based sauce Dried fruit Breakfast cereal with milk and fruit Homemade cakes/muffins/scones Soup and bread 4.15.4 Amount of Carbohydrate Reviews looking at the carbohydrate requirements in younger athletes conclude that intakes should be in the order of 50–60 of energy intake. The age-related differ- ences in glycolytic capacity which appear to relate to stage of development rather than chronological age mean that it is difficult to set age-specific requirements. Work by Riddell and colleagues has shown that carbohydrate utilization during exercise shows age- and sex-related differences 67–70. Consideration of carbohy- drate intake in young athletes with type 1 diabetes needs to account for both perfor- mance and hypoglycemia prevention particularly during endurance sports. In a review of physical activity and pediatric diabetes Riddell and Iscoe 50 suggest that carbohydrate requirements for youth with diabetes are of the magnitude of 1.0–1.5 g/kg body weight/h of exercise during peak insulin action. The amount of carbohydrate required to maintain blood glucose levels will fall with diminishing insulin levels. An alternative method of estimating carbohydrate requirement is the amount which supports the energy cost of the activity. If the energy cost of the exer- cise is known using the assumption that 60 of total energy is provided by carbo- hydrate allows the calculation of carbohydrate requirements. Example: Energy expenditure of 435 kcal/h for a 45-kg boy doing basketball would equate to 65-g carbohydrate per hour of basketball. When exercise is performed during peak insulin action reductions in insulin can be used as an alternative to consuming additional carbohydrate. This strategy should be used within a management plan that ensures total daily energy intake is adequate for the volume of training being undertaken. For anaerobic sports adjustment in insulin doses may be needed to maintain blood glucose levels and enable appropriate amounts of carbohydrate to be con- sumed for fuel. 4.15.5 Type of Carbohydrate Nutritional recommendations for diabetes promote healthy low-fat low glycemic index GI carbohydrate choices. The glycemic index describes the rate at which a carbohydrate food produces glucose in the blood. At present there is no evidence to support advising particular carbohydrate types during exercise in children and

slide 112:

4 Physical Activity in Childhood Diabetes 90 90 K.A. Matyka and S.F. Annan adolescents. Diets should be based on the same healthy carbohydrate choices recommended in diabetes management. However where higher carbohydrate requirements are difficult to achieve the addition of high GI carbohydrate foods may make the diet more palatable. The use of medium to high GI carbohydrate foods in the recovery period may be of particular importance in achieving recom- mended amounts of carbohydrate immediately post-exercise. 4.15.6 Practical Carbohydrate Management • Young athletes should be advised to consume a diet that provides 50–60 of their total energy requirements as carbohydrate. Carbohydrate sources should be spread across the day to ensure that there are opportunities to maximize both muscle and liver glycogen both before and after exercise. For exercise performed during peak insulin activity 1–1.5 g carbohydrate/kg/h of activity is recommended. • The amount of carbohydrate intake during exercise will depend on the duration and type of exercise to be performed and the timing of the exercise in relation to the peak action of the insulin. • For all exercise it is recommended that the energy cost of the activity is used to guide carbohydrate requirements during exercise. • Carbohydrate needs during exercise will change and should be reviewed on a regular basis. • Carbohydrate advice should include guidance on the amount and type of carbo- hydrate to be consumed before and after exercise to maximize muscle glycogen stores. • Insulin management needs to be adjusted according to food intake and blood glucose responses. • Carbohydrate consumed during exercise should be distributed throughout the activity wherever possible consuming carbohydrate every 10–20 min through- out exercise rather than all at the beginning of a training bout. 4.16 Protein Children and adolescents have higher protein requirements than adults to support growth. Protein requirements in athletes will be higher than their peers. Protein recommendations in diabetes management decrease to 0.8–1 g protein/kg body weight in later adolescence. This level of protein intake will not be high enough for competitive athletes. However protein intakes are often higher than the recom- mended intakes given in national Recommended Daily Allowances RDAs. Aiming for a protein intake of 10–15 of total energy requirements will usually meet pro- tein needs associated with training and development 71. Protein requirements in

slide 113:

4 Physical Activity in Childhood Diabetes 91 91 K.A. Matyka and S.F. Annan adult athletes vary with type of sport with endurance athletes having lower protein requirements than strength/power athletes 72. The range of protein requirements in adults is 1.2–1.7 g/kg/day 66. Adolescent athletes are unlikely to need more than 2 g protein/kg/day 73. Provided a varied diet is consumed protein intakes will be adequate but additional advice may be needed for vegetarian athletes and those with poor dietary choices 74. Consuming protein mixed with carbohydrate recovery snacks post-exercise may be beneficial in the prevention of late-onset hypoglycemia. Recovery snack ideas include fruit smoothie low-fat milk shake yogurt drinks mini pancakes fruit and yogurt. 4.16.1 Practice Tips • Most young athletes will achieve adequate protein intakes if they consume 10–15 of total energy as protein. • Vegetarian athletes may need additional advice about quality of protein intake. • The addition of low-fat dairy products to the post-exercise recovery meal/snack will provide a mix of protein and carbohydrate that may be beneficial in prevent- ing late-onset hypoglycemia. 4.17 Fat To Cure Diabetes Naturally Click Here There is no difference in recommendations for fat intake from those made for the general population. While younger athletes may use fat in preference to carbohy- drate as a fuel source during exercise they do not need to consume fat as a fuel source. Fat should provide no more than 30 of dietary energy and with no more than 10 from saturated fat. Food choices should be as low fat as possible in most situations. Careful advice about snack choices used to increase carbohydrate intake will prevent increases in saturated fat intake. 4.18 Fluid Hydration and Thermoregulation Excess heat produced during exercise is lost through evaporation of sweat and con- vection of heat from the surface of the skin. The ability to perform exercise is affected by hydration status. Dehydration of 1–2 in adults has been demonstrated to compromise function and performance. Studies comparing adults and children have shown similar effects of dehydration on performance. Exertional heat illness e.g. cramps exhaustion and heat stroke will occur with losses of 3 body weight.

slide 114:

4 Physical Activity in Childhood Diabetes 92 92 K.A. Matyka and S.F. Annan Dehydration can be elicited during exercise due to the environment prior state of hydration and duration of exercise. Thirst is recognized as a poor indicator of

slide 115:

4 Physical Activity in Childhood Diabetes 93 93 K.A. Matyka and S.F. Annan hydration and fluid needs so young athletes need guidance and drinking plans to achieve adequate fluid intakes. Clear guidelines exist for adults about voluntary fluid intake during activity a review by Rowland has suggested that fluid requirements in child athletes aged 8–13 years are 13 ml/kg/h of exercise and 4 ml/kg in the post-exercise recovery period 75. The American Academy of Pediatrics 76 also provides guidance on fluid and climatic heat stress in child and adolescent athletes. This statement pro- vides additional advice about exercise in conditions that increase heat stress i.e. high temperatures and humidity. Recommendations include reduction in intensity in exercise when relative humidity and air temperature are above critical levels. Heat stress in the young athlete with diabetes may exacerbate hyperglycemia particularly during competition anaerobic activity and when hyperglycemia exists due to lack of insulin. Fluid advice needs to be practical and achieve an appropriate daily fluid intake. Fluid requirements can be assessed by pre- and post-exercise weights. If weight is lost through an exercise bout this is due to inadequate fluid intake during exercise. As a general guide weight loss × 1.5 will replace fluid losses e.g. 500 g of weight loss requires at least 750 ml of additional fluid. Regular monitoring of weight changes during training in different climatic conditions will provide infor- mation about individual sweat losses and fluid needs. 4.19 Practical Fluid Management • Before exercise sufficient fluid should be consumed through the day to ensure adequate levels of hydration. A drink should be consumed with each meal and snack. Drinking plans should encourage intake of around 500 ml of fluid 1–2 h before activity. Drinking additional fluid 15 min before exercise will help to ensure adequate hydration at the start of training/competition. Sipping 150– 200 ml fluid is advised. Water is the most appropriate drink choice before exer- cise. Beverages with high concentrations of sugar empty slowly from the stomach and for this reason glucose/energy drinks are not recommended as pre-exercise beverages. • During exercise fluid should be consumed every 15–20 min for exercise that lasts 60 min or longer or is of high intensity a sports drink is recommended. This may also help prevent problems with low blood glucose levels. Commercial sports drinks also provide sodium and electrolytes. These encourage drinking as they improve taste. Water is an appropriate fluid choice for exercise lasting less than 60 min however flavoring the water with sugar squashes may improve intake due to the improved taste. • Post-exercise fluid is needed as part of the muscle recovery process. Ideally a drink should be consumed within 15 min of completing a bout of exercise. This can be a carbohydrate-containing fluid. Young athletes should be encouraged to drink as much as possible after exercise. Consuming food and fluid post-exercise helps rehydration as well reducing post-exercise hypoglycemia risks.

slide 116:

4 Physical Activity in Childhood Diabetes 94 94 K.A. Matyka and S.F. Annan 4.20 Vitamins and Minerals To Stop Diabetes In Few Days Click Here Vitamins and minerals have key roles in metabolism for athletes these roles include immune function antioxidant supply and energy metabolism. If food intakes meet energy requirements from a varied balanced diet then it is likely that vitamin and mineral intakes will be adequate. RDAs can be used to assess adequacy of vitamin and mineral intakes however it is not known if these are appropriate for higher activity levels. In the general population calcium and iron intakes are often below recommended levels. Calcium requirements are greater during childhood and ado- lescence. Restriction of dairy products can occur particularly as a method of reduc- ing fat and calorie intake. Iron intakes are also affected by energy restriction as well as increased losses associated with endurance and high-intensity training. Female athletes are at particular risk of iron depletion/deficiency due the combined effects of higher requirements due to growth and menstrual losses. Iron depletion in young athletes is common. Particular attention to vitamin and mineral intakes will be needed for sports where a lower energy intake is required to maintain lower body weights e.g. gymnastics and dance wrestling and boxing. 4.20.1 Practice Tips • Nutrition advice should include assessment and monitoring of vitamin and min- eral intakes. • Use of low-fat dairy products as recovery foods will help ensure adequate cal- cium intakes. • Achieving the recommended “5 a day” will help to ensure adequate vitamin intakes. 4.21 Supplements and Ergogenic Aids Adolescent athletes are likely to use supplements. This supplement use ranges from multivitamin and mineral supplements to products marketed to improve perfor- mance. Supplement use in a group of junior athletes at World Junior Championships was as high as 62. Popular supplements include whey protein and creatine as well as caffeine. Most sporting authorities recommend that these supplements are not used in athletes aged under 18 years. Athletes with diabetes need the same guidance as their peers about supplement use including counseling about the risk of contami- nation and lack of evidence for performance benefits. Additional counseling should be provided about antidoping and insulin use. In some sports Therapeutic Use

slide 117:

4 Physical Activity in Childhood Diabetes 95 95 K.A. Matyka and S.F. Annan Exemption is required under the age of 18 years. Advice should be sort from indi- vidual sporting bodies.

slide 118:

4 Physical Activity in Childhood Diabetes 96 96 K.A. Matyka and S.F. Annan 4.22 Sport-Specific Considerations 4.22.1 Endurance Sports Training programs for endurance sports generally increase energy and macronutri- ent requirements significantly. Iron and calcium intakes may be of particular concern in younger endurance athletes. Requirements for energy protein carbohy- drate iron and calcium should be reviewed regularly. 4.22.2 Power/Strength Sports Strength and power sports are predominantly anaerobic activities and therefore gly- colytic in nature which can present very specific challenges for the young athlete with diabetes. The expected blood glucose response to this type of activity is increasing blood glucose profile during the sport. Achieving an adequate energy intake during the training or competition necessitates counseling about appropriate insulin adjust- ment strategies to maintain blood glucose levels. This may include advice to increase insulin delivery to allow fuel utilization. Anaerobic exercise usually depletes glyco- gen stores so can have profound effects on blood glucose levels 1–2 h post-exercise. Using recovery snacks in the immediate post-exercise period can prevent this. Many of these sports will have weight categories and young athletes may use inappropriate strategies including fluid calorie and carbohydrate restriction to achieve target weights. These athletes are likely to benefit from the support of a sports dietitian to allow them to achieve weight targets with an appropriate nutri- tional intake. 4.22.3 Team Sports Team sports are often characterized by intermittent high-intensity exercise which moderates blood glucose effects. Nutritional needs include adequate fluid replace- ment as well as sufficient energy intake to promote muscle recovery and mainte- nance of lean body mass. 4.22.4 Competition and Travel All athletes need advice and support about what to eat and drink during competition particularly when travel is involved. The need to adjust insulin monitor blood glucose levels and achieve an appropriate nutritional intake needs planning. It is likely due to

slide 119:

4 Physical Activity in Childhood Diabetes 97 97 K.A. Matyka and S.F. Annan the hormonal responses to competition stress that additional insulin or adjustments in timing of insulin delivery will be needed. High blood glucose levels will impair per- formance ability. To ensure adequate fuel supply to exercising muscles meals snacks and insulin need to be timed to achieve target blood glucose levels during events. When competition involves travel to different venues availability of suitable food choices may be an issue. Fussy eating will compromise both nutritional intake and blood glucose management if food refusal results in inadequate intake. It may be nec- essary to provide additional support and plan with team managers who have a pastoral role about how they will ensure the athlete with diabetes consumes an adequate amount of food and fluid. The principles of management of food fluid and travel include ensuring adequate fluid is consumed during travel researching food availabil- ity at the destination and taking supplies to ensure that energy and carbohydrate needs are met as well as the usual considerations for travel and type 1 diabetes. 4.22.5 Practical Tips for Travel and Competition • Stick to familiar foods and drinks find out what food will be available and pack suitable kit bag snacks to maintain energy and carbohydrate intake. • Have small regular snacks during tournaments and matches where possible con- sume carbohydrate and fluid at half time check blood glucose levels and adjust insulin according to responses to exercise and competition. 4.23 Summary Nutrition is a key component of the management of diabetes and sports perfor- mance. For all young people advice based on healthy food choices with appropriate use of carbohydrate to prevent exercise-induced hypoglycemia is needed. Individual energy requirements will dictate food and fluid needs and wherever possible indi- vidual management strategies should be devised based on nutritional requirements type of sport and blood glucose responses. 4.24 Conclusion In recent years there has been an increasing focus on rigorous diabetes manage- ment with the use of intensive diabetes regimens and nutritional interventions. Physical activity is important for both physical and mental health and should be recommended for all children and young people with type 1 diabetes. However much more work needs to be done if we are going to be able to support our young patients in being active without the added risks of marked glycemic variability or increased treatment burden.

slide 120:

96 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 96 References 1. Armstrong N van Mechelen W. Paediatric exercise science and medicine. Oxford: Oxford University Press 2008. 2. Mulvihill C Rivers K Aggleton P. Physical activity ‘at our time’: qualitative research among young people aged 5 to 15 years and parents. Health Education Authority 2000. ISBN 0 7521 1748 3. 3. Williams HG Pfeiffer KA O’Neill JR Dowda M McIver KL Brown WH Patel R. Motor skill performance and physical activity in preschool children. Obesity. 200816:1421–6. 4. McKenzie TL Sallis JF Nader PR Broyles SL Nelson JA. Anglo- and Mexican-American preschoolers at home and at recess: activity patterns and environmental influences. J Dev Behav Pediatr. 199213:173–80. 5. Health Survey for England 2002. Joint Health Surveys Unit: National Centre for Social Research Department of Epidemiology and Public Health at the Royal Free and University College Medical School. In: Sproston K Primatesta P editors. http://www.archive2.official- documents.co.uk/document/deps/doh/survey02/hcyp/hcyp01.htm 6. Cockburn C Clarke G. “Everybody’s looking at you”: girls negotiating the ‘femininity defi- cit’ they incur in physical education. Women’s Studies Int Forum. 200225:651–65. 7. Bunt JC Salbe AD Harper IT Hanson RL Tataranni PA. Weight adiposity and physical activity as determinants of an insulin sensitivity index in Pima Indian children. Diabetes Care. 200326:2524–30. 8. Adamo KB Prince SA Tricco AC Connor-Gorber S Tremblay M. A comparison of indirect versus direct measures for assessing physical activity in the pediatric population: a systematic review. Int J Pediatr Obes. 20094:2–27. 9. Reilly JJ Penpraze IV Hislop I Davies G Grant S Paton JY . Objective measurement of physi- cal activity and sedentary behaviour: review with new data. Arch Dis Child. 200893:614–9. 10. Baranowski T Dworkin R Cieslik CJ et al. Reliability and validity of self-report of aerobic activity: Family Health Project. Res Q Exerc Sport. 198455:308–17. 11. Sallis JF. Self-report measures of children’s physical activity. J Sch Health. 199161:215–9. 12. Brage S Brage N Franks PW Ekelund U Wareham NJ. Reliability and validity of the com- bined heart rate and movement sensor Actiheart. Eur J Clin Nutr. 200559:561–70. 13. Brage S Brage N Franks P Ekelund U Wong M Andersen L Froberg K Wareham N. Branched equation modelling of simultaneous accelerometry and heart rate monitoring improves estimate of directly measured physical activity energy expenditure. J Appl Physiol. 200496:343–51. 14. WHO. Global recommendations on physical activity for health. WHO Press Geneva Switzerland. 2010. 15. Lobelo F Liese AD Liu J Mayer-Davis EJ D’Agostino Jr RB Pate RR Hamman RF Dabelea D. Physical activity and electronic media use in the SEARCH for diabetes in youth case-con- trol study. Pediatrics. 2010125:e1364–71. 16. Benevento D Bizzarri C Pitocco D Crino A Moretti C Spera S Tubili C Costanza F Maurizi A Cipolloni L Cappa M Pozzilli P IMDIAB Group. Computer use free time activi- ties and metabolic control in patients with type 1 diabetes. Diabetes Res Clin Pract. 201088:e32–4. 17. Overby NC Margeirsdottir HD Brunborg C Anderssen SA Andersen LF Dahl-Jorgensen K Norwegian Study Group for Childhood Diabetes. Physical activity and overweight in children and adolescents using intensified insulin treatment. Pediatr Diabetes. 200910:135–41. 18. Massin MM Lebrethon MC Rocour D Gerard P Bourguignon JP. Patterns of physical activ- ity determined by heart rate monitoring among diabetic children. Arch Dis Child. 200590:1223–6. 19. Sarnblad S Ekelund U Aman J. Physical activity and energy intake in adolescent girls with Type 1 diabetes. Diabet Med. 200522:893–9.

slide 121:

97 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 97 20. Ekeland E Heian F Hagen KB Abbott J. Nordheim L. Exercise to improve self esteem in children and young people. Cochrane Database Syst Rev. 2004. 21. Hood KK Huestis S Maher A Butler D V olkening L Laffel LMB. Depressive symptoms in children and adolescents with type 1 diabetes: association with diabetes-specific characteris- tics. Diabetes Care. 200629:1389–91. 22. Edmunds S Roche D Stratton G Wallymahmed K Glenn SM. Physical activity and psycho- logical well-being in children with Type 1 diabetes. Psychol Health Med. 200712:353–63. 23. Bowes S Lowes L Warner J Gregory JW. Chronic sorrow in parents of children with Type 1 diabetes. J Adv Nurs. 200965:992–1000. 24. Mackey ER Streisand R. Brief report: the relationship of parental support and conflict to physical activity in preadolescents with type 1 diabetes. J Pediatr Psychol. 200833: 1137–41. 25. Fereday J MacDougall C Spizzo M Darbyshire P Schiller W. “There’s nothing I can’t do–I just put my mind to anything and I can do it”: a qualitative analysis of how children with chronic disease and their parents account for and manage physical activity. BMC Pediatr. 20099:1. 26. Aman J Skinner TC de Beaufort CE Swift PG Aanstoot HJ Cameron F Hvidoere Study Group on Childhood Diabetes. Associations between physical activity sedentary behavior and glycemic control in a large cohort of adolescents with type 1 diabetes: the Hvidoere Study Group on Childhood Diabetes. Pediatr Diabetes. 200910:234–9. 27. Janssen I LeBlanc AG. Systematic review of the health benefits of physical activity and fitness in school aged children and youth. Int J Behav Nutr Phys Activity. 20107:40. 28. Grundy SM Benjamin IJ Burke GL Chait A Eckel RH Howard BV Mitch W Smith Jr SC Sowers JR. Diabetes and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation. 1999100:1134–46. 29. Tsuji H Venditti Jr FJ Manders ES Evans JC Larson MG Feldman CL Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham heart study. Circulation. 199490:878–83. 30. Dekker JM Crow RS Folsom AR Hannan PJ Liao D Swenne CA Schouten EG. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC study. Circulation. 2000102:1239–44. 31. Chen SR Lee YJ Chiu HW Jeng C. Impact of physical activity on heart rate variability in children with type 1 diabetes. Childs Nervous System. 200824:741–7. 32. Maggio AB Hofer MF Martin XE Marchand LM Beghetti M Farpour-Lambert NJ. Reduced physical activity level and cardiorespiratory fitness in children with chronic diseases. Eur J Pediatr. 2010169:1187–93. 33. Heyman E Delamarche P Berthon P Meeusen R Briard D Vincent S DeKerdanet M Delamarche A. Alteration in sympathoadrenergic activity at rest and during intense exercise despite normal aerobic fitness in late pubertal adolescent girls with type 1 diabetes. Diabetes Metab. 200733:422–9. 34. Komatsu WR Gabbay MAL Castro ML Saraiva GL Chacra AR De Barros Neto TL Dib SA. Aerobic exercise capacity in normal adolescents and those with type 1 diabetes mellitus. Pediatr Diabetes. 20056:145–9. 35. Herbst A Kordonouri O Schwab KO Schmidt F Holl RW. DPV Initiative of the German Working Group for Pediatric Diabetology Germany. Impact of physical activity on cardiovas- cular risk factors in children with type 1 diabetes: a multicenter study of 23251 patients. Diabetes Care. 200730:2098–100. 36. Trigona B Aggoun Y Maggio A Martin XE Marchand LM Beghetti M Farpour-Lambert NJ. Preclinical noninvasive markers of atherosclerosis in children and adolescents with type 1 diabetes are influenced by physical activity. J Pediatr. 2010157:533–9. 37. McMahon SK Ferreira LD Ratnam N Davey RJ Youngs LM Davis EA Fournier PA Jones TW. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metabol. 200792:963–8.

slide 122:

98 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 98 38. Temple MY Bar-Or O Riddell MC. The reliability and repeatability of the blood glucose response to prolonged exercise in adolescent boys with IDDM. Diabetes Care. 1995 18:326–32. 39. Tsalikian E Mauras N Beck RW Tamborlane WV Janz KF Chase HP Wysocki T Weinzimer SA Buckingham BA Kollman C Xing D Ruedy KJ Diabetes Research in Children Network Direcnet Study Group. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatrics. 2005147:528–34. 40. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care. 200023:s50–4. 41. Herbst A Bachran R Kapellen T Holl RW. Effects of regular physical activity on control of glycemia in pediatric patients with type 1 diabetes mellitus. Arch Pediatr Adolesc Med. 2006160:573–7. 42. Nansel TR Iannotti RJ Simons-Morton BG Plotnick LP Clark LM Zeitzoff L. Long-term maintenance of treatment outcomes: diabetes personal trainer intervention for youth with type 1 diabetes. Diabetes Care. 200932:807–9. 43. Roberts L Jones TW Fournier PA. Exercise training and glycemic control in adolescents with poorly controlled type 1 diabetes mellitus. J Pediatr Endocrinol. 200215:621–7. 44. Brazeau A Rabasa-Lhoret R Strychar I Mircescu H. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 200831:2108–9. 45. Robertson K Adolfsson P Scheiner G Hanas R Riddell MC. Exercise in children and adoles- cents with diabetes. Pediatr Diabetes. 200910:154–68. 46. Berman N Bailey R Barstow TJ Cooper DM. Spectral and bout detection analysis of physical activity patterns in healthy prepubertal boys and girls. Am J Hum Biol. 199810:289–97. 47. Tsalikian E Kollman C Tamborlane WB Beck RW Fiallo-Scharer R Fox L Janz KF Ruedy KJ Wilson D Xing D Weinzimer SA Diabetes Research in Children Network DirecNet Study Group. Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care. 200629:2200–4. 48. Admon G Weinstein Y Falk B Weintrob N Benzaquen H Ofan R Fayman G Zigel L Constantini N Phillip M. Exercise with and without an insulin pump among children and adolescents with type 1 diabetes mellitus. Pediatrics. 2005116:e348–55. 49. Taplin CE Cobry E Messer L McFann K Chase HP Fiallo-Scharer R. Preventing post- exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatrics. 2010157:784–8. 50. Riddell MC Iscoe KE. Physical activity sport and pediatric diabetes. Pediatr Diabetes. 20067:60–70. 51. Smart C Aslander-van Vliet E Waldron S. Nutritional management in children and adoles- cents with diabetes. Pediatric Diabetes. 200910 Suppl 12:100–17. 52. Rovner AJ Nansel TR. Are children with type 1 diabetes consuming a healthful diet: a review of the current evidence and strategies for dietary change. Diabetes Educ. 200935:97–107. 53. Mehta SN Haynie DL Higgins LA Bucey NN Rovner AJ V olkening LK et al. Emphasis on carbohydrates may negatively influence dietary patterns in youth with type 1 diabetes. Diabetes Care. 200932:2174–6. 54. Steen SN. Timely statement of The American Dietetic Association: nutrition guidance for adolescent. J Am Diet Assoc. 199696:611. 55. Steen SN. Timely statement of The American Dietetic Association: nutrition guidance for child athletes. J Am Diet Assoc. 199696:610. 56. Meyer F O’Connor H Shirreffs SM. Nutrition for the young athlete. J Sports Sci. 200725:73–82. 57. Jeukendrup A Cronin L. Nutrition and elite young athletes. Med Sports Sci. 201156:47–58. 58. Neumark-Sztainer D Story M. Factors influencing food choices of adolescents: findings from focus-group discussions. J Am Diet Assoc. 199999:929. 59. Schofield WN. Predicting basal metabolic rate new standards and review of previous work. Hum Nutr Clin Nutr. 198539 Suppl 1:5–41.

slide 123:

99 K.A. Matyka and S.F. Annan 4 Physical Activity in Childhood Diabetes 99 60. Rodríguez G Moreno LA Sarría A Fleta J Bueno M. Resting energy expenditure in children and adolescents: agreement between calorimetry and prediction equations. Clin Nutr. 200221:255–60. 61. National Health and Medical Research Council. Nutrient reference values for Australia and New Zealand. 2006. 62. Department of Health. Report on health and social subjects 41: dietary reference values for food energy and nutrients for the United Kingdom. London: HMSO 1991. 63. Ainsworth BE Haskell WL Whitt MC Irwin ML Swartz AM Strath SJ et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc. 200032:S498–504. 64. Ridley K Ainsworth BE Olds TS. Development of a compendium of energy expenditures for youth. Int J Behav Nutr Phys Act. 20085:1–8. 65. Ridley K Olds TS. Assigning energy costs to activities in children: a review and synthesis. Med Sci Sports Exerc. 200840:1439–46. 66. Position of the American Dietetic Association. Dietitians of Canada and the American College of Sports Medicine: nutrition and athletic performance. J Am Diet Assoc. 2009109:509–27. 67. Riddell MC. The endocrine response and substrate utilization during exercise in children and adolescents. J Appl Physiol. 2008105:725–33. 68. Timmons BW Bar-Or O Riddell MC. Energy substrate utilization during prolonged exercise with and without carbohydrate intake in preadolescent and adolescent girls. J Appl Physiol. 2007103:995–1000. 69. Timmons BW Bar-Or O Riddell MC. Influence of age and pubertal status on substrate utiliza- tion during exercise with and without carbohydrate intake in healthy boys. Appl Physiol Nutr Metab. 200732:416–25. 70. Timmons BW Bar-Or O Riddell MC. Oxidation rate of exogenous carbohydrate during exer- cise is higher in boys than in men. J Appl Physiol. 200394:278–84. 71. Phillips SM Moore DR Tang JE. A critical examination of dietary protein requirements ben- efits and excesses in athletes. Int J Sport Nutr Exerc Metab. 200717:S58–76. 72. Tipton KD Witard OC. Protein requirements and recommendations for athletes: relevance of ivory tower arguments for practical recommendations. Clin Sports Med. 200726:17–36. 73. Petrie HJ Stover EA Horswill CA. Nutritional concerns for the child and adolescent competi- tor. Nutrition. 200420:620–31. 74. Barr SI Rideout CA. Nutritional considerations for vegetarian athletes. Nutrition. 200420:696–703. 75. Rowland T. Fluid replacement requirements for child athletes. Sports Med. 201141:279–88. 76. American Academy of Pediatrics. Committee on Sports Medicine and Fitness. Climatic heat stress and the exercising child and adolescent. Pediatrics. 2000106:158–9.

slide 124:

Chapter 5 The Role of Newer Technologies CSII and CGM and Novel Strategies in the Management of Type 1 Diabetes for Sport and Exercise To Get Rid Of Diabetes Permanently Click Here Alistair N. Lumb 5.1 Introduction Long-acting insulin analogues insulin glargine Lantus sanofi-aventis insulin detemir Levemir Novo Nordisk are now used to provide basal insulin therapy for the majority of people using multiple daily injection MDI treatment regimens for type 1 diabetes. These insulins have provided significant benefit in terms of greater stability of circulating insulin levels 1 2 which in turn has led to more stable blood glucose levels and a reduction in rates of hypoglycemia particularly noctur- nal hypoglycemia 3 4. However as has been explained elsewhere in this volume circulating insulin levels can vary considerably during sport and exercise in those without diabetes. An unfortunate consequence of stabilizing insulin levels in those with type 1 diabetes is therefore a significant risk of dysglycemia during exercise. For example during endurance exercise in those without diabetes such as pro- longed running or cycling insulin levels fall 5 to allow the mobilization of carbo- hydrate and lipid fuel sources 6 with insulin secretion falling to below fasting levels 7. These fuel sources provide the energy required by exercising muscle and allow blood glucose levels to be maintained within a tight range. In people with diabetes using MDI therapy insulin levels remain reasonably stable during exercise 5. This limits the body’s ability to mobilize the required fuel sources and therefore results in a significant risk of hypoglycemia. The somewhat inelegant solution to this problem is usually the ingestion of carbohydrate which can be problematic to maintain in some sports and also reduces the benefit of exercise if weight control is one of the intended outcomes. In spite of the option to ingest more carbohydrate it is well recognized that the major limiting factor preventing adults with type 1 diabetes from taking on a more

slide 125:

A.N. Lumb B.A. Ph.D. M.B.B.S. M.R.C.P. Diabetes Centre Wycombe Hospital Buckinghamshire Healthcare NHS Trust Queen Alexandra Road High Wycombe Buckinghamshire HP11 2TT UK e-mail: alilumbhotmail.com I. Gallen ed. Type 1 Diabetes DOI 10.1007/978-0-85729-754-9_5 © Springer-Verlag London Limited 2012 101

slide 126:

102 102 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 102 102 2 active lifestyle is the fear of hypoglycemia 8 and some experts suggest that this may also be the case for children 9. The aim of this chapter is to discuss how tech- nologies such as continuous subcutaneous insulin infusion CSII or “insulin pump” therapy and continuous glucose monitoring CGM can be used to help overcome the particular challenges presented by sport and exercise in the context of type 1 diabetes. Some novel strategies to avoid hypoglycemia will also be considered which at least offer an alternative to the requirement for carbohydrate ingestion. 5.2 Continuous Subcutaneous Insulin Infusion and Hypoglycemia During Exercise CSII has become an increasingly important option in the therapy of type 1 diabetes over recent years. Treatment involves the insertion of a temporary cannula into the subcutaneous tissue through which rapid-acting insulin is infused continuously using an electronically controlled pump. CSII therapy permits numerous bolus insu- lin doses to be given without the need for a physical injection each time and also means that background insulin levels can be adjusted much more easily than with MDI therapy as they are provided by a variable infusion of rapid-acting analogue insulin rather than a subcutaneous bolus of longer-acting insulin. This gives much greater flexibility in insulin delivery than MDI therapy. It is recognized in people without diabetes that aerobic exercise is associated with a fall in insulin concentrations 5. In view of this the strategies for adjustment of CSII therapy during exercise have focused on the reduction or cessation of insu- lin infusion during exercise based on the reasonable theory that this should approx- imate more closely to the physiological situation and therefore reduce rates of hypoglycemia. Early studies carried out in adults using CSII therapy in the 1980s and therefore in the era predating rapid-acting analogue insulins showed mixed results 10 11. As expected continuing basal insulin infusion at the usual rate was demonstrated to result in hypoglycemia. A 50 reduction in the prandial insulin bolus with a meal taken 90 min prior to exercise was shown to reduce rates of hypo- glycemia and a reduction in insulin basal rate between 50 and 100 was also shown to be beneficial in reducing rates of hypoglycemia 11. In contrast cessation of basal infusion 30 min prior to 45 min of exercise at 60 VO max with basal infusion stopped for a total of 3 h and hence restarted at the usual rate 105 min following exercise resulted in the avoidance of hypoglycemia during postprandial exercise in the morning but not in the afternoon 10. Three out of seven participants performing postprandial exercise in the afternoon suffered hypoglycemia and comparison with previous results suggested little benefit of the strategy of cessation of basal insulin infusion over leaving the infusion running at the usual rate. Interestingly in the three participants who did suffer hypoglycemia insulin levels did not decline during exercise. This failure to achieve the expected reduction in circulating insulin by reducing infused insulin likely explains why the strategy failed to produce the anticipated results.

slide 127:

103 103 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 103 103 2 Avoiding hypoglycemia during exercise is a particular focus for children adoles- cents and their parents as children’s play tends to be very active. Strategies to allow children to play safely while avoiding significant hypoglycemia are clearly impor- tant for children to live as normally as possible with diabetes and therefore the majority of the more recent evidence regarding the management of CSII therapy for sport and exercise therefore comes from work with younger people with type 1 diabetes. Studies in children using CSII with analogue insulins have yielded clearer evi- dence of the benefits of reducing basal insulin infusion rate during exercise. One such study designed to simulate unplanned postprandial exercise in children and adolescents aged between 10 and 19 years compared the effect of reducing basal rate to 50 of normal during exercise with that of removing the insulin pump alto- gether for the exercise period 12. Exercise occurred on average just under 2 h following the most recent meal which was accompanied by the usual insulin bolus in order to simulate the unplanned exercise and consisted of 40–45 min exercise on a cycle ergometer at 60 VO max. Little difference was found in the physiological response to exercise between the two groups and two of ten participants suffered hypoglycemia defined as blood glucose 70 mg/dl equivalent to 3.9 mmol/l in each group. Interestingly the exercise sessions with a hypoglycemic event began at lower glucose levels and higher insulin levels for three subjects 10–50 higher than the other sessions performed by the same participants again suggesting that the problem for these individuals was a failure to achieve the intended reduction in circulating insulin by the reduction in insulin being infused. This is consistent with the notion that the strategy of reducing insulin delivery is the correct one but that if doing so does not result in a reduction in circulating insulin levels then problems with hypoglycemia may persist. It also demonstrates that insulin levels at the start of exercise are important and therefore reducing infused insulin some time before exercise may be more useful than making the reduction at the start of exercise. We shall return to this later. A study in children and adolescents aged between 8 and 17 investigated whether stopping basal insulin at the start of exercise could reduce the frequency of hypogly- cemia compared to when basal insulin infusion is continued at its usual rate 13. Exercise occurred approximately 4 h following the most recent meal and consisted of four sessions of 15 min walking on a treadmill to a target heart rate of 140 bpm with a 5-min rest between each session. The two conditions were presented in a crossover design. In the condition where the basal insulin infusion was suspended this was done at the start of exercise with the basal infusion restarted after 2 h and thus 45 min after the exercise period. Exercise started with blood glucose between 120 and 200 mg/dl 6.7 and 11.1 mmol/l. There was a significant reduction in the fall in blood glucose during exercise when basal insulin was suspended leading to a reduction in rates of hypoglycemia from 43 to 16. Only 9 of the children who suspended basal insulin and started exercise with a blood glucose 130 mg/dl 7.2 mmol/l suffered hypoglycemia. The beneficial effect of suspending basal insu- lin was consistent in subgroups based on HbA1c age gender and usual frequency of exercise. However a consequence of stopping basal insulin was a significant

slide 128:

104 104 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 104 104 increase in the rates of hyperglycemia. No abnormal ketone levels were recorded during the exercise period although it should be noted that ketone readings were not recorded in the 45 min after exercise finished. Taken together the results of these studies suggest how CSII therapy might be adjusted for exercise although the optimal strategy has not been identified and will likely vary from person to person. With CSII therapy using rapid-acting insulin ana- logues it has been demonstrated that a reduction in basal insulin infusion at the start of a relatively short period of moderate exercise will help avoid hypoglycemia both during the period of exercise and also immediately afterward. The optimal reduction is not clear but for most people basal insulin infusion should be reduced by some- where between 50 and 100 i.e. suspension of basal insulin. Whether there is a benefit of an earlier reduction in basal rate has not yet been investigated. The avail- able evidence suggests that circulating insulin levels at the start of exercise are impor- tant and the time-action profile of the available rapid-acting analogue insulins suggests that the earliest effect of a reduction in basal rate will occur at around 10–15 min 14 15. In order to reduce circulating insulin levels at the start of exer- cise therefore it might seem sensible to suggest that a reduction in basal infusion rate should be made some time prior to starting exercise. Unfortunately there is as yet no experimental evidence to support this view or guide when such a reduction should be made. An extension of this reasoning would be to consider whether basal rate should be increased again before exercise finishes as insulin levels in those without diabetes would increase at the end of exercise. Again while this strategy makes physiological sense and has been used with some success in individual ath- letes there are as yet no data to support whether this might be beneficial in general. As one might suspect suspending basal insulin at the start of exercise does increase the risk of hyperglycemia although it was not observed to increase the risk of ketosis during a short period of exercise and may therefore be the ideal option in groups e.g. very young children where significant hypoglycemia may have long- term consequences. It should be noted however that the avoidance of hypoglycemia may not be the only focus of attention for athletes of any age with type 1 diabetes. Many report that hyperglycemia has a deleterious effect on performance and there are also obvious implications for overall glycemic control. Furthermore it is impor- tant to note that while significant ketosis was not observed during 45 min of exercise following the suspension of basal insulin the theoretical risk of ketosis remains for longer suspension of basal infusion and this has also not been investigated in detail. 5.3 Continuous Glucose Monitoring and Exercise Continuous glucose monitoring CGM has been increasingly available since the late 1990s. This technology employs a sensor to measure glucose concentrations in the subcutaneous tissue using a glucose oxidase reaction or microdialysis method and circulating glucose is then estimated from this concentration using an algorithm and some assumptions about the equilibrium in glucose levels between the two

slide 129:

105 105 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 105 105 2 regions 6. Earlier systems recorded glucose data which could only be accessed once the sensor had been removed but “real-time” CGM systems have become available which allow users to access glucose readings and information about their rate and direction of change while the sensor is being worn. Many experts feel that CGM will prove to be a useful technology to help people with type 1 diabetes improve metabolic control around exercise – both through the ability to react to changes detected at the time of exercise and also through the provision of informa- tion which will allow individuals to plan more accurately how to adjust carbohy- drate intake and insulin doses for exercise in the future 6. The use of real-time continuous glucose monitoring systems in general has been shown to reduce hypoglycemia in well-controlled adults and children with type 1 diabetes while also allowing for an improvement in overall glycemic control 16 17. Data looking at the accuracy of CGM during exercise have been encouraging. CGM accurately determines interstitial glucose levels during 1 h of intensive cycling exer- cise spinning and also accurately reflects the direction of change of blood glucose levels 18. In a separate study the FreeStyle Navigator CGM system was found to accurately reflect the magnitude of the fall in blood glucose levels seen with moder- ate treadmill exercise in a group of children albeit with a 10-min delay 19. This delay however represents one of the major challenges with using CGM to prevent hypoglycemia during exercise. There is a recognized time lag between changes in blood glucose and changes in glucose levels in the interstitial compart- ment at rest 20 which is similar to the 10-min time lag reported above. As a result in both of the above studies the CGM was unable to keep up with the rapidly falling glucose levels seen during intense aerobic exercise and therefore tended to overes- timate the actual blood glucose reading when compared with capillary blood sam- ples 18 19. In one study designed to examine the factors affecting CGM system calibration CGM accurately detected only 65 of hypoglycemic events during exercise when three calibrations per day were used and only 69 when four calibra- tions per day were used 21. Strategies are now being developed to overcome this limitation. Using real-time CGM with an alarm people with uncomplicated type 1 diabetes and no evidence of hypoglycemia unawareness suffered significantly fewer episodes of hypoglycemia during exercise 30 min at 40 VO max when a low-glucose warning alarm was set to 5.5 mmol/l compared to when the alarm was set to 4 mmol/l or no alarm was used 22. The alarm was used to trigger carbohydrate intake to avoid incipient hypogly- cemia. Interestingly the CGM still overestimated capillary glucose by an average of 1.6 mmol/l meaning that even using the higher alarm threshold did not completely eliminate hypoglycemia. Based on their results the authors therefore recommend this strategy in situations where glucose levels can be expected to fall rapidly such as during moderate exercise similar to that used in their experimental protocol. An extension of this strategy has been piloted during a sports camp for adoles- cents with diabetes 9. Participants aged between 9 and 17 wore real-time CGM during a variety of different exercise situations. An algorithm was used in which carbohydrate intake was advised based both on real-time CGM readings and also the sensor’s indication of their rate of change. Blood glucose levels were maintained

slide 130:

106 106 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 106 106 within target to a great extent with a reduction in hypoglycemia compared to expected levels and no hyperglycemia. The authors recognize that this is a pilot study in which there was no control group and variables such as exercise intensity age and body weight were not taken into account. Also of concern was that no results were obtained from 6 of 25 participants recruited because of sensor data loss or the sensor falling out. However the algorithm was surprisingly successful in spite of these limitations and this certainly suggests a possible important future role for CGM in the management of diabetes in the context of sport and exercise. 5.4 CSII CGM and Nocturnal Hypoglycemia Nocturnal hypoglycemia following exercise is a well-recognized problem in type 1 diabetes and has been observed following both aerobic 23 24 and mixed forms 25 of exercise. The exact mechanism for this is not clear although it is certainly possible that the exercise-induced recruitment of GLUT-4 receptors to the surface of the muscle cell may be involved. Another contributing factor is likely to be that exercise blunts the counterregulatory response to subsequent hypoglycemia 26. One strategy which has been used to combat the risk of nocturnal hypoglycemia following exercise is to reduce basal insulin doses on the night after an exercise bout. This can be problematic when done in the context of an MDI regimen as it increases the risk of subsequent hyperglycemia. In those using CSII it would be reasonable to suspect that reducing basal insulin for some of the nights following exercise might be able to reduce the risk of noctur- nal hypoglycemia without significant hyperglycemia resulting. As with many other aspects of the management of CSII for exercise this hypothesis has been tested in children 27. Children and adolescents with type 1 diabetes treated with CSII underwent 4 × 15 min bursts of treadmill exercise at around 4 p.m. with 5-min rest periods in between. For the night after the exercise they either reduced their basal insulin by 20 from 9 p.m. to 3 a.m. took 2.5 mg orally of terbutaline a b-adreno- ceptor agonist or received no intervention. Both ingestion of terbutaline and reduc- tion in basal insulin infusion resulted in a reduction of nocturnal hypoglycemia but ingestion of terbutaline did result in an increase in morning hyperglycemia as had previously been found with adults 28. While further studies may permit a more appropriate dose of terbutaline to be selected in future being able to reduce noctur- nal basal insulin infusion for a limited period of time offers a means to reduce noc- turnal hypoglycemia without the need for additional pharmacological therapy. In those treated with CSII this represents a successful solution to the problem of noc- turnal hypoglycemia following exercise. As the authors themselves say “The flex- ibility to adjust basal rates by the hour remains one of the most attractive features of an insulin pump and is … particularly useful for the active person with T1DM.” An attractive strategy combining CSII and CGM may be of particular benefit in those experiencing nocturnal hypoglycemia following exercise. There is a commer- cially available insulin pump Paradigm ® Veo™ Medtronic Inc. Northridge CA

slide 131:

107 107 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 107 107 2 which can be set to cease insulin infusion for a period of 2 h in response to CGM glucose readings below a certain threshold referred to as the low-glucose suspend LGS function. In a six-center trial 31 adults with type 1 diabetes were studied dur- ing a period of standard CSII therapy compared with a 3-week period using CSII with LGS 29. In those with the highest frequency of nocturnal hypoglycemia there was a significant reduction in the duration of nocturnal hypoglycemia defined as CGM glucose 2.2 mmol/l or 40 mg/dl from 46.2 min/day for conventional CSII to 1.8 min/day for CSII with LGS. Clearly this strategy could be beneficial in avoiding hypoglycemia following exercise. Furthermore knowing that hypoglycemia can affect the counterregulatory hormone response to subsequent exercise and that this effect increases with increasing severity of hypoglycemia 30 it is possible that preventing nocturnal hypoglycemia in this way could also help prevent hypoglyce- mia and maintain performance during exercise the following day. 5.5 Novel Strategies for Preventing Hypoglycemia During Exercise The majority of strategies designed to reduce dysglycemia primarily hypoglyce- mia during exercise involve adjustments to carbohydrate intake or insulin dosing. More recently consideration has been given to trying to prevent exercise-induced hypoglycemia through augmentation of the counterregulatory response to exercise. One very inventive way is the use of a 10-s maximal effort sprint either before 31 or after 32 exercise. When such a sprint was performed at the beginning of a recovery period after 20 min of moderate exercise at 40 VO max there was no further fall in blood glucose levels whereas a further significant fall in glucose lev- els was seen in the control condition when no sprint was performed 32. Performing the sprint was associated with an increase in catecholamine cortisol growth hor- mone and lactate levels although it is not clear which of these were important for attenuating the fall in blood glucose. Interestingly performing a 10-s sprint prior to similar exercise did not attenuate the drop in blood glucose levels seen during the exercise but it did again attenuate the drop in blood glucose levels seen after exer- cise in the control group where no sprint was performed 31. This was in spite of a significant rise in circulating catecholamine and lactate levels immediately follow- ing the sprint. Both of these studies therefore demonstrate the benefit of the 10-s maximal sprint performed either before or after exercise in preventing a postexercise fall in blood glucose. This is particularly useful in that it provides a strategy which does not require preplanning and ingestion of significant amounts of carbohydrate. Interestingly it is also possible that the benefit of performing a 10-s sprint prior to exercise was underestimated. The augmented catecholamine response was not shown to affect the fall in blood glucose levels during exercise but this was with blood glucose levels well above hypoglycemia. Glucose fell on average by 3 mmol/l during the exercise period and given that exercise commenced at around

slide 132:

108 108 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 108 108 11 mmol/l this suggests a fall from 11 to 8 mmol/l. It has been demonstrated that carbohydrate oxidation is favored over fat oxidation as the source of energy for exercising muscle at a blood glucose level of 11 mmol/l when compared with 7 mmol/l 33 so participants in the trial would have been predisposed to preferential use of carbohydrate and hence a fall in blood glucose. This may have masked any benefit of the higher levels of catecholamines during the exer- cise period and may explain why the benefit was only seen when glucose levels fell into the normal range during the period of recovery. It would be useful to see whether the 10-s sprint might attenuate the fall in blood glucose during moderate exercise if blood glucose at the start of exercise was closer to the normal range. Caffeine is of benefit in hypoglycemia particularly nocturnal hypoglycemia in type 1 diabetes when the hypoglycemia is not specifically related to exercise 34 35. In particular caffeine enhances the counterregulatory hormone response to hypoglycemia as well as increases symptoms accompanying hypoglycemia which allow earlier treatment of hypoglycemia and therefore reduce the chance of neuro- glycopenia developing 36. With exercise we have found that caffeine in doses of 5 mg/kg taken 30 min prior to exercise reduces the need for carbohydrate treatment to prevent hypoglycemia during exercise in people with type 1 diabetes 37. This is a preliminary study but offers another strategy for the prevention of hypoglycemia during exercise in type 1 diabetes which does not require much planning and does not involve the ingestion of extra carbohydrate. 5.6 Practical Aspects of CSII and Exercise While CSII appears to provide an excellent solution to many of the problems posed by managing type 1 diabetes for sport and exercise there are important practical considerations which need to be taken into account. Insulin pump therapy is expen- sive to provide relative to MDI with a significant initial outlay for the pump and then ongoing costs for consumables. Improving athletic performance may not be seen as an appropriate justification for the extra cost although a reduction in hypo- glycemia and improvement in metabolic control could be. While the pumps are robust it may not be practical to wear them for some contact sports because of the risk of damage even if they are carried in a protective case. There are some reports that newer patch pumps can be placed in locations on the body where they are pro- tected from damage e.g. the inner thigh but these may not always be ideal loca- tions for insulin delivery. Participation in sport may also increase the risk of cannula displacement which carries the risk of ketoacidosis if not detected early enough. Not all pumps are adequately waterproof for swimming and increased exposure to treated swimming pool water or seawater may reduce the useful life of any water- proof seals. The risk to the pump can be reduced by keeping it in a waterproof container while in the water but this reduces access to the pump and may result in excessive bulkiness.

slide 133:

109 109 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 109 109 5.7 Summary and Practical Advice To Kill Diabetes Forever Click Here The importance of insulin in the regulation of fuel production during exercise means that there is a significant risk of dysglycemia during exercise in type 1 diabetes where insulin is exogenously administered. The flexibility in basal insulin infusion afforded by CSII is an attractive solution to the problem of hypoglycemia with aero- bic exercise in theory at least allowing the person with diabetes to approximate more closely the metabolic state during exercise which is seen in those without diabetes. In doing this it is hoped that performance will be optimized. It seems likely that insulin infusion rates should be reduced prior to exercise as circulating insulin levels at the start of exercise are a predictor of hypoglycemia during exercise. Exactly when such a reduction should be made is not clear. For practical purposes based on the pharmacokinetics of the rapid-acting analogue insulins used in CSII therapy the reduction should probably be made 30–45 min prior to the start of exercise. The exact amount by which basal infusion should be reduced is also not clear but based on available evidence it is likely to be some- where between 50 and 100 i.e. cessation of basal insulin infusion. It is not clear when a normal basal rate should be restarted but doing so at the end of exer- cise may reduce the risk of postexercise hyperglycemia although as detailed below later reductions may be required for the avoidance of nocturnal hypoglyce- mia. Complete removal of the insulin pump at the start of aerobic exercise is a strategy that will help avoid hypoglycemia but at the expense of hyperglycemia. It is possible that this will result in an impairment of athletic performance and therefore may be the best strategy for those in whom the avoidance of hypogly- cemia is the paramount consideration but not for those in whom performance is of greater importance. CGM can provide useful information regarding the direction of change of blood glucose levels during exercise although when using standard real-time CGM there is still a significant risk of hypoglycemia in aerobic exercise when blood glucose levels fall rapidly. Strategies are being developed to help mitigate this risk. Low- glucose thresholds need to be set significantly higher than the minimum glucose level hoped for with benefit seen for alarms used to trigger carbohydrate replace- ment and checking of capillary glucose when glucose falls to 5.5 mmol/l. An algo- rithm used to guide carbohydrate replacement taking into account both the level of interstitial glucose and its rate of change may point the way to how CGM technology could best be employed in the future to help avoid hypoglycemia during exercise. Nocturnal hypoglycemia following exercise is a well-recognized phenomenon in type 1 diabetes. Reducing the CSII basal rate by 20 between 9 p.m. and 3 a.m. has been shown to reduce the risk of this in children without increasing the risk of morn- ing hyperglycemia. This result may well transfer to adults although the timing of the reduction may need to be altered due to adults going to sleep later in the day. Low-glucose suspend insulin pumps have been shown to be useful in reducing noc- turnal hypoglycemia in those most at risk of this and this may also be a useful technique to avoid nocturnal hypoglycemia following exercise.

slide 134:

110 110 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 110 110 Augmenting the counterregulatory hormone response to exercise offers an alternative means of avoiding hypoglycemia which can help avoid the significant planning often required for the adjustment of insulin doses. It may also help avoid or at least reduce the need for extra carbohydrate supplementation which can be prob- lematic if one of the aims of exercise is weight control. A 10-s maximal effort sprint either immediately before or after exercise attenuates a postexercise fall in blood glucose. While it has not been shown to attenuate the fall in glucose during exercise this was tested during exercise in conditions of hyperglycemia when carbohydrate oxidation is favored. High doses of caffeine have also been shown to reduce the need for carbohydrate supplementation to avoid hypoglycemia during exercise. 5.8 Areas for Future Research Further research is needed to identify the optimal way to manage CSII for exercise. A clearer understanding of the pharmacokinetics and pharmacodynamics of rapid- acting insulin analogues when used for CSII will be useful to underpin this. Further research is required to identify both the optimal time to alter basal insulin rate prior to exercise and also to identify exactly what this alteration should be to permit ath- letes with diabetes to optimize their performance. It would also be helpful to test whether restarting the normal basal rate prior to finishing an exercise session would avoid postexercise hyperglycemia and may permit greater reductions to or even cessation of basal insulin infusion to be made prior to exercise without subsequent hyperglycemia. It may well be that the alterations to basal rate which provide the best approximation to normal physiology will provide the optimum means of man- aging CSII for exercise but this also requires further testing. More detailed analysis of strategies using CGM to guide carbohydrate replace- ment during exercise is required to see whether the early promise shown by these strategies can be fulfilled. The use of low-glucose suspend technology to avoid noc- turnal hypoglycemia following exercise should also be assessed as well as the effect this has on the counterregulatory response to any subsequent exercise. Assessment of the effect of the 10-s maximal sprint during euglycemic exercise would be inter- esting to see whether such a strategy might be able to protect against the fall in blood glucose in these conditions. Similarly using other means to augment the counterregulatory hormone response to exercise might also offer further strategies to help avoid hypoglycemia during exercise without the requirement for significant carbohydrate ingestion. 5.9 Conclusions The ability to adjust basal insulin infusion rates in CSII therapy means that in our clinic we now class CSII therapy as the gold standard in athletes with diabetes where it is practical. It is difficult to assess blood glucose levels accurately with

slide 135:

111 111 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 111 111 CGM during a period of rapid change such as during exercise meaning that closed- loop insulin delivery is likely to remain difficult in this context for some time. However current knowledge permits individuals to develop extremely suc- cessful strategies for the management of diabetes for sport and exercise using CSII. Real- time CGM is likely to play an increasingly important role in this permitting accurate carbohydrate replacement based on individual requirements. Managing diabetes for sport and exercise is not easy but improvements in the available tech- nology and our understanding of how best to use it can only help to increase the numbers of successful athletes with diabetes. References 1. Heise T Nosek L Ronn BB Endahl L Heinemann L Kapitza C et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004536:1614–20. 2. Lepore M Pampanelli S Fanelli C Porcellati F Bartocci L Di V A et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine NPH insulin and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 20004912:2142–8. 3. Ratner RE Hirsch IB Neifing JL Garg SK Mecca TE Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care. 2000235:639–43. 4. Hermansen K Fontaine P Kukolja KK Peterkova V Leth G Gall MA. Insulin analogues insulin detemir and insulin aspart versus traditional human insulins NPH insulin and regular human insulin in basal-bolus therapy for patients with type 1 diabetes. Diabetologia. 2004474:622–9. 5. Petersen KF Price TB Bergeron R. Regulation of net hepatic glycogenolysis and gluconeo- genesis during exercise: impact of type 1 diabetes. J Clin Endocrinol Metab. 2004899:4656–64. 6. Riddell M Perkins BA. Exercise and glucose metabolism in persons with diabetes mellitus: perspectives on the role for continuous glucose monitoring. J Diabetes Sci Technol. 200934:914–23. 7. Marliss EB Vranic M. Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes. 200251 Suppl 1:S271–83. 8. Brazeau AS Rabasa-Lhoret R Strychar I Mircescu H. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 20083111:2108–9. 9. Riddell MC Milliken J. Preventing exercise-induced hypoglycemia in type 1 diabetes using real-time continuous glucose monitoring and a new carbohydrate intake algorithm: an obser- vational field study. Diabetes Technol Ther. 2011138:819–25. 10. Edelmann E Staudner V Bachmann W Walter H Haas W Mehnert H. Exercise-induced hypoglycaemia and subcutaneous insulin infusion. Diabet Med. 198636:526–31. 11. Sonnenberg GE Kemmer FW Berger M. Exercise in type 1 insulin-dependent diabetic patients treated with continuous subcutaneous insulin infusion. Prevention of exercise induced hypoglycaemia. Diabetologia. 19903311:696–703. 12. Admon G Weinstein Y Falk B Weintrob N Benzaquen H Ofan R et al. Exercise with and without an insulin pump among children and adolescents with type 1 diabetes mellitus. Pediatrics. 20051163:e348–55. 13. Tsalikian E Kollman C Tamborlane WB Beck RW Fiallo-Scharer R Fox L et al. Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care. 20062910:2200–4.

slide 136:

112 112 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 112 112 14. Heise T Nosek L Spitzer H Heinemann L Niemoller E Frick AD et al. Insulin glulisine: a faster onset of action compared with insulin lispro. Diabetes Obes Metab. 200795:746–53. 15. Arnolds S Rave K Hovelmann U Fischer A Sert-Langeron C Heise T. Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers. Exp Clin Endocrinol Diabetes. 20101189:662–4. 16. Battelino T Phillip M Bratina N Nimri R Oskarsson P Bolinder J. Effect of continuous glu- cose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011344:795–800. 17. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment: evidence from the Juvenile Diabetes Research Foundation continuous glucose monitoring JDRF-CGM trial. Diabetes Care. 2010331:17–22. 18. Iscoe KE Campbell JE Jamnik V Perkins BA Riddell MC. Efficacy of continuous real-time blood glucose monitoring during and after prolonged high-intensity cycling exercise: spinning with a continuous glucose monitoring system. Diabetes Technol Ther. 200686:627–35. 19. Wilson DM Beck RW Tamborlane WV Dontchev MJ Kollman C Chase P et al. The accu- racy of the FreeStyle Navigator continuous glucose monitoring system in children with type 1 diabetes. Diabetes Care. 2007301:59–64. 20. Boyne MS Silver DM Kaplan J Saudek CD. Timing of changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes. 20035211:2790–4. 21. Buckingham BA Kollman C Beck R Kalajian A Fiallo-Scharer R Tansey MJ et al. Evaluation of factors affecting CGMS calibration. Diabetes Technol Ther. 200683:318–25. 22. Iscoe KE Davey RJ Fournier PA. Increasing the low-glucose alarm of a continuous glucose monitoring system prevents exercise-induced hypoglycemia without triggering any false alarms. Diabetes Care. 2011346:e109. 23. McMahon SK Ferreira LD Ratnam N Davey RJ Youngs LM Davis EA et al. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adoles- cents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab. 2007923:963–8. 24. Tsalikian E Mauras N Beck RW Tamborlane WV Janz KF Chase HP et al. Impact of exer- cise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 20051474:528–34. 25. Maran A Pavan P Bonsembiante B Brugin E Ermolao A Avogaro A et al. Continuous glu- cose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther. 20101210: 763–8. 26. Sandoval DA Guy DL Richardson MA Ertl AC Davis SN. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 dia- betes. Diabetes. 2004537:1798–806. 27. Taplin CE Cobry E Messer L McFann K Chase HP Fiallo-Scharer R. Preventing post- exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr. 20101575: 784–8. 28. Raju B Arbelaez AM Breckenridge SM Cryer PE. Nocturnal hypoglycemia in type 1 diabe- tes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab. 2006916: 2087–92. 29. Choudhary P Shin J Wang Y Evans ML Hammond PJ Kerr D et al. Insulin pump therapy with automated insulin suspension in response to hypoglycemia: reduction in nocturnal hypo- glycemia in those at greatest risk. Diabetes Care. 2011349:2023–5. 30. Galassetti P Tate D Neill RA Richardson A Leu SY Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab. 20062906:E1109–17. 31. Bussau V A Ferreira LD Jones TW Fournier PA. A 10-s sprint performed prior to moderate- intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Diabetologia. 2007509:1815–8.

slide 137:

113 113 A.N. Lumb 5 The Role of Newer Technologies CSII and CGM 113 113 32. Bussau V A Ferreira LD Jones TW Fournier PA. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care. 2006293:601–6. 33. Jenni S Oetliker C Allemann S Ith M Tappy L Wuerth S et al. Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus–a pro- spective single-blinded randomised crossover trial. Diabetologia. 2008518:1457–65. 34. Watson J Kerr D. The best defense against hypoglycemia is to recognize it: is caffeine useful Diabetes Technol Ther. 199912:193–200. 35. Richardson T Thomas P Ryder J Kerr D. Influence of caffeine on frequency of hypoglycemia detected by continuous interstitial glucose monitoring system in patients with long-standing type 1 diabetes. Diabetes Care. 2005286:1316–20. 36. Debrah K Sherwin RS Murphy J Kerr D. Effect of caffeine on recognition of and physiologi- cal responses to hypoglycaemia in insulin-dependent diabetes. Lancet. 19963478993: 19–24. 37. Gallen IW Ballav C Lumb AN Carr J. Caffeine supplementation reduces exercise induced decline in blood glucose and subsequent hypoglycaemia in adults with type 1 diabetes T1DM treated with multiple daily insulin injection MDI. Poster 1184-P presented at the 70th Scientific Sessions of the American Diabetes Association Orlando Florida: 25–29 June 2010.

slide 138:

Chapter 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise Click Here If You Also Want To Be Free From Diabetes Lisa M. Younk and Stephen N. Davis 6.1 Introduction Attention to diet including meal composition and timing is integral to all athletes’ training programs. Athletes with type 1 diabetes mellitus type 1 DM face the added task of administering insulin to carefully match energy availability and requirements. Avoiding both hyper- and hypoglycemia is a continual challenge for all patients with type 1 DM but is even more difficult for athletes who experience extreme changes in fuel utilization between periods of rest and exercise. Hyperglycemia during exercise can be detrimental to performance. Insulin- induced hypoglycemia however not only hinders performance but also can render uncommonly seizure coma and/or death and more commonly decreased qual- ity of life and/or increased anxiety with regard to glycemic control. Counterregulation is the term used to describe the systemic response to a blood glucose that falls below the body’s normal postabsorptive level. The primary goal of counterregulation is to maintain an adequate supply of blood glucose to the brain. While this priority does not change during exercise it is also important that the exer- cising muscle continues to receive enough substrate to maintain performance level. Counterregulation occurs in healthy individuals generally only during periods of fast- ing and exercise. Patients with type 1 DM rely on this response much more frequently both during rest regardless of absorptive state and exercise as hyperinsulinization L.M. Younk B.S. Department of Medicine University of Maryland School of Medicine 10-055 Bressler Research Building 655 W. Baltimore St. Baltimore MD 21201 USA e-mail: lyounkmedicine.umaryland.edu S.N. Davis M.B.B.S. FRCP FACP Department of Medicine University of Maryland School of Medicine 22 S. Greene Street Room N3W42 Baltimore MD 21201 USA

slide 139:

e-mail: sdavismedicine.umaryland.edu I. Gallen ed. Type 1 Diabetes DOI 10.1007/978-0-85729-754-9_6 © Springer-Verlag London Limited 2012 115

slide 140:

116 116 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 116 116 occurs as a result of the need to administer exogenous insulin that to this day does not adequately mimic physiological fluctuations in endogenous insulin secretion. This chapter will describe and compare the counterregulatory responses that occur during hypoglycemia and exercise in healthy individuals and in individuals with type 1 DM. Factors that increase the risk for hypoglycemia will also be dis- cussed with special attention to the risk associated with blunted counterregulation and hypoglycemia unawareness. A general overview of the current state of research regarding the causes of and treatments for these syndromes is provided. The chapter will conclude with clinical approaches to preventing and responding to an acute hypoglycemic event. 6.2 Normal Nondiabetic Cascade of Events During Hypoglycemia Unlike muscle cells which can modulate fuel selection among blood glucose fatty acid triglyceride and/or glycogen metabolism neurons rely acutely almost entirely on glucose transported from the bloodstream across the blood-brain barrier. Normal brain function is supported only within a narrow range of glucose levels. Thus when blood glucose begins to fall numerous changes occur throughout the body to maintain an adequate supply of substrate to the brain. Glucose uptake is inhibited peripherally blood flow is shunted away from the splenic bed and skeletal muscle and hepatic glucose production increases. The counterregulatory response to acute hypoglycemia in healthy individuals pri- marily involves a decrease in insulin secretion followed by increases in glucagon and epinephrine. Cortisol and growth hormone also increase during hypoglycemia but gen- erally only gain importance during prolonged glucose deprivation. Stepped hyperinsu- linemic hypoglycemic clamps of decreasing glucose levels have been used to investigate thresholds for the onset of counterregulatory hormones in healthy individu- als 1–4. Under resting conditions insulin secretion decreases at 4.5 mmol/l 1 2. Glucagon epinephrine growth hormone cortisol and pancreatic polypeptide an indi- rect marker of parasympathetic activation all increase 3.6–3.9 mmol/l 1–5. Muscle sympathetic nerve activity MSNA a direct real-time measurement of sympathetic activation increases between 3.3 and 3.8 mmol/l 5. These responses occur at similar thresholds between men and women albeit with lower levels of counterregulatory hor- mones generated in women 2 5 6. The reason for these differences is not well under- stood but increased levels of estrogen appear to play an important role 7. Although the secretion of counterregulatory hormones is critical for the protection against hypoglycemia it is ultimately an individual’s symptoms – his or her perception of the physiological changes associated with hypoglycemia – that prompts ingestion of food and consequent cessation of counterregulation. Symptoms can be classified according to origin see Table 6.1. Autonomic symptoms also known as neurogenic symptoms are adrenergic and cholinergic symptoms generated as a result of increased neural sympathetic activity and catecholamine release from the adrenal medulla. From studies in adrenalectomized patients it appears that these symptoms arise primarily

slide 141:

117 117 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 117 117 Table 6.1 Symptoms of hypoglycemia Autonomic/neurogenic Neuroglycopenic Unspecified Sweaty Confused difficulty thinking/ concentrating General malaise Shaky tremor trembling Blurry vision Headache Palpitations pounding heart Tired drowsy Nausea Anxious nervous Difficulty speaking Tingling Uncoordinated Hungry Odd behavior Weak Dizzy Warm from the sympathetic neural response 8 although in another study adrenergic symp- toms were correlated primarily with epinephrine levels 9. Work from our laboratory has determined that during euglycemic conditions epinephrine levels simulating those found during moderate hypoglycemia are responsible for 20 of autonomic symp- toms 10. Sweating shakiness/tremor/trembling palpitations/pounding heart anx- iousness/nervousness tingling and hunger are typical autonomic symptoms experienced during hypoglycemia 8 11. Neuroglycopenic symptoms arise from the effects of low blood glucose in the brain per se and cannot be reduced by pharmacologic adrenergic or panautonomic blockade 12. Included in this group are confusion/difficulty think- ing or concentrating blurred vision tiredness/drowsiness difficulty speaking discoor- dination odd behavior weakness dizziness and warmness 11. Neuroglycopenic symptoms intensify as blood glucose continues to fall progressing to severe cognitive dysfunction if hypoglycemia is not treated. In addition to the autonomic and neurogly- copenic symptoms described above patients may also detect a feeling of general mal- aise which could include headache and/or nausea 13. Emotional responses may also increase 14 along with a shift in general mood states during hypoglycemia. In healthy people the threshold for autonomic and neuroglycopenic symptoms can be slightly variable 15 but is generally 3.0 mmol/l. Cognitive dysfunction arises 2.6 mmol/l 1–4. Although men tend to have a more robust counterregula- tory response to hypoglycemia symptoms do not appear to follow a pattern of sex- ual dimorphism with similar symptom scores reported by both genders during equivalent levels of hypoglycemia 2 5 6 16. 6.3 Counterregulation During Exercise During moderate exercise similar to hypoglycemia a decrement in insulin and an increment in glucagon occur stimulating glucose production to prevent a fall in blood glucose level 17 18. When somatostatin insulin and glucagon are infused into healthy individuals to prevent changes in hormone levels during exercise blood glucose falls from 5.5 to 3.4 mmol/l 19. Likewise when only insulin is allowed to decrease or only glucagon is allowed to increase blood glucose still falls. Only when both actions happen is euglycemia maintained. However because the fall in

slide 142:

118 118 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 118 118 2max a d glucose is still rescued at mild levels of hypoglycemia when insulin and/or glucagon is held constant it is clear that other hormones are also involved in counterregula- tion during exercise 19. In fact epinephrine and norepinephrine are both impor- tant for enhancing glucose production and for limiting the increase in glucose uptake that occurs during exercise 20. When a-/b- alpha-/beta- adrenergic blockade is imposed during exercise in healthy individuals blood glucose falls as a result of increased glucose utilization but is eventually rescued by decreased insulin secre- tion and increased glucagon secretion 20. Preventing catecholamine action and changes in insulin and glucagon through adrenergic blockade and somatostatin infusion causes a precipitous fall in blood glucose during exercise due to diminished glucose production and an early exaggerated increase in noninsulin-mediated glu- cose utilization 20 21. As such insulin glucagon and catecholamines are the primary hormonal regulators of glucose levels during moderate exercise. Sympathetic neural norepinephrine may be the primary glucoregulatory catecholamine during exercise as opposed to epinephrine during hypoglycemia 20. When euglycemia is maintained during exercise a robust counterregulatory response still occurs as indicated by significant rises in epinephrine and norepi- nephrine. This suggests that mechanisms that induce hormone secretion during exercise may be at least partially independent of those responsible for counterregu- lation during resting hypoglycemia 22. The counterregulatory response to exercise becomes much more intense if blood glucose does fall below fasting levels. Sotsky et al. 22 reported that glucagon cortisol norepinephrine epinephrine and growth hormone all increased to a significantly greater degree during hypoglycemic exer- cise compared to euglycemic exercise. The hormonal response to intense exercise 80 VO – such as occurs in short bursts in many sports – is much different from the response during moderate exercise. Rather than insulin and glucagon regulating glucose levels catecholamines are the primary mediators of glucose production and uptake increasing 14- to 18-fold during intense exercise 23 24. Such increases drive a huge increase in glucose rate of appearance R as glucose is mobilized through hepatic glycogenolysis. Glucose rate of disappearance R also increases although to a lesser degree as cate- cholamines also stimulate muscle glycogenolysis which moderates glucose uptake. The disproportionate rise in glucose R compared to R results in hyperglycemia but a d insulin concentration during exercise does not change dramatically. Upon cessation of exercise though catecholamine levels quickly decrease while insulin increases drastically for up to 60 min to reverse hyperglycemia 24 25. 6.4 Impaired Cascade of Events in Type 1 Diabetes During Hypoglycemia and Exercise People with type 1 DM have multiple impairments in the counterregulatory response to hypoglycemia and exercise placing them at high risk of severe hypo- glycemia. Endogenous insulin secretion is absent and therefore systemic insulin

slide 143:

119 119 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 119 119 2max levels maintained by exogenous delivery cannot be decreased despite changes in energy demand. In some studies careful replacement of insulin to maintain eug- lycemia or to allow very slight increases in blood glucose .5 mmol/l rise in blood glucose during 30 min of exercise did not cause hypoglycemia during exercise 26 27. However in another study when basal insulin was infused to generate similar levels of free insulin in healthy controls and type 1 DM blood glucose fell further in type 1 DM than controls likely due to other defects in counterregu- lation 28. Beyond the first few years of onset of type 1 DM the glucagon response to hypoglycemia is lost 29 30. The mechanism of this defect remains under inves- tigation but the impairment could be a result of a lack of change in intra-islet insulin concentrations which may be necessary in order to trigger pancreatic a alpha-cell glucagon secretion. In support of this theory infusion of a sulfonylu- rea into healthy people during a hyperinsulinemic-hypoglycemic glucose clamp to induce a hyperinsulinemic environment within the islet cells resulted in dimin- ished glucagon secretion 31. In a second study 32 somatostatin was infused to block insulin secretion in healthy people prior to a hyperinsulinemic-hypoglyce- mic glucose clamp. This prevented a fall in intra-islet insulin concentration upon onset of hypoglycemia. Upon cessation of somatostatin infusion during the clamp glucagon levels increased but were blunted by 30. The glucagon response to exercise is retained however in type 1 DM 26 33 suggesting a divergence in the signaling mechanisms that control glucagon secretion during hypoglycemia and exercise. Increments in epinephrine are generally blunted in type 1 DM both during hypo- glycemia and exercise. When controls and type 1 DM exercised at 60–65 VO for 60 min at similar blood glucose levels the epinephrine and norepinephrine response to the ambient hypoglycemia was significantly lower in type 1 DM than in controls 28. Even when controls exercised at euglycemia the epinephrine and norepinephrine response tended to be greater compared to type 1 DM subjects exer- cising under hypoglycemic conditions. Failure of either the glucagon or the epinephrine response can be mostly com- pensated for by secretion of the other hormone. Failure of both hormones to increase in response to exercise however will result in hypoglycemia in healthy individuals 20. Moreover even with an intact glucagon and epinephrine response during exer- cise excessive insulin can blunt hepatic glucose production and increase muscle glucose uptake increasing the risk of hypoglycemia. Unlike moderate exercise patients with type 1 DM can mount a normal response to intense exercise as glucoregulation under these conditions is driven primarily by release of catecholamines. The challenge becomes the fact that hyperglycemia arises during intense exercise that requires increments in insulin during the postex- ercise period. Unless adequate rapid-acting insulin is injected to mimic the normal hyperinsulinemic response in nondiabetic individuals there will be a prolonged period of hyperglycemia which carries with it deleterious effects on overall glyce- mic control and long-term health 34 35.

slide 144:

120 120 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 120 120 6.5 Additional Risk for Hypoglycemia During and After Exercise In light of an inability to decrease insulin levels and the presence of an altered counterregulatory response a number of factors further influence the risk of hypoglycemia during exercise in type 1 DM. These factors affect insulin require- ments counterregulatory responses and symptom identification. Excess insulin and inadequate carbohydrate supplementation and lack of blood glucose monitoring are the primary factors that potentiate the risk of hypoglycemia. Beyond the scope of this chapter these topics are covered extensively in Chaps. 3 5 and 7. 6.5.1 V ariability in Insulin Uptake and Action Exogenously administered insulin has intrinsic intra- and interindividual variability in uptake and action 36. Newer insulin analogs including long-acting e.g. glargine detemir and rapid-acting e.g. aspart lispro glulisine formulations do however offer less variability and lower risk of hypoglycemia than older treatment options e.g. NPH regular 37–39. Intramuscular insulin injection exacerbates variability significantly increasing insulin absorption rate especially during exercise resulting in higher free insulin levels and greater insulin action. The difference is likely due to a fivefold increase in skeletal muscle blood flow during exercise whereas adipose tissue blood flow does not appear to change significantly 40. There has been a trend toward shorter smaller-gauge needles since the introduction of subcutaneous insulin injection thereby reducing the risk of intramuscular injection. The site at which insulin is injected can also contribute to variability in insulin uptake and action. During leg exercise absorption of rapid-acting insulin injected into the leg is increased compared to insulin injected into the arm or the abdomen resulting in higher peak insulin levels and greater decreases in blood glucose 41 42. Arm and abdominal injection decreased the risk of hypoglycemia by 57 and 89 41. Variable thicknesses of subcutaneous tissue at different sites are likely responsible for variations in insulin absorption with lower absorption rates occur- ring in areas where thickness is increased. Some have suggested that this is a func- tion of subcutaneous blood flow which also decreases with increasing thickness 43 but others have not been able to confirm this 42. 6.5.2 Exercise Duration and Intensity Both the duration and intensity of exercise will greatly influence insulin and carbo- hydrate requirements before during and after exercise. Perhaps the greatest vari- ability occurs between moderate and intense exercise. As described above intense

slide 145:

121 121 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 121 121 d exercise generates hyperglycemia which requires a sustained elevated glucose R after exercise to return glucose levels back down to postabsorptive levels. As this requires physiological hyperinsulinemia 34 athletes with type 1 DM may need to cover this postexercise hyperglycemia with extra insulin 35. This strategy must be carried out carefully as counterregulation is blunted by exercise and insulin sensi- tivity is increased making them vulnerable to hypoglycemia. Repeated bouts of intense exercise can further exacerbate glucose control. The hyperglycemic response to repeated bouts of intense exercise performed after brief rest intervals 5 min can be additive 23. If rest periods are longer i.e. 1 h the responses to each bout are largely independent of each other in healthy individuals although hyperglycemia may be lower during repetitions 24. In type 1 DM however this pattern may not be so clear as hyperglycemia from the first bout of exercise could still be present if not sufficiently corrected between bouts. 6.5.3 Temperature Increased ambient temperature causes increases in skin temperature and enhanced subcutaneous blood flow which can in turn accelerate insulin absorption 44 45. At rest warmer room temperature 30°C was associated with a three- to fivefold increase in insulin levels and correspondingly lower blood glucose levels compared to cooler room temperature 10°C. This effect was maintained during exercise causing larger decrements in blood glucose 46. Temperature increases can also increase workload as indicated by increased heart rate and lactate levels causing a greater reliance on counterregulatory hor- mones including cortisol epinephrine and norepinephrine 47–49. Similarly swimming in cold water can also result in enhanced release of catecholamines likely as a result of thermoreception 49. Thermoregulation in cold environments can be compromised by hypoglycemia. Hypoglycemia was induced in healthy men in a cool room 18–19°C with air blow- ing to cause sustained shivering 50. When blood glucose fell to 2.5 mmol/l shiver- ing subsided and subjects did not feel cold. Despite the cool environment hypoglycemia-induced peripheral vasodilation and sweating occurred allowing skin and core temperature to fall to the point that subjects required rewarming. Reciprocally the colder environment hampered recovery from hypoglycemia. 6.5.4 Age In healthy older individuals a greater stimulus may be required for release of glu- cagon and epinephrine compared to younger people 2.8 versus 3.3 mmol/l 51. Hormonal responses to mild hypoglycemia can be less robust as well 51 52. These differences disappear at 2.8 mmol/l indicating that deeper hypoglycemia can still

slide 146:

122 122 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 122 122 m elicit a normal counterregulatory response 52. However symptom scores are lower in older versus younger adults during hypoglycemia even when counterregu- lation is of similar magnitude 53. Autonomic symptoms appear to be primarily impaired while neuroglycopenic symptoms remain relatively intact 51. Thus diminished symptoms and attenuated counterregulatory responses at milder hypo- glycemia mean that older athletes may be more susceptible to larger falls in blood glucose. However although specific studies of hormonal responses to exercise in older adults with type 1 DM are lacking healthy older adults are able to mount a similar hormonal response to submaximal exercise as their younger counterparts of similar training level 54. Deficits did arise in the lactate growth hormone and cortisol response to maximal exercise in the older individuals although the reper- cussions of such declines are not completely clear. 6.5.5 Increased Insulin Sensitivity The risk of hypoglycemia is increased immediately and several hours following an exercise session 55. The more immediate effects of exercise upon glucose uptake and utilization are independent of insulin and are mediated by lasting effects of contraction-stimulated glucose uptake 56 57. The increased risk of hypoglycemia beyond the first few hours after exercise is primarily a result of increased insulin sensitivity which may vary according to duration and intensity of the exercise 56. Insulin-mediated glucose uptake was increased in healthy untrained men immedi- ately and 48 h following 60 min of cycle ergometer exercise 58. Effects are local- ized as increases in insulin-stimulated glucose uptake are specific to the exercised muscles 59 60. The increased insulin sensitivity is largely a result of a reduced K wherein a lower concentration of insulin is required to induce half-maximal glucose uptake 61. While some have suggested that glycogen depletion and con- sequent increased glycogen synthase activity are responsible for driving increases in insulin sensitivity 58 62 it now seems more likely that enhanced GLUT4 translo- cation and possibly microvascular perfusion are responsible for these changes. GLUT4 translocation may be regulated by distal portions of the insulin signaling pathway 57. Clinically these findings are supported by the fact that extra carbohy- drate needs to be taken 63 and/or insulin doses need to be reduced 64 65 before during and following exercise to prevent postexercise hypoglycemia. As a caveat in a study of marathoners with type 1 DM whole-body glucose disposal and glu- cose oxidation rates were decreased despite increased glycogen synthase activity following a competitive marathon 66. This apparent reduction in insulin sensitiv- ity was attributed to dramatically increased lipid oxidation rates that were observed postexercise. Additionally muscle damage such as that induced by eccentric con- tractions can cause insulin resistance 67 due to decreased GLUT4 transcription 68 and/or impaired proximal insulin signaling 69. Therefore athletes will need to modify insulin and diet regimens according to variations in workouts and competitions.

slide 147:

123 123 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 123 123 Special care may need to be taken to prevent postexercise hypoglycemia in those who participate in afternoon or evening exercise. Glucose requirements following exercise exhibit a biphasic pattern with increases occurring both immediately and 7–11 h after exercise 70 71. Thus the risk of hypoglycemia is elevated during hours of sleep. 6.5.6 Impaired Symptom Identification Recognizing a symptom or perceiving a change in physiological state is only part of the battle in responding appropriately to hypoglycemia. A person may identify a symptom but still fail to associate that symptom with hypoglycemia. A number of factors can influence a person’s ability to rationally establish a link between the symptom and the cause 72. Specific to athletes feelings generally associated with hypoglycemia can be masked by normal sympathetic neural and sympathoadrenal responses to exercise. Sweating for example is a normal response to both stimuli. Shivering or a cold sweat following exercise in cool environment i.e. cold water or air may be interpreted as a normal response but such physiological responses may also occur during hypoglycemia. Exercise and competition also can cause anxiety increased heart rate and fatigue. However in a study by Nermoen et al. 73 patients exercising at 50 of their maximal heart rate reported symptoms of hypoglycemia during hypoglycemia 2 mmol/l but not during euglycemia indicating that the symptoms were actually discernable from those occurring in response to exercise. Symptoms also arose at higher blood glucose levels compared to when hypoglyce- mia was induced with the subjects lying in bed. As the authors pointed out though exercise of higher intensity than experienced in the study could obscure the percep- tion of hypoglycemia-associated changes. Moreover despite altered symptom thresholds in the study only 6 of 10 subjects answered “yes” when asked if they felt hypoglycemic during hypoglycemic exercise indicating a disconnect between iden- tification of symptoms and identification of hypoglycemia. 6.5.7 Hypoglycemia-Associated Autonomic Failure and Impaired Hypoglycemia Unawareness 6.5.7.1 Background While excess insulin levels certainly can cause hypoglycemia it is often the failure of counterregulatory responses and/or an impaired ability to detect a low blood sugar hypoglycemia unawareness that permits the onset of severe hypoglycemia in patients with diabetes. Although overt diabetic autonomic neuropathy DAN has been associated with blunted epinephrine and symptom responses to hypogly- cemia and exercise 74–76 blunted hormone and symptom responses have been

slide 148:

124 124 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 124 124 a observed in patients without DAN as well 28 77–81. Studies have shown that counterregulatory responses during exercise in this population are qualitatively similar but quantitatively reduced compared to healthy individuals 6 28 82. Therefore it is likely that although DAN contributes to impaired counterregulation and hypoglycemia unawareness 83 a separate condition is responsible for these defects in patients who lack even subclinical DAN 84. It was observed that patients who suffered from recurring hypoglycemia also exhibited impaired secretion of glucagon epinephrine and growth hormone in response to insulin-induced hypoglycemia 85 86. This led to the hypothesis that hypoglycemia could be the initial event responsible for impaired counterregulation. It is now widely appreciated that previous autonomic activation i.e. during hypo- glycemia or exercise is a principal precipitating event for blunted counterregula- tory responses to subsequent hypoglycemia and exercise in type 1 DM 79. This effect has been termed hypoglycemia-associated autonomic failure or HAAF 87. HAAF is differentiated from DAN in that the former does not necessarily affect key measures of cardiovascular autonomic function used to assess subclinical or overt DAN including heart rate variability during deep breathing 88. Furthermore a prior hypoglycemic stimulus in healthy nondiabetic people can also blunt glucose counterregulation during hypoglycemia indicating that blunting effects can occur completely independently of the diabetic disease state 89–91. To substantiate and elaborate upon the theory of HAAF researchers have used insulin infusion tests and the hyperinsulinemic glucose clamp technique to experi- mentally induce and measure the effects of recurrent hypoglycemia in healthy type 1 and type 2 DM individuals. These studies have uncovered a number of key find- ings. In healthy individuals repeated hypoglycemia blunts glucagon epinephrine norepinephrine cortisol growth hormone and pancreatic polypeptide responses to hypoglycemia 89 90. The blunting of epinephrine and pancreatic polypeptide indicates that both sympathetic and parasympathetic activities respectively are attenuated during repeated hypoglycemia. In addition to reduced hormonal responses metabolic responses glucose R and free fatty acid mobilization as well as neurogenic and neuroglycopenic symptoms are significantly reduced in healthy individuals during repeated hypoglycemia. Furthermore the blood glucose levels at which responses are initiated are reset so that blood glucose must fall further in order to induce counterregulation 90 91. These findings have been extended to patients with type 1 DM who also exhibit reduced epinephrine pancreatic polypeptide and symptom responses to hypoglyce- mia along with altered glycemic thresholds after repeated hypoglycemia 79 92. Taken together the above observations promote the unifying concept that multiple factors that contribute to risk of recurring hypoglycemia – blunted counterregula- tory responses hypoglycemia unawareness and altered counterregulatory thresh- olds – are largely the result of antecedent hypoglycemia 79 92. Importantly hypoglycemia-induced blunting of counterregulation is not simply an acute phe- nomenon. When investigators induced hypoglycemia in patients with type 1 DM for 2 h twice a week for 1 month blunting effects similar to those described above were still significant at the end of the trial 93.

slide 149:

125 125 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 125 125 2max The depth of antecedent hypoglycemia affects the degree to which counterregulation is blunted during subsequent hypoglycemia 94. In healthy males two 2-h bouts of hypoglycemia one morning and one afternoon at 3.9 mmol/l induced blunting of epi- nephrine MSNA and glucagon during next day hypoglycemia 2.9 mmol/l. When first day hypoglycemia was set at 3.3 or 2.9 mmol/l norepinephrine growth hormone and pancreatic polypeptide responses were also blunted as well as endogenous glucose pro- duction and lipolysis. The duration of the hypoglycemic stimulus is also of importance. In nondiabetic subjects two 5-min or 30-min bouts of hypoglycemia blunted hormonal responses to next day hypoglycemia quite similarly to two 2-h bouts of antecedent hypoglyce- mia 95. This finding is of clinical significance as patients who successfully detect and correct a low blood sugar quickly should be aware that their bodies’ responses to subsequent bouts of hypoglycemia may still be impaired. Interestingly the shorter bouts of hypoglycemia did not blunt symptom responses. However it is unknown whether multiple days of short duration hypoglycemia could become more prob- lematic eventually blunting symptoms as well. Even more relevant to athletes with type 1 DM researchers have found that hypoglycemia and exercise reciprocally blunt counterregulatory responses. Thus in healthy people and patients with type 1 DM antecedent hypoglycemia blunts the primary neuroendocrine and metabolic responses to exercise 96 97. Similar to above the depth of antecedent hypoglycemia dose-dependently blunts these responses with lower blood glucose causing greater blunting effects which become most apparent after 30 min of exercise 82. Vice versa counterregulation during hypoglycemia is blunted by antecedent exercise in a quantitatively similar fashion as antecedent hypoglycemia see Fig. 6.1. In healthy individuals day 1 exercise two 90-min bouts blunted gluca- gon epinephrine norepinephrine growth hormone pancreatic polypeptide MSNA and endogenous glucose production responses to day 2 hypoglycemia 98. When patients with type 1 DM exercised in the morning epinephrine MSNA and endog- enous glucose production were blunted during a hypoglycemic clamp in the after- noon of the same day 99. In the above exercise studies subjects exercised at 50 VO . It has now been shown that exercise at even 30 VO 2max is sufficient to blunt neuroendocrine and metabolic counterregulatory responses during hypoglycemia in type 1 DM 100. Similar studies of higher exercise intensities are sparse. Because high-intensity exercise causes an increase in blood glucose some investigators have studied the postexercise glycemic effects of adding bouts of intermittent high-intensity exercise IHE during moderate-intensity exercise. In one such study 101 2 h after 30 min of moderate exercise with IHE blood glucose was higher in the IHE group com- pared to a group that exercised continuously at moderate intensity MOD. However during sleeping hours blood glucose levels were significantly lower and hypogly- cemia occurred more frequently in the IHE group. Contrarily other researchers 102 found that nocturnal glucose levels were higher and hypoglycemia was less frequent following IHE compared to MOD. Importantly in this study there was a late decrease in blood glucose at 6 a.m. in the IHE group suggesting that increased

slide 150:

126 126 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 126 126 EGP mg/kg/min Epinephrine pg/ml D MSNA bursts/min Glucagon pg/ml 800 400 Antecedent Euglycemia Antecedent Exercise Antecedent Hypoglycemia 300 150 0 0 2 16 1 8 0 0 Final 30 Min-Day 2 Final 30 Min-Day 2 Fig. 6.1 Key counterregulatory responses during the final 30 min of a 2-h hyperinsulinemic-hypogly- cemic 3.0 mmol/l glucose clamp on the morning following previous day euglycemia solid bars exercise hatched bars and hypoglycemia open bars. Antecedent euglycemia and hypoglycemia studies consisted of two 2-h clamps in the morning and afternoon of day 1. Antecedent exercise con- sisted of two 90-min bouts of moderate intensity 50 VO cycling exercise in the morning and 2max afternoon of day 1. MSNA muscle sympathetic nerve activity EGP endogenous glucose production p 0.05 for antecedent euglycemia versus antecedent hypoglycemia and exercise 98 Reprinted by permission of the publisher from Galassetti 98 The American Physiological Society insulin sensitivity might still occur albeit in a delayed fashion after this form of exercise. The discrepancy in findings could be due to several factors. The type of IHE differed between studies and the former study recruited untrained subjects while trained athletes were studied in the latter. Indeed trained athletes have altered hormonal and metabolic responses during exercise that could account for differ- ences in the glycemic responses described above and may even have an altered susceptibility to HAAF. Further research is needed to clarify these issues and to determine the underlying metabolic and hormonal factors that contribute to the altered glycemic trends following IHE. Studies of the blunting effects on counter- regulation in type 1 DM athletes are also needed. This information could be critical to both a deeper understanding of the mechanisms of HAAF and the development of better hypoglycemia prevention strategies in athletes with type 1 DM who often exercise at intensities well above 50 VO . 2max Nonetheless the above information illustrates the need for athletes with type 1 DM to pay consistent attention to fluctuations in blood glucose before during and after exercise both for safety and performance reasons. Sleep is a key period of

slide 151:

127 127 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 127 127 vulnerability in type 1 DM with higher rates of prolonged hypoglycemia observed during nighttime than during the day 103–105. While the mechanism responsible for the increased frequency of severe hypoglycemia during sleep remains to be char- acterized it is known that epinephrine cortisol and pancreatic polypeptide responses to hypoglycemia during sleep are delayed and reduced in people with type 1 DM 106–108. Perhaps due to the reduced hormonal response patients are less likely to awaken during an episode of hypoglycemia 106 preventing them from taking cor- rective measures. In athletes who have exercised in the previous days these altered responses will be superimposed upon the blunted responses and increased insulin sensitivity associated with antecedent exercise exacerbating the risk of hypoglyce- mia. Despite attenuated counterregulation and lack of awareness during sleep noc- turnal hypoglycemia still blunts counterregulatory hormone and symptom responses to next day hypoglycemia 109 110. Therefore devising strategies to detect low blood glucose levels during the night will not only increase safety during sleep but also will provide information critical to controlling blood glucose in the day ahead. As noted above impaired hypoglycemia awareness is often coincident with blunted counterregulation. In fact the two phenomena are significantly associated 78. In a study of healthy people and patients with and without a history of hypo- glycemia unawareness a delayed sympathoadrenal response was observed only in those with hypoglycemia unawareness 111. In diabetes the glycemic threshold for autonomic symptoms is widely variable and subject to change. Impairment of hypoglycemia awareness occurs along a continuum with gradually decreasing intensity and/or number of symptoms 81. Under poor glucose control symptoms occur at higher blood glucose levels 112. Conversely tight glycemic control often accompanied by increased frequency of hypoglycemia can cause the threshold for symptoms to be significantly downshifted to lower blood glucose levels 113. This circumstance is cause for concern as the thresholds for the onset of symptoms and cognitive dysfunction can become superimposed or even reversed. In subjects with intensively treated diabetes or insulinoma the onset of autonomic and neuroglyco- penic symptoms occurred 2.0–2.3 mmol/l compared to 2.6–3.3 mmol/l in poorly controlled and nondiabetic subjects. Onset of cognitive dysfunction however occurred similarly in all groups at 3.0–3.2 mmol/l 114 115. Depending on the severity of neuroglycopenia impaired cognitive functioning prior to symptom onset may preclude patients from recognizing or responding to their symptoms. Furthermore a rapid fall in blood glucose leaves little time between the recognition of symptoms and the onset of more severe cognitive dysfunction thus requiring a rapid appropriate response to symptoms if they are detected. 6.5.8 Mechanism of Impairment Why does antecedent hypoglycemia or exercise cause reduced neuroendocrine metabolic and symptom responses to subsequent hypoglycemia or exercise Much effort has been put in to teasing apart the mechanisms by which the body senses and

slide 152:

128 128 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 128 128 responds to a falling glucose level and the changes that occur within the central nervous system in the face of recurring hypoglycemia. Evidence suggests that changes occur centrally to maintain appropriate substrate levels in the most glucose- sensitive areas of the brain allowing for continued brain function during lower sys- temic blood glucose levels. This would shift the initiation of responses to hypoglycemia to lower glycemic levels at which adaptations begin to fail and cen- tral glucoprivation ensues. This is an attractive explanation as the alterations would then reflect an intrinsic protective survival response of the central nervous system to repeated bouts of hypoglycemia. Supporting this theory mild recurring hypoglyce- mia 25–40 mg/dl in awake unrestrained rats was shown to protect against brain damage and loss of spatial learning and memory induced by severe hypoglycemia 10–15 mg/dl 116. How does the central nervous system detect a falling blood glucose level Glucose-sensing neurons appear to be the signaling link between falling glucose levels and the counterregulatory response. The membrane potential of this subset of neurons is altered by changes in ambient glucose level. Glucose-excited neurons increase firing rate as glucose levels increase while glucose-inhibited neurons decrease firing rate as glucose levels increase. It is believed that fluctuations in the firing rates of these neurons modulate downstream signaling mechanisms that con- trol hormone release. Both types of glucose-sensing neurons are found in regions of the brain that have been implicated in the counterregulatory response including the lateral hypothalamus 117 and the arcuate and ventromedial nuclei of the ventro- medial hypothalamus 118–120. These neurons are also located in hindbrain 121 in the dorsal motor nucleus of the vagus 122 the nucleus of the solitary tract 123 and the area postrema 124. Some research also suggests that glucose- sensing neurons are located in the higher processing forebrain. These regions are associated with the blunting effects of repeated hypoglycemia. Localized glucope- nia in the ventromedial hypothalamus of rats after chronic hypoglycemia induced lower counterregulatory responses compared to controls not exposed to prior hypo- glycemia 125. Similarly antecedent injection of 5-thio-glucose into the third ven- tricle to cause glucoprivation within the hypothalamus resulted in reduced epinephrine and glucagon responses to subsequent hypoglycemia 126. A number of intracellular elements may be involved in the glucose-sensing mechanism of certain neurons. Glucokinase a known mediator of glucose sensing in pancreatic b cells is also located in glucose-sensing neurons in the rat brain 127 128. Inhibition of glucokinase slows Ca 2+ oscillations an indirect indicator of membrane potential in glucose-excited neurons and increases Ca 2+ oscillations in glucose-inhibited neurons 128 129. Conversely pharmacologic activation of glu- cokinase increases and decreases Ca 2+ oscillations in glucose-excited and glucose- inhibited neurons respectively 128. Glucokinase mRNA expression is increased in the ventromedial nuclei and the arcuate following acute insulin-induced hypogly- cemia in rats 130. This change was associated with reduced epinephrine responses to subsequent hypoglycemia. Accordingly acute pharmacologic activation of glu- cokinase in the ventromedial hypothalamus during hypoglycemia was shown to blunt epinephrine norepinephrine and glucagon responses 131. Inhibition of

slide 153:

129 129 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 129 129 2 A A glucokinase or reduction of glucokinase mRNA boosted the epinephrine response to hypoglycemia 131. Stimulation of AMP-activated protein kinase AMPK may also be required for normal glucose sensing. Neuroglucopenia increased AMPK a alpha and a 1 1 2 alpha activity in the rat brain 132. Stimulation of AMPK via injection of 5-ami- noimidazole-4-carboxamide ribonucleotide AICAR into the ventromedial hypo- thalamus of rats significantly increased hepatic glucose production during a hyperinsulinemic hypoglycemic clamp 133. Conversely downregulation of AMPK via gene silencing blunts counterregulation with significant reductions in glucagon epinephrine and endogenous glucose production responses during hypoglycemia 134. Gene expression of AMPK a alpha and a alpha was shown to increase 1 1 2 2 after three repeated bouts of hypoglycemia 135 and AMPK activity was blunted after 4 days of repeated neuroglucopenia 132. Consequent blunted counterregula- tion glucagon and epinephrine can be rescued by injection of AICAR prior to acute or clamped hypoglycemia in both nondiabetic and diabetic rats 132 135 136. ATP-sensitive K+ channels also similar to those found in pancreatic b beta cells are found on glucose-excited neurons 120 and are closed by ATP which increases with increasing levels of ambient glucose. Closure leads to membrane depolarization Ca 2+ influx and generally increased action potential frequency 137. As would be predicted pharmacologic closure of ATP-sensitive K+ channels using sulfonylureas leads to blunted counterregulatory responses to hypoglycemia 138 while microinjections of K+ channel openers significantly enhance counter- regulation 139. Microinjections of diazoxide another K+ channel opener into recurrently hypoglycemic rats were also found to rescue the epinephrine response to hypoglycemia resulting in less reliance on exogenously infused glucose 139. Glucose-sensing neurons must translate a changing glucose signal into a change in synaptic neurotransmitter release to generate a physiological response to the orig- inal stimulus. Changes have been observed in a number of neurotransmitters during acute and repeated hypoglycemia including glutamate a fast-acting excitatory neurotransmitter prevalent in the ventromedial hypothalamus. Researchers created a knockout mouse model lacking glutamate synaptic vesicular transporters in SF1 neurons found in the ventromedial hypothalamus. Knockout mice displayed impaired counterregulation during both fasting and insulin-induced hypoglycemia 140. No information is available however regarding changes in glutamate levels during acute and recurring hypoglycemia. The inhibitory neurotransmitter g gamma-aminobutyric acid GABA on the other hand has been heavily studied in relation to hypoglycemia. Levels of both GABA and glutamic acid decarboxylase the enzyme responsible for GABA synthe- sis increase in the ventromedial hypothalamus of rats in response to acute and recur- ring systemic hypoglycemia 141 142. The increased levels may partially mediate impaired counterregulation as administration of alprazolam in healthy humans to induce GABA receptor activation either 90 min or 1 day prior to insulin-induced hypoglycemia results in blunted epinephrine norepinephrine glucagon pancreatic polypeptide MSNA growth hormone ACTH and metabolic responses 143 144. Reciprocally GABA receptor antagonism in the ventromedial hypothalamus of rats

slide 154:

130 130 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 130 2 2 enhances the counterregulatory response to hypoglycemia and rescues the blunting effects of repeated hypoglycemia 142 145. Norepinephrine synaptically released in the ventromedial hypothalamus may drive increases in GABA as the first and second peaks of the biphasic rise in GABA during infusion of 2-deoxyglucose were blocked by administration of a alpha - and b beta-adrenoceptor antagonists respectively 146. The corticotrophin-releasing factor CRF family of CRF and urocortins UCN I-III may work in opposing fashion to modulate counterregulatory responses. Stimulation of primarily CRF receptor I CRFRI via microinjection of CRF ampli- fies glucagon and epinephrine responses to hypoglycemia in rats 147. Meanwhile stimulation of CRFRII via microinjection of UCNI delays and suppresses counter- regulation which can be corrected by infusion of a CRFRII antagonist 147. The ventromedial hypothalamus contains CRFR I and II with a greater distribution of CRFRII 148 as well as UCNIII which is highly selective for CRFRII 147. Some have hypothesized that it is the balance in the agonism of the two receptors that at least in part dictates the degree of hormonal response during hypoglycemia. Additionally UCN agonism of CRFRII 24 h prior to hypoglycemia blunts counter- regulation suggesting that activation of this receptor during hypoglycemia could contribute to HAAF 147. It is likely that the signaling elements described above are affected by many metabolic molecules and thus can integrate several sources of feedback into a uni- fied signaling response. Insulin lipids neuropeptides neuropeptide Y and alpha- melanocyte-stimulating hormone and leptin for example have all been shown to affect a number of signaling pathways and subsequent neurotransmitter release 149–153. Alterations in brain substrate utilization may also occur during hypoglycemia thereby subsequently activating signaling cascades to induce a counterregulatory response. The brain increases glycogen utilization during hypoglycemia as mea- sured by 13 C NMR spectroscopy in both healthy humans 154 and rats 155. Glycogen is stored primarily within astrocytes and is metabolized to lactate which can be transferred to axons to support energy demand 156. In awake rats treated with a glycogen phosphorylase inhibitor that blocked glycogen utilization during euglycemia but not during hypoglycemia brain glycogen content increased by 88 under euglycemic conditions 157. Compared to controls rats treated with the gly- cogen phosphorylase inhibitor maintained brain functioning longer and had reduced cell death during hypoglycemia glucose nadir 1 mM suggesting that glycogen is indeed utilized during hypoglycemia. There is evidence that glycogen supercom- pensation occurs in both rats 132 155 and humans 154 after one or multiple bouts of hypoglycemia. These observations have led to the hypothesis that enhanced glycogen utilization during hypoglycemia blunts counterregulatory responses by inhibiting activation of AMPK 132. In addition to lactate generated from glycogenolysis lactate appears to be an abundantly available energy source in the brain as a result of astrocyte glucose metabolism stimulated by glutamate released during neuronal activity 158. Research suggests that lactate is readily metabolized by neural tissue even in the presence of

slide 155:

131 131 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 131 A1c Hb glucose 159 160. Under euglycemic conditions systemic lactate infusion in humans causes increased brain lactate uptake and metabolism and reduced glucose uptake 161 and lactate metabolism increases under increased neural stimulation 160. Excess lactate infused into the ventromedial hypothalamus during systemic hypoglycemia dramatically diminishes counterregulatory responses indicating that normal neuronal signaling responses to hypoglycemia were blocked despite decreas- ing glucose availability 162. Consistent with this interpretation systemic lactate infusion during severe hypoglycemia was shown to maintain neuronal excitability 160. Adaptations at the blood-brain barrier may occur to increase transport of lac- tate as well as other monocarboxylic acids MCA such as acetate acetoacetate and b beta-hydroxybutyrate in response to repeated hypoglycemia. In subjects with well-controlled diabetes and recent recurrent hypoglycemia alterations in MCA transport were indirectly indicated by twofold increases in brain acetate concentra- tions oxidative acetate metabolism and brain acetate transport 163. Data are inconsistent regarding changes in brain glucose uptake and metabolism in response to recurrent hypoglycemia. After rats were subjected to 5 days of insulin injection to induce mild hypoglycemia GLUT1 mRNA and protein were increased in the brain which could mean that the brain is able to adapt to hypoglycemia by increas- ing brain glucose transport capacity 164. Supporting this in healthy adults brain glucose uptake fell during a stepped hypoglycemic clamp but was maintained follow- ing 56 h of hypoglycemia 3.0 mmol/l 165. In diabetes patients with near-normal A1c and a significantly greater frequency of hypoglycemia normal levels of glucose uptake were observed while uptake decreased in patients with higher Hb levels 166. Additionally it has been shown that patients with type 1 DM and a history of hypoglycemia unawareness have increased cerebral glucose concentrations compared to healthy controls 167. However healthy subjects who underwent three episodes of hypoglycemia 30 min each over 24 h had no change in brain glucose content 168. In this study though the hypoglycemic stimuli may not have been prolonged or severe enough to induce changes in brain glucose uptake as counterregulatory hormones were not universally blunted among all subjects. In those subjects that did have severe blunting of one or more counterregulatory hormones brain glucose concentration was increased following antecedent hypoglycemia 168. Glucose sensors located peripherally in the portal vein 169 170 and the carotid artery 171 probably also contribute to the signaling response to hypoglycemia. Portal vein afferent denervation or maintenance of portal vein glucose concentra- tions significantly blunted the epinephrine response to systemic hypoglycemia in rats 172. Sensing likely occurs in capsaicin-sensitive primary sensory neurons of spinal afferents from the portal vein 173 174. The primary site for glucose sensing may shift based on the rate of fall of blood glucose with the portal vein playing a greater role in counterregulation when the rate of fall of glucose is low 175. Hypoglycemia increases transmitter secretion from glomus cells in the carotid artery in a concentration-dependent manner which can in turn stimulate afferent nerve fibers. It has been suggested that transmitter secretion in response to hypogly- cemia is mediated by inhibition of K+ channel activity membrane depolarization and Ca2+ influx 176. Resection of carotid bodies in dogs led to reduced

slide 156:

132 132 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 132 2 2 counterregulatory responses during clamped hypoglycemia 171 but contradictory evidence exists showing that low blood glucose does not directly activate carotid body chemoreceptors in the rat 177. Some have also suggested that reduced b beta-adrenergic sensitivity plays a role in the increased risk for hypoglycemia following antecedent hypoglycemia. Patients with type 1 DM who meet the criteria for hypoglycemia unawareness can have reduced sensitivity to isoproterenol a b beta-adrenergic agonist 178 179 that could be the result of a dysfunction in the proximal b beta -adrenergic signal- ing pathway 180. Additionally b beta-adrenergic sensitivity is reduced follow- ing one bout of hypoglycemia in patients with type 1 DM 181 while avoiding hypoglycemia for a period of 4 months improved both b beta-adrenergic and hypoglycemic symptom responses 182. 6.6 Recovering Counterregulatory Responses and Hypoglycemia Awareness Several studies have focused on reversing deficits in counterregulation and hypogly- cemia awareness through strict avoidance of hypoglycemia. In a very short-term study patients were subjected to an acute bout of hypoglycemia 2.2 mmol/l once daily for 3 days 183. Following these repeated episodes of hypoglycemia patients underwent a hypoglycemic clamp before and after 2 days of avoiding hypoglyce- mia. During the second clamp epinephrine ACTH cortisol and symptom scores were all significantly improved compared to the first clamp indicating that even short-term avoidance of hypoglycemia improves counterregulation. Relaxation of glycemic control over the short term can also reverse counterregulatory deficiencies 182 184. In a 3-month study 184 increasing mean daily blood glucose to 8–10 mmol/l decreased episodes of hypoglycemia from 4.7 to 1.9 episodes per per- son per week. Epinephrine growth hormone and symptom responses during a sub- sequent hypoglycemic clamp were all greater compared to responses preceding the intervention. In a second 4-month study reducing insulin doses to increase prepran- dial and bedtime glucose targets from 5.6 to 8.0 and 10.0 mmol/l respectively decreased the frequency of hypoglycemia from 8.4 to 1.4 episodes per week. Thereafter autonomic and neuroglycopenic symptom responses to hypoglycemia were improved 182. In these studies Hb A1c increased from 6.9 to 8.0 and from 6.8 to 7.4 respectively 182 184. While preventing severe hypoglycemia is certainly important the goal is to do so without increasing the risk of microvascular and macrovascular complications that arise with poorer glucose control. Some argue that recovery of hypoglycemia awareness does not have to compromise glycemic control 185–187. In a 1-year intervention study 186 187 subjects with hypoglycemia unawareness who switched from conventional to intensive insulin ther- apy decreased their frequency of hypoglycemia from 0.5 to 0.045 episodes per patient- day through targeted physiological insulin replacement and intensive education. Improvements in hormone and symptom responses were observed between 2 weeks

slide 157:

133 133 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 133 Hb A1c and 3 months of starting the intervention and were sustained for the duration of the study. Although the study group claimed that glycemic control was not worsened A1c did increase from 5.83 to 6.94 indicating that there was some deterioration of mean daily blood glucose levels. In a second study 185 patients under either strict Hb A1c 6.5 or poor Hb A1c 8.2 glycemic control all with impaired awareness of hypoglycemia were provided with education and assistance in modifying diet exer- cise and insulin dosing to avoid hypoglycemia. It took subjects 4 months on average to meet the study endpoint of an absence of hypoglycemia for 3 weeks. Epinephrine and symptom scores during hypoglycemia improved and were initiated at higher blood glucose levels. Hb did not significantly increase during the study in either group. Some research suggests that improvements are only partial. After 3 months of intensively avoiding hypoglycemia patients exhibited normal symptom responses during hypoglycemia but neuroendocrine responses including epinephrine pan- creatic polypeptide and cortisol were not recovered 188. Conversely another study found an improvement in epinephrine but not symptom responses after a return from intensive to conventional insulin therapy 189. The reason for these inconsistent observations is still not understood. Some differences may be explained by varying research procedures including inclusion criteria for hypoglycemia unawareness hypoglycemic clamp methods length of interventions and sample size. However it is clear that more studies are needed to better identify effective strategies for treating impaired hormone and symptom responses during hypogly- cemia. The above studies do indicate that patient education regarding diet exer- cise and fine-tuning insulin replacement as well as regular glucose monitoring can be effective tools for avoiding hypoglycemia and improving counterregulation. Furthermore relaxing glycemic control at least temporarily may be helpful. 6.7 Preventing Severe Hypoglycemia Hypoglycemia can be severely debilitating both long- and short term. Avoidance of hypoglycemia is crucial to sustained quality of life in all patients with diabetes. In athletes with diabetes avoidance of hypoglycemia is vital also to continued athletic success. In those who compete at high speeds in hazardous environments i.e. water and/or in close proximity to others i.e. basketball cycling hypoglycemia can be especially dangerous increasing the risk for bodily injury to the patient or others. Aspects of visual information processing including contrast sensitivity inspection time visual change detection and visual movement detection can be impaired by hypoglycemia 190 191. Auditory functioning also changes with diminished auditory temporal processing and lower ability to discriminate single- tone loudness 192 193. Psychomotor function and performance on tasks associ- ated with visual and auditory selective attention are also diminished 194 195. These deficits could slow judgment and reaction time and/or result in mistakes. During a fitness camp developed specifically for active individuals with type 1 DM continuous glucose monitoring systems were used to follow glycemic

slide 158:

134 134 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 134 fluctuations in 12 subjects over 5 days 196. On average subjects were hypoglycemic hyperglycemic and euglycemic 7 11 and 82 of the time respectively. From over 60 h of data collected in each patient a total of 75 hypoglycemic episodes were recorded with at least 1 episode occurring in each person. The wide glycemic variability occurred despite patients demonstrating a substantial degree of knowl- edge regarding the appropriate use of carbohydrate and insulin during exercise and despite the 24-h availability of expert support staff i.e. physician coaches physi- cian assistants exercise physiologists. Such is the depth of the ongoing struggle that athletes face in adequately managing their blood glucose levels. Fear of hypoglycemia is an all too real issue that often arises in type 1 DM. In addi- tion to diminishing quality of life this fear poses a major barrier to both glycemic control and exercise 197. The development of a comprehensive plan to prevent hypo- glycemia will not only provide individuals with the knowledge to increase safety dur- ing exercise and avoid deterioration of glycemic control but also will build confidence in making self-treatment decisions that will hopefully translate into less anxiety. Does the athlete have impaired hypoglycemia unawareness This can be assessed by collecting a patient history of frequency of moderate to severe biochemical hypo- glycemia with or without associated symptoms 198 or a self-report questionnaire that can be used to generate a more comprehensive understanding of the person’s hypoglycemia awareness level. The self-report questionnaire has been shown to cor- relate well with symptom recognition and thresholds during a stepped hypoglycemic clamp 199. If impaired hypoglycemia awareness is present the athlete is very likely to develop hypoglycemia either during or after exercise. Priority should be placed upon correction of this syndrome prior to beginning or continuing training. Differing disease duration insulin requirements diet training regimens and choice of sport necessitate an individualized approach to diabetes management. Special attention is required during the initiation of an exercise training regimen and during major shifts in level of activity diet or insulin dosage as these changes tend to increase the frequency of low blood glucose readings 200. A number of different strategies can be used to minimize the risk of hypoglycemia see Table 6.2 and the patient and the health-care team should work together to develop the understanding and skills to use each strategy successfully. Regular blood glucose monitoring and adequate adjust- ment of insulin and carbohydrate intake are crucial to prevention of hypoglycemia and detailed information regarding these topics is available in Chaps. 3 5 and 7. 6.7.1 Improving Symptom Identification Failure to identify symptoms associate symptoms with hypoglycemia or respond appropriately to hypoglycemia can lead to more severe hypoglycemia 72. Thus a comprehensive understanding of symptoms and how to react to those symptoms is imperative. Patients tend to consistently experience specific sets of symptoms during hypoglycemia 201 202. Some studies show that patients tend to rely much more on autonomic than neuroglycopenic symptoms 12. However although the onset of

slide 159:

6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 135 Table 6.2 Strategies for lowering the risk of hypoglycemia during exercise Risk factor Reducing risk Behavioral Insulin injection Intramuscular injection Use shorter needles 4–5 mm Injection into working limb Inject insulin into abdominal subcutaneous tissue especially if performing leg exercise Alternating injection site Inject into same site but rotate injections within site Insulin dose Administering full dose will result in a Reduce basal and/or bolus doses before during and/or after exercise physiologically hyperinsulinemic state during exercise Exercising during peak insulin action Avoid exercise within the first few hours following injection of short- or rapid-acting insulin If exercise is unplanned and occurs during peak insulin action consume extra carbohydrate Carbohydrate intake Failure to consume adequate carbohydrate before during or after exercise Consume carbohydrate if blood glucose is 5.6 mmol/l prior to exercise Consume additional carbohydrate based on duration and intensity Continue monitoring blood glucose during and after exercise to determine if and when more carbohydrate should be taken Blood glucose monitoring Failure to detect a low blood glucose Perform multiple blood glucose measurements before during if exercise is of sufficient duration and after exercise. Alternatively a continuous blood glucose monitoring system can be used Biological impairments Hypoglycemia- associated autonomic failure Reduced hormonal metabolic and symptom response to exercise and hypoglycemia as a result of a former episode of exercise or hypoglycemia Reverse hypoglycemia-associated autonomic failure by consistently avoiding hypogly- cemic episodes: Temporarily relax glycemic control goals in order to avoid hypoglycemia Increase preprandial and bedtime glucose targets – reduce insulin doses and/or increase between-meal carbohydrate intake Regularly assess trends in blood glucose changes and modify insulin dose accordingly Implement or increase frequency of blood glucose monitoring Increase understanding of symptoms associated with hypoglycemia and increase ability to identify and react to symptoms

slide 160:

136 L.M. Younk and S.N. Davis Table 6.2 continued Risk factor Reducing risk Absolute insulin deficiency Environmental Inability to reduce circulating insulin levels Focus on reducing other risk factors Extreme temperature Hot and cold environments can alter hormonal responses to exercise and hypoglycemia as well as obscure symptoms of hypoglycemia Reduce exposure to temperature extremes Train under environmental conditions similar to those anticipated during competition Forces of nature Increased wind waves etc. will increase the intensity of the workout Consume extra carbohydrate Reduce speed to maintain planned intensity Others Travel Change in activity level eating pattern and/or sleep Plan for travel – pack enough snacks take regular walking/rest breaks arrive early enough to rest Altered competition schedule Delays overtime extra games/matches etc. Have extra snacks available continue monitoring blood glucose consider reducing insulin and/or consuming more carbohydrate after competition

slide 161:

6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 137 137 137 137 L.M. Younk and S.N. Davis autonomic and neuroglycopenic symptoms and cognitive dysfunction may occur at different glycemic thresholds regardless of the rate of fall of blood glucose 203 in an everyday life situation blood glucose may fall at a rate brisk enough that the onset of all symptoms may occur temporally nearly simultaneously. As such neuroglyco- penic symptoms are frequently reported during hypoglycemia as well 204. Health-care professionals should help the athlete to identify symptom trends dur- ing rest and exercise and to determine which symptoms are most helpful in recogniz- ing hypoglycemia under each condition. The athlete should also learn to monitor for additional symptoms – both autonomic and neuroglycopenic – and factors that can confound identification of symptoms especially during exercise or competition. When patients have at least one recognizable symptom that typically occurs during hypoglycemia half of the episodes of blood glucose 3.95 mmol/l can be detected. When the number of recognizable typical symptoms is increased to four or more three-quarters of hypoglycemic episodes can be identified 201. Furthermore being mindful of the potential for hypoglycemia should help to increase vigilance and sen- sitivity to physiological changes. In one study of healthy people subjected to a previ- ous episode of insulin-induced hypoglycemia half of the subjects were told that they would receive insulin during a second session and half were told that they would receive saline. Of those two groups half were given the opposite intervention of what they expected. Those anticipating insulin infusion had higher symptom scores com- pared to those expecting saline regardless of the actual intervention 205. Teammates coaches family members and friends can also be of major impor- tance in identifying symptoms of hypoglycemia. Education should be provided to members of the athlete’s support system regarding signs and symptoms of hypogly- cemia and appropriate treatment measures. 6.7.2 Record Keeping The importance of record keeping should be stressed. With so many variables con- tributing to fluctuations in blood glucose levels recording blood glucose levels insulin dosing times and doses meal intake times and amount of carbohydrate exercise duration and intensity and other relevant details will help the patient to make informed self-treatment decisions as well as determine reasons for glycemic excursions. A number of record-keeping utilities are now available online some of which can also be accessed by physicians and health-care professionals to monitor patients’ treatment regimens. 6.7.3 Intermittent High-Intensity Exercise Because intense exercise causes a rise in blood glucose a group of researchers has studied the antihypoglycemic effects of introducing short bursts of IHE before dur- ing or after a session of moderate exercise 206–208. In one group of individuals

slide 162:

6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 138 138 138 138 L.M. Younk and S.N. Davis 2max 206 performing 4-s sprints every 2 min over the course of 30 min of moderate exercise 40 VO caused blood glucose to fall to a significantly lesser degree compared to a nonsprint group. Furthermore for 60 min postexercise glucose con- tinued to fall in the nonsprinters but stabilized in the IHE group. Performing a 10-s maximal sprint before 20 min of exercise 40 VO prevented a fall in blood 2max glucose only during the early recovery period 207 but a 10-s sprint after the same exercise stabilized glucose levels for a full 2 h following exercise 208. In all three interventions exercise was performed 3.5 h after the last meal beyond peak insulin action and with preexercise blood glucose levels 11 mmol/l. Therefore if athletes wish to employ such a preventive strategy timing and duration of sprints will need to be determined empirically based on prandial state and preex- ercise blood glucose level. Also as discussed earlier evidence is conflicting as to whether or not late-onset exercise-associated hypoglycemia can be avoided using this method 101 102. Therefore glucose monitoring before and throughout sleep- ing hours is strongly recommended. 6.8 Treatment of Acute Hypoglycemia When hypoglycemia is detected by symptoms and/or biochemical measurement treatment will depend on the degree of hypoglycemia and the patient’s state of con- sciousness and his or her willingness and ability to administer or receive treatment see Table 6.3. Mild to moderate hypoglycemia can generally be initially treated with 15–20 g of simple carbohydrate such as glucose tablets or gel soft drinks or juice 209 210. The carbohydrate source should be low in fat so that absorption will not be slowed. If after 15 min symptoms have not abated or blood glucose is still low the treatment should be repeated 209 210. Lower blood glucose 2.8 mmol/l should be treated with 30 g of carbohydrate 210. These recommen- dations are not specific to athletes who may become hypoglycemic during pro- longed moderately intense exercise. Thus larger amounts of carbohydrate may be required to treat hypoglycemia under these conditions. Once blood glucose levels return to normal it is important that the patient consumes a meal including more complex carbohydrate to prevent subsequent bouts of hypoglycemia 209 210. During more severe hypoglycemia glucose gel jelly or honey can be used as these substances can be placed in the mouth against the cheek by another person 210 and are readily absorbed through the buccal mucosa. In the unconscious patient glucagon 1 mg should be administered subcutaneously or intramuscularly to stimulate hepatic glycogenolysis 209 210. Although very effective glucagon does take approximately 10 min to begin to affect blood glucose levels which is considerably longer than intravenous glucose. However unlike intravenous glucose glucagon available as a kit can be safely administered by friends family members and coaches with proper education 209–211. Those who plan to administer gluca- gon when necessary should receive hands-on training to ensure that glucagon can be

slide 163:

6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 139 139 139 139 L.M. Younk and S.N. Davis Table 6.3 Recommended interventions for an acute hypoglycemic event Level of hypoglycemia Immediate intervention Comments Mild to moderate Patient is conscious Consume carbohydrate snack: Blood glucose 2.8 mmol/l Simple carbohydrate should be used i.e. glucose tablets or gel soft drinks juice 15–20 g carbohydrate Glucose gel jelly or honey can be placed against inner cheek Blood glucose 2.8 mmol/l Avoid snacks that contain fat 30 g carbohydrate Repeat after 15 min if blood glucose remains low or symptoms have not subsided Severe Patient is unconscious Glucagon 1 mg injection Subcutaneous or intramuscular injection is acceptable Call for emergency medical assistance if necessary Make sure kit is not expired and is readily accessible Glucagon has a delayed onset of action 10 min compared to glucose Do not attempt to administer carbohydrate orally delivered in an adequate quantity and in a timely manner 211. Caregivers should be made aware of the location where glucagon kits are stored and kits should be regularly checked for expiration date 211. If emergency care is required medical staff may also administer glucagon 1 mg intramuscularly or intravenously as well as 50 ml of dextrose 20 or 25 ml of dextrose 50 intravenously. Athletes may need to allow themselves’ a recovery period before engaging in exercise following a hypoglycemic episode. In one study responses to hypoglyce- mia were not blunted 2 days after induction of a 2-h bout of hypoglycemia 212. However the severity and duration of a hypoglycemic event could affect the length of time required to recover full counterregulatory responses. 6.9 Conclusion Although rapidly improving the treatment of type 1 DM is not perfect and the risk of hypoglycemia remains especially under metabolically challenging conditions such as exercise. Athletes should be sufficiently educated regarding attendant risks and behavioral strategies that can be used to successfully minimize those risks. With practice athletes can personalize and master such strategies to avoid hypoglycemia as well as enhance performance and the enjoyment of sport and exercise.

slide 164:

140 140 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 140 140 References 1. Cryer PE. Hierarchy of physiological responses to hypoglycemia: relevance to clinical hypo- glycemia in type I insulin dependent diabetes mellitus. Horm Metab Res. 199729:92–6. 2. Fanelli C Pampanelli S Epifano L Rambotti AM Ciofetta M Modarelli F et al. Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to symptoms of and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia. 199437:797–807. 3. Mitrakou A Ryan C Veneman T Mokan M Jenssen T Kiss I et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion symptoms and cerebral dysfunction. Am J Physiol. 1991260:E67–74. 4. Schwartz NS Clutter WE Shah SD Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 198779:777–81. 5. Davis SN Shavers C Costa F. Differential gender responses to hypoglycemia are due to altera- tions in CNS drive and not glycemic thresholds. Am J Physiol Endocrinol Metab. 2000279:E1054–63. 6. Davis SN Fowler S Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes. 200049:65–72. 7. Sandoval DA Ertl AC Richardson MA Tate DB Davis SN. Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia. Diabetes. 200352:1749–55. 8. DeRosa MA Cryer PE. Hypoglycemia and the sympathoadrenal system: neurogenic symp- toms are largely the result of sympathetic neural rather than adrenomedullary activation. Am J Physiol Endocrinol Metab. 2004287:E32–41. 9. Hoffman RP Sinkey CA Anderson EA. Hypoglycemic symptom variation is related to epi- nephrine and not peripheral muscle sympathetic nerve response. J Diabetes Complications. 199711:15–20. 10. Aftab Guy D Sandoval D Richardson MA Tate D Davis SN. Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes. Am J Physiol Endocrinol Metab. 2005289:E258–65. 11. Deary IJ. Symptoms of hypoglycemia and effects on mental performance and emotions. In: Frier B Fisher M editors. Hypoglycemia in clinical diabetes. 2nd ed. Chichester: Wiley 2007. p. 25–48. 12. Towler DA Havlin CE Craft S Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic predominantly cholinergic rather than neuroglycopenic symptoms. Diabetes. 199342:1791–8. 13. Deary IJ Hepburn DA MacLeod KM Frier BM. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia. 199336:771–7. 14. Hermanns N Kubiak T Kulzer B Haak T. Emotional changes during experimentally induced hypoglycaemia in type 1 diabetes. Biol Psychol. 200363:15–44. 15. Vea H Jorde R Sager G Vaaler S Sundsfjord J. Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia. 199235:958–61. 16. Geddes J Warren RE Sommerfield AJ McAulay V Strachan MW Allen KV et al. Absence of sexual dimorphism in the symptomatic responses to hypoglycemia in adults with and with- out type 1 diabetes. Diabetes Care. 200629:1667–9. 17. Wolfe RR Nadel ER Shaw JH Stephenson LA Wolfe MH. Role of changes in insulin and glucagon in glucose homeostasis in exercise. J Clin Invest. 198677:900–7. 18. Tuttle KR Marker JC Dalsky GP Schwartz NS Shah SD Clutter WE et al. Glucagon not insulin may play a secondary role in defense against hypoglycemia during exercise. Am J Physiol. 1988254:E713–9. 19. Hirsch IB Marker JC Smith LJ Spina RJ Parvin CA Holloszy JO et al. Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Physiol. 1991 260: E695– 704.

slide 165:

141 141 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 141 141 20. Hoelzer DR Dalsky GP Clutter WE Shah SD Holloszy JO Cryer PE. Glucoregulation during exercise: hypoglycemia is prevented by redundant glucoregulatory systems sympathochro- maffin activation and changes in islet hormone secretion. J Clin Invest. 198677:212–21. 21. Marker JC Hirsch IB Smith LJ Parvin CA Holloszy JO Cryer PE. Catecholamines in pre- vention of hypoglycemia during exercise in humans. Am J Physiol. 1991260:E705–12. 22. Sotsky MJ Shilo S Shamoon H. Regulation of counterregulatory hormone secretion in man during exercise and hypoglycemia. J Clin Endocrinol Metab. 198968:9–16. 23. Marliss EB Vranic M. Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes. 200251 Suppl 1:S271–83. 24. Marliss EB Simantirakis E Miles PD Purdon C Gougeon R Field CJ et al. Glucoregulatory and hormonal responses to repeated bouts of intense exercise in normal male subjects. J Appl Physiol. 199171:924–33. 25. Marliss EB Simantirakis E Miles PD Hunt R Gougeon R Purdon C et al. Glucose turnover and its regulation during intense exercise and recovery in normal male subjects. Clin Invest Med. 199215:406–19. 26. Martin MJ Robbins DC Bergenstal R LaGrange B Rubenstein AH. Absence of exercise- induced hypoglycaemia in type i insulin-dependent diabetic patients during maintenance of normoglycaemia by short-term open-loop insulin infusion. Diabetologia. 198223:336–42. 27. Zinman B Marliss EB Hanna AK Minuk HL Vranic M. Exercise in diabetic man: glucose turnover and free insulin responses after glycemic normalization with intravenous insulin. Can J Physiol Pharmacol. 198260:1236–40. 28. Schneider SH Vitug A Ananthakrishnan R Khachadurian AK. Impaired adrenergic response to prolonged exercise in type I diabetes. Metabolism. 199140:1219–25. 29. Gerich JE Langlois M Noacco C Karam JH Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973182:171–3. 30. Bolli G de Feo P Compagnucci P Cartechini MG Angeletti G Santeusanio F et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 198332:134–41. 31. Banarer S McGregor VP Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes. 200251:958–65. 32. Gosmanov NR Szoke E Israelian Z Smith T Cryer PE Gerich JE et al. Role of the decre- ment in intraislet insulin for the glucagon response to hypoglycemia in humans. Diabetes Care. 200528:1124–31. 33. Zander E Schulz B Chlup R Woltansky P Lubs D. Muscular exercise in type I-diabetics. II. Hormonal and metabolic responses to moderate exercise. Exp Clin Endocrinol. 1985 85:95–104. 34. Purdon C Brousson M Nyveen SL Miles PD Halter JB Vranic M et al. The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects. J Clin Endocrinol Metab. 199376:566–73. 35. Sigal RJ Purdon C Fisher SJ Halter JB Vranic M Marliss EB. Hyperinsulinemia prevents prolonged hyperglycemia after intense exercise in insulin-dependent diabetic subjects. J Clin Endocrinol Metab. 199479:1049–57. 36. Heinemann L. Variability of insulin absorption and insulin action. Diabetes Technol Ther. 20024:673–82. 37. Freeman JS. Insulin analog therapy: improving the match with physiologic insulin secretion. J Am Osteopath Assoc. 2009109:26–36. 38. Miles HL Acerini CL. Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus. Paediatr Drugs. 200810:163–76. 39. Hirsch IB. Insulin analogues. N Engl J Med. 2005352:174–83. 40. Frid A Ostman J Linde B. Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM. Diabetes Care. 199013:473–7. 41. Koivisto V A Felig P. Effects of leg exercise on insulin absorption in diabetic patients. N Engl J Med. 1978298:79–83.

slide 166:

142 142 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 142 142 42. Ferrannini E Linde B Faber O. Effect of bicycle exercise on insulin absorption and subcutaneous blood flow in the normal subject. Clin Physiol. 19822:59–70. 43. Hildebrandt P. Skinfold thickness local subcutaneous blood flow and insulin absorption in diabetic patients. Acta Physiol Scand Suppl. 1991603:41–5. 44. Hildebrandt P. Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Influence of species physico-chemical properties of insulin and physiological factors. Dan Med Bull. 199138:337–46. 45. Sindelka G Heinemann L Berger M Frenck W Chantelau E. Effect of insulin concentration subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia. 199437:377–80. 46. Ronnemaa T Koivisto V A. Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients. Diabetes Care. 198811:769–73. 47. Ronnemaa T Marniemi J Leino A Karanko H Puukka P Koivisto V A. Hormone response of diabetic patients to exercise at cool and warm temperatures. Eur J Appl Physiol Occup Physiol. 199162:109–15. 48. Morris JG Nevill ME Boobis LH Macdonald IA Williams C. Muscle metabolism tempera- ture and function during prolonged intermittent high-intensity running in air temperatures of 33 degrees and 17 degrees C. Int J Sports Med. 200526:805–14. 49. Galbo H Houston ME Christensen NJ Holst JJ Nielsen B Nygaard E et al. The effect of water temperature on the hormonal response to prolonged swimming. Acta Physiol Scand. 1979105:326–37. 50. Gale EA Bennett T Green JH MacDonald IA. Hypoglycaemia hypothermia and shivering in man. Clin Sci Lond. 198161:463–9. 51. Meneilly GS Cheung E Tuokko H. Altered responses to hypoglycemia of healthy elderly people. J Clin Endocrinol Metab. 199478:1341–8. 52. Ortiz-Alonso FJ Galecki A Herman WH Smith MJ Jacquez JA Halter JB. Hypoglycemia counterregulation in elderly humans: relationship to glucose levels. Am J Physiol. 1994 267:E497–506. 53. Brierley EJ Broughton DL James OF Alberti KG. Reduced awareness of hypoglycaemia in the elderly despite an intact counter-regulatory response. QJM. 199588:439–45. 54. Silverman HG Mazzeo RS. Hormonal responses to maximal and submaximal exercise in trained and untrained men of various ages. J Gerontol A Biol Sci Med Sci. 199651:B30–7. 55. MacDonald MJ. Postexercise late-onset hypoglycemia in insulin-dependent diabetic patients. Diabetes Care. 198710:584–8. 56. Garetto LP Richter EA Goodman MN Ruderman NB. Enhanced muscle glucose metabolism after exercise in the rat: the two phases. Am J Physiol. 1984246:E471–5. 57. Maarbjerg SJ Sylow L Richter EA. Current understanding of increased insulin sensitivity after exercise - emerging candidates. Acta Physiol Oxf. 2011202:323–35. 58. Mikines KJ Sonne B Farrell PA Tronier B Galbo H. Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol. 1988254:E248–59. 59. Annuzzi G Riccardi G Capaldo B Kaijser L. Increased insulin-stimulated glucose uptake by exercised human muscles one day after prolonged physical exercise. Eur J Clin Invest. 199121:6–12. 60. Frosig C Sajan MP Maarbjerg SJ Brandt N Roepstorff C Wojtaszewski JF et al. Exercise improves phosphatidylinositol-345-trisphosphate responsiveness of atypical protein kinase C and interacts with insulin signalling to peptide elongation in human skeletal muscle. J Physiol. 2007582:1289–301. 61. Wojtaszewski JF Nielsen JN Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans. J Appl Physiol. 200293:384–92. 62. Bogardus C Thuillez P Ravussin E Vasquez B Narimiga M Azhar S. Effect of muscle gly- cogen depletion on in vivo insulin action in man. J Clin Invest. 198372:1605–10. 63. Hernandez JM Moccia T Fluckey JD Ulbrecht JS Farrell PA. Fluid snacks to help persons with type 1 diabetes avoid late onset postexercise hypoglycemia. Med Sci Sports Exerc. 200032:904–10.

slide 167:

143 143 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 143 143 64. Sonnenberg GE Kemmer FW Berger M. Exercise in type 1 insulin-dependent diabetic patients treated with continuous subcutaneous insulin infusion. Prevention of exercise induced hypoglycaemia Diabetologia. 199033:696–703. 65. Rabasa-Lhoret R Bourque J Ducros F Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen ultralente-lispro. Diabetes Care. 200124:625–30. 66. Tuominen JA Ebeling P Vuorinen-Markkola H Koivisto V A. Post-marathon paradox in IDDM: unchanged insulin sensitivity in spite of glycogen depletion. Diabet Med. 199714:301–8. 67. Asp S Richter EA. Decreased insulin action on muscle glucose transport after eccentric con- tractions in rats. J Appl Physiol. 199681:1924–8. 68. Kristiansen S Jones J Handberg A Dohm GL Richter EA. Eccentric contractions decrease glucose transporter transcription rate mRNA and protein in skeletal muscle. Am J Physiol. 1997272:C1734–8. 69. Del Aguila LF Krishnan RK Ulbrecht JS Farrell PA Correll PH Lang CH et al. Muscle damage impairs insulin stimulation of IRS-1 PI 3-kinase and Akt-kinase in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000279:E206–12. 70. McMahon SK Ferreira LD Ratnam N Davey RJ Youngs LM Davis EA et al. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adoles- cents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab. 200792:963–8. 71. Tsalikian E Mauras N Beck RW Tamborlane WV Janz KF Chase HP et al. Impact of exer- cise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 2005147:528–34. 72. Gonder-Frederick L Cox D Kovatchev B Schlundt D Clarke W. A biopsychobehavioral model of risk of severe hypoglycemia. Diabetes Care. 199720:661–9. 73. Nermoen I Jorde R Sager G Sundsfjord J Birkeland K. Effects of exercise on hypoglycaemic responses in insulin-dependent diabetes mellitus. Diabetes Metab. 199824:131–6. 74. Bottini P Boschetti E Pampanelli S Ciofetta M Del Sindaco P Scionti L et al. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a nonselective defect. Diabetes. 199746:814–23. 75. Hilsted J Madsbad S Krarup T Sestoft L Christensen NJ Tronier B et al. Hormonal meta- bolic and cardiovascular responses to hypoglycemia in diabetic autonomic neuropathy. Diabetes. 198130:626–33. 76. Hoeldtke RD Boden G Shuman CR Owen OE. Reduced epinephrine secretion and hypoglycemia unawareness in diabetic autonomic neuropathy. Ann Intern Med. 198296: 459–62. 77. Boden G Reichard Jr GA Hoeldtke RD Rezvani I Owen OE. Severe insulin-induced hypo- glycemia associated with deficiencies in the release of counterregulatory hormones. N Engl J Med. 1981305:1200–5. 78. Ryder RE Owens DR Hayes TM Ghatei MA Bloom SR. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy. BMJ. 1990301:783–7. 79. Dagogo-Jack SE Craft S Cryer PE. Hypoglycemia-associated autonomic failure in insulin- dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to symptoms of and defense against subsequent hypoglycemia. J Clin Invest. 1993 91:819–28. 80. Berlin I Grimaldi A Payan C Sachon C Bosquet F Thervet F et al. Hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients. Diabetes Care. 198710:742–7. 81. Hepburn DA Patrick AW Eadington DW Ewing DJ Frier BM. Unawareness of hypoglycae- mia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabet Med. 19907:711–7.

slide 168:

144 144 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 144 144 82. Galassetti P Tate D Neill RA Richardson A Leu SY Davis SN. Effect of differing anteced- ent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab. 2006290:E1109–17. 83. Hoeldtke RD Boden G. Epinephrine secretion hypoglycemia unawareness and diabetic autonomic neuropathy. Ann Intern Med. 1994120:512–7. 84. Webb SM Fernandez Castaner M. Glucose counterregulation in diabetic autonomic neuropa- thy. Clin Physiol. 19855 Suppl 5:66–71. 85. Adamson U Lins PE Efendic S Hamberger B Wajngot A. Impaired counter regulation of hypoglycemia in a group of insulin-dependent diabetics with recurrent episodes of severe hypoglycemia. Acta Med Scand. 1984216:215–22. 86. Sjobom NC Adamson U Lin PE. The prevalence of impaired glucose counter-regulation during an insulin-infusion test in insulin-treated diabetic patients prone to severe hypoglycae- mia. Diabetologia. 198932:818–25. 87. Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle. Diabetes. 199241:255–60. 88. Kennedy FP Bolli GB Go VL Cryer PE Gerich JE. The significance of impaired pancreatic polypeptide and epinephrine responses to hypoglycemia in patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 198764:602–8. 89. Davis MR Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metab. 199173:995–1001. 90. Heller SR Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 199140:223–6. 91. Widom B Simonson DC. Intermittent hypoglycemia impairs glucose counterregulation. Diabetes. 199241:1597–602. 92. Lingenfelser T Renn W Sommerwerck U Jung MF Buettner UW Zaiser-Kaschel H et al. Compromised hormonal counterregulation symptom awareness and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients. Diabetes. 199342:610–8. 93. Ovalle F Fanelli CG Paramore DS Hershey T Craft S Cryer PE. Brief twice-weekly epi- sodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus. Diabetes. 199847:1472–9. 94. Davis SN Shavers C Mosqueda-Garcia R Costa F. Effects of differing antecedent hypogly- cemia on subsequent counterregulation in normal humans. Diabetes. 199746:1328–35. 95. Davis SN Mann S Galassetti P Neill RA Tate D Ertl AC et al. Effects of differing dura- tions of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglyce- mia in normal humans. Diabetes. 200049:1897–903. 96. Davis SN Galassetti P Wasserman DH Tate D. Effects of antecedent hypoglycemia on sub- sequent counterregulatory responses to exercise. Diabetes. 200049:73–81. 97. Galassetti P Tate D Neill RA Morrey S Wasserman DH Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes. 200352:1761–9. 98. Galassetti P Mann S Tate D Neill RA Costa F Wasserman DH et al. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab. 2001280:E908–17. 99. Sandoval DA Guy DL Richardson MA Ertl AC Davis SN. Acute same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab. 2006290:E1331–8. 100. Sandoval DA Guy DL Richardson MA Ertl AC Davis SN. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Diabetes. 200453:1798–806. 101. Maran A Pavan P Bonsembiante B Brugin E Ermolao A Avogaro A et al. Continuous glucose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther. 201012:763–8.

slide 169:

145 145 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 145 145 102. Iscoe KE Riddell MC. Continuous moderate-intensity exercise with or without intermittent high-intensity work: effects on acute and late glycaemia in athletes with Type 1 diabetes mel- litus. Diabet Med. 2011287:824–32. 103. Iscoe KE Campbell JE Jamnik V Perkins BA Riddell MC. Efficacy of continuous real-time blood glucose monitoring during and after prolonged high-intensity cycling exercise: spin- ning with a continuous glucose monitoring system. Diabetes Technol Ther. 20068:627–35. 104. The DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med. 199190:450–9. 105. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose mon- itoring in children and adults with type 1 diabetes. Diabetes Care. 201033:1004–8. 106. Banarer S Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 dia- betes: reduced awakening from sleep during hypoglycemia. Diabetes. 200352:1195–203. 107. Jones TW Porter P Sherwin RS Davis EA O’Leary P Frazer F et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998338:1657–62. 108. Matyka KA Crowne EC Havel PJ Macdonald IA Matthews D Dunger DB. Counterregulation during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes. Diabetes Care. 199922:1144–50. 109. Veneman T Mitrakou A Mokan M Cryer P Gerich J. Induction of hypoglycemia unaware- ness by asymptomatic nocturnal hypoglycemia. Diabetes. 199342:1233–7. 110. Fanelli CG Paramore DS Hershey T Terkamp C Ovalle F Craft S et al. Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes. Diabetes. 1998 47:1920–7. 111. Hepburn DA Patrick AW Brash HM Thomson I Frier BM. Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation. Diabet Med. 19918:934–45. 112. Boyle PJ Schwartz NS Shah SD Clutter WE Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in non- diabetics. N Engl J Med. 1988318:1487–92. 113. Clarke WL Gonder-Frederick LA Richards FE Cryer PE. Multifactorial origin of hypogly- cemic symptom unawareness in IDDM. Association with defective glucose counterregula- tion and better glycemic control. Diabetes. 199140:680–5. 114. Amiel SA Pottinger RC Archibald HR Chusney G Cunnah DT Prior PF et al. Effect of antecedent glucose control on cerebral function during hypoglycemia. Diabetes Care. 199114:109–18. 115. Maran A Lomas J Macdonald IA Amiel SA. Lack of preservation of higher brain function dur- ing hypoglycaemia in patients with intensively-treated IDDM. Diabetologia. 199538:1412–8. 116. Puente EC Silverstein J Bree AJ Musikantow DR Wozniak DF Maloney S et al. Recurrent moderate hypoglycemia ameliorates brain damage and cognitive dysfunction induced by severe hypoglycemia. Diabetes. 201059:1055–62. 117. Oomura Y Ooyama H Sugimori M Nakamura T Yamada Y . Glucose inhibition of the glu- cose-sensitive neurone in the rat lateral hypothalamus. Nature. 1974247:284–6. 118. Borg MA Sherwin RS Borg WP Tamborlane WV Shulman GI. Local ventromedial hypo- thalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest. 199799:361–5. 119. Borg WP Sherwin RS During MJ Borg MA Shulman GI. Local ventromedial hypothala- mus glucopenia triggers counterregulatory hormone release. Diabetes. 199544:180–4. 120. Song Z Levin BE McArdle JJ Bakhos N Routh VH. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes. 200150:2673–81. 121. Andrew SF Dinh TT Ritter S. Localized glucoprivation of hindbrain sites elicits corticoster- one and glucagon secretion. Am J Physiol Regul Integr Comp Physiol. 2007292:R1792–8. 122. Balfour RH Hansen AM Trapp S. Neuronal responses to transient hypoglycaemia in the dorsal vagal complex of the rat brainstem. J Physiol. 2006570:469–84.

slide 170:

146 146 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 146 146 123. Mizuno Y Oomura Y . Glucose responding neurons in the nucleus tractus solitarius of the rat: in vitro study. Brain Res. 1984307:109–16. 124. Funahashi M Adachi A. Glucose-responsive neurons exist within the area postrema of the rat: in vitro study on the isolated slice preparation. Brain Res Bull. 199332:531–5. 125. Borg MA Borg WP Tamborlane WV Brines ML Shulman GI Sherwin RS. Chronic hypo- glycemia and diabetes impair counterregulation induced by localized 2-deoxy-glucose perfu- sion of the ventromedial hypothalamus in rats. Diabetes. 199948:584–7. 126. Sanders NM Taborsky Jr GJ Wilkinson CW Daumen W Figlewicz DP. Antecedent hind- brain glucoprivation does not impair the counterregulatory response to hypoglycemia. Diabetes. 200756:217–23. 127. Roncero I Alvarez E Vazquez P Blazquez E. Functional glucokinase isoforms are expressed in rat brain. J Neurochem. 200074:1848–57. 128. Kang L Dunn-Meynell AA Routh VH Gaspers LD Nagata Y Nishimura T et al. Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes. 200655:412–20. 129. Dunn-Meynell AA Routh VH Kang L Gaspers L Levin BE. Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes. 200251:2056–65. 130. Kang L Sanders NM Dunn-Meynell AA Gaspers LD Routh VH Thomas AP et al. Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic gluco- sensing neurons. Am J Physiol Regul Integr Comp Physiol. 2008294:R784–92. 131. Levin BE Becker TC Eiki J Zhang BB Dunn-Meynell AA. V entromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia. Diabetes. 200857:1371–9. 132. Alquier T Kawashima J Tsuji Y Kahn BB. Role of hypothalamic adenosine 5¢-monophos- phate-activated protein kinase in the impaired counterregulatory response induced by repeti- tive neuroglucopenia. Endocrinology. 2007148:1367–75. 133. McCrimmon RJ Fan X Ding Y Zhu W Jacob RJ Sherwin RS. Potential role for AMP- activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes. 200453:1953–8. 134. McCrimmon RJ Shaw M Fan X Cheng H Ding Y Vella MC et al. Key role for AMP- activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes. 200857:444–50. 135. McCrimmon RJ Fan X Cheng H McNay E Chan O Shaw M et al. Activation of AMP- activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes. 200655:1755–60. 136. Fan X Ding Y Brown S Zhou L Shaw M V ella MC et al. Hypothalamic AMP-activated pro- tein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes. Am J Physiol Regul Integr Comp Physiol. 2009296:R1702–8. 137. Levin BE Routh VH Kang L Sanders NM Dunn-Meynell AA. Neuronal glucosensing: what do we know after 50 years Diabetes. 200453:2521–8. 138. Evans ML McCrimmon RJ Flanagan DE Keshavarz T Fan X McNay EC et al. Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and trig- gering counterregulatory epinephrine and glucagon responses. Diabetes. 200453:2542–51. 139. McCrimmon RJ Evans ML Fan X McNay EC Chan O Ding Y et al. Activation of ATP- sensitive K + channels in the ventromedial hypothalamus amplifies counterregulatory hor- mone responses to hypoglycemia in normal and recurrently hypoglycemic rats. Diabetes. 200554:3169–74. 140. Tong Q Ye C McCrimmon RJ Dhillon H Choi B Kramer MD et al. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 20075:383–93. 141. Beverly JL De Vries MG Bouman SD Arseneau LM. Noradrenergic and GABAergic sys- tems in the medial hypothalamus are activated during hypoglycemia. Am J Physiol Regul Integr Comp Physiol. 2001280:R563–9.

slide 171:

147 147 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 147 147 142. Chan O Cheng H Herzog R Czyzyk D Zhu W Wang A et al. Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia. Diabetes. 200857:1363–70. 143. Giordano R Grottoli S Brossa P Pellegrino M Destefanis S Lanfranco F et al. Alprazolam a benzodiazepine activating GABA receptor reduces the neuroendocrine responses to insu- lin-induced hypoglycaemia in humans. Clin Endocrinol Oxf. 200359:314–20. 144. Hedrington MS Farmerie S Ertl AC Wang Z Tate DB Davis SN. Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans. Diabetes. 201059:1074–81. 145. Chan O Zhu W Ding Y McCrimmon RJ Sherwin RS. Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. Diabetes. 200655:1080–7. 146. Beverly JL de Vries MG Beverly MF Arseneau LM. Norepinephrine mediates glucoprivic- induced increase in GABA in the ventromedial hypothalamus of rats. Am J Physiol Regul Integr Comp Physiol. 2000279:R990–6. 147. McCrimmon RJ. Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia- induced hormonal counterregulation. J Clin Invest. 2006116:1723–30. 148. Chalmers DT Lovenberg TW De Souza EB. Localization of novel corticotropin-releasing factor receptor CRF2 mRNA expression to specific subcortical nuclei in rat brain: compari- son with CRF1 receptor mRNA expression. J Neurosci. 199515:6340–50. 149. Cotero VE Routh VH. Insulin blunts the response of glucose-excited neurons in the ventro- lateral-ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab. 2009296:E1101–9. 150. Wang R Cruciani-Guglielmacci C Migrenne S Magnan C Cotero VE Routh VH. Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels. J Neurophysiol. 200695:1491–8. 151. Paranjape SA Chan O Zhu W Horblitt AM McNay EC Cresswell JA et al. Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo. Diabetes. 201059:1521–7. 152. Wang R Liu X Hentges ST Dunn-Meynell AA Levin BE Wang W et al. The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes. 200453:1959–65. 153. Canabal DD Song Z Potian JG Beuve A McArdle JJ Routh VH. Glucose insulin and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2007292: R1418–28. 154. Oz G Kumar A Rao JP Kodl CT Chow L Eberly LE et al. Human brain glycogen metabo- lism during and after hypoglycemia. Diabetes. 200958:1978–85. 155. Choi IY Seaquist ER Gruetter R. Effect of hypoglycemia on brain glycogen metabolism in vivo. J Neurosci Res. 200372:25–32. 156. Brown AM Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 200755:1263–71. 157. Suh SW Bergher JP Anderson CM Treadway JL Fosgerau K Swanson RA. Astrocyte gly- cogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphory- lase inhibitor CP-316819 R-R S-5-chloro-N-2-hydroxy-3-methoxymethylamino- 3-oxo-1-phenylmethylpro pyl-1 H-indole-2-carboxamide. J Pharmacol Exp Ther. 2007321:45–50. 158. Pellerin L Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 199491:10625–9. 159. Larrabee MG. Lactate metabolism and its effects on glucose metabolism in an excised neural tissue. J Neurochem. 199564:1734–41. 160. Wyss MT Jolivet R Buck A Magistretti PJ Weber B. In vivo evidence for lactate as a neu- ronal energy source. J Neurosci. 201131:7477–85.

slide 172:

148 148 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 148 148 161. van Hall G Stromstad M Rasmussen P Jans O Zaar M Gam C et al. Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab. 200929:1121–9. 162. Borg MA Tamborlane WV Shulman GI Sherwin RS. Local lactate perfusion of the ventro- medial hypothalamus suppresses hypoglycemic counterregulation. Diabetes. 200352: 663–6. 163. Mason GF Petersen KF Lebon V Rothman DL Shulman GI. Increased brain monocarboxy- lic acid transport and utilization in type 1 diabetes. Diabetes. 200655:929–34. 164. Koranyi L Bourey RE James D Mueckler M Fiedorek Jr FT Permutt MA. Glucose trans- porter gene expression in rat brain: pretranslational changes associated with chronic insulin- induced hypoglycemia fasting and diabetes. Mol Cell Neurosci. 19912:244–52. 165. Boyle PJ Nagy RJ O’Connor AM Kempers SF Yeo RA Qualls C. Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci U S A. 199491: 9352–6. 166. Boyle PJ Kempers SF O’Connor AM Nagy RJ. Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med. 1995333:1726–31. 167. Criego AB Tkac I Kumar A Thomas W Gruetter R Seaquist ER. Brain glucose concentra- tions in patients with type 1 diabetes and hypoglycemia unawareness. J Neurosci Res. 200579:42–7. 168. Criego AB Tkac I Kumar A Thomas W Gruetter R Seaquist ER. Brain glucose concentrations in healthy humans subjected to recurrent hypoglycemia. J Neurosci Res. 200582:525–30. 169. Hevener AL Bergman RN Donovan CM. Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes. 199746:1521–5. 170. Matveyenko A V Bohland M Saberi M Donovan CM. Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglyce- mia. Am J Physiol Endocrinol Metab. 2007293:E857–64. 171. Koyama Y Coker RH Stone EE Lacy DB Jabbour K Williams PE et al. Evidence that carotid bodies play an important role in glucoregulation in vivo. Diabetes. 200049: 1434–42. 172. Hevener AL Bergman RN Donovan CM. Portal vein afferents are critical for the sympathoa- drenal response to hypoglycemia. Diabetes. 200049:8–12. 173. Fujita S Bohland M Sanchez-Watts G Watts AG Donovan CM. Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons. Am J Physiol Endocrinol Metab. 2007293:E96–E101. 174. Fujita S Donovan CM. Celiac-superior mesenteric ganglionectomy but not vagotomy sup- presses the sympathoadrenal response to insulin-induced hypoglycemia. Diabetes. 200554: 3258–64. 175. Saberi M Bohland M Donovan CM. The locus for hypoglycemic detection shifts with the rate of fall in glycemia: the role of portal-superior mesenteric vein glucose sensing. Diabetes. 200857:1380–6. 176. Pardal R Lopez-Barneo J. Low glucose-sensing cells in the carotid body. Nat Neurosci. 20025:197–8. 177. Conde SV Obeso A Gonzalez C. Low glucose effects on rat carotid body chemoreceptor cells’ secretory responses and action potential frequency in the carotid sinus nerve. J Physiol. 2007585:721–30. 178. Berlin I Grimaldi A Landault C Zoghbi F Thervet F Puech AJ et al. Lack of hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients. J Clin Endocrinol Metab. 198866:273–8. 179. Korytkowski MT Mokan M Veneman TF Mitrakou A Cryer PE Gerich JE. Reduced beta- adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness. Diabetes Care. 199821:1939–43. 180. Trovik TS Vaartun A Jorde R Sager G. Dysfunction in the beta 2-adrenergic signal pathway in patients with insulin dependent diabetes mellitus IDDM and unawareness of hypoglycae- mia. Eur J Clin Pharmacol. 199548:327–32.

slide 173:

149 149 L.M. Younk and S.N. Davis 6 Hypoglycemia and Hypoglycemia Unawareness During and Following Exercise 149 149 181. Fritsche A Stumvoll M Grub M Sieslack S Renn W Schmulling RM et al. Effect of hypo- glycemia on beta-adrenergic sensitivity in normal and type 1 diabetic subjects. Diabetes Care. 199821:1505–10. 182. Fritsche A Stefan N Haring H Gerich J Stumvoll M. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes. Ann Intern Med. 2001134:729–36. 183. Lingenfelser T Buettner U Martin J Tobis M Renn W Kaschel R et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoid- ance of hypoglycemia in IDDM. Diabetes Care. 199518:321–5. 184. Liu D McManus RM Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control. Clin Invest Med. 199619:71–82. 185. Cranston I Lomas J Maran A Macdonald I Amiel SA. Restoration of hypoglycaemia aware- ness in patients with long-duration insulin-dependent diabetes. Lancet. 1994344:283–7. 186. Fanelli C Pampanelli S Epifano L Rambotti AM Di Vincenzo A Modarelli F et al. Long- term recovery from unawareness deficient counterregulation and lack of cognitive dysfunc- tion during hypoglycaemia following institution of rational intensive insulin therapy in IDDM. Diabetologia. 199437:1265–76. 187. Fanelli CG Epifano L Rambotti AM Pampanelli S Di Vincenzo A Modarelli F et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to symptoms of and cognitive function during hypo- glycemia in intensively treated patients with short-term IDDM. Diabetes. 199342:1683–9. 188. Dagogo-Jack S Rattarasarn C Cryer PE. Reversal of hypoglycemia unawareness but not defective glucose counterregulation in IDDM. Diabetes. 199443:1426–34. 189. Davis M Mellman M Friedman S Chang CJ Shamoon H. Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. Am J Med. 199497:535–42. 190. McCrimmon RJ Deary IJ Huntly BJ MacLeod KJ Frier BM. Visual information processing during controlled hypoglycaemia in humans. Brain. 1996119Pt 4:1277–87. 191. Ewing FM Deary IJ McCrimmon RJ Strachan MW Frier BM. Effect of acute hypoglyce- mia on visual information processing in adults with type 1 diabetes mellitus. Physiol Behav. 199864:653–60. 192. Strachan MW Ewing FM Frier BM McCrimmon RJ Deary IJ. Effects of acute hypoglycae- mia on auditory information processing in adults with Type I diabetes. Diabetologia. 200346:97–105. 193. McCrimmon RJ Deary IJ Frier BM. Auditory information processing during acute insulin- induced hypoglycaemia in non-diabetic human subjects. Neuropsychologia. 199735: 1547–53. 194. Geddes J Deary IJ Frier BM. Effects of acute insulin-induced hypoglycaemia on psychomo- tor function: people with type 1 diabetes are less affected than non-diabetic adults. Diabetologia. 200851:1814–21. 195. McAulay V Deary IJ Sommerfield AJ Frier BM. Attentional functioning is impaired during acute hypoglycaemia in people with Type 1 diabetes. Diabet Med. 200623:26–31. 196. Iscoe KE Corcoran M Riddell MC. High rates of nocturnal hypoglycemia in a unique sports camp for athletes with type 1 diabetes: lessons learned from continuous glucose monitoring systems. Can J Diabetes. 200832:182–9. 197. Brazeau AS Rabasa-Lhoret R Strychar I Mircescu H. Barriers to physical activity among patients with type 1 diabetes. Diabetes Care. 200831:2108–9. 198. Clarke WL Cox DJ Gonder-Frederick LA Julian D Schlundt D Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic fre- quency and associated symptoms. Diabetes Care. 199518:517–22. 199. Janssen MM Snoek FJ Heine RJ. Assessing impaired hypoglycemia awareness in type 1 diabetes: agreement of self-report but not of field study data with the autonomic symptom threshold during experimental hypoglycemia. Diabetes Care. 200023:529–32.

slide 174:

150 150 L.M. Younk and S.N. Davis 200. Clarke WL Cox DJ Gonder-Frederick LA Julian D Schlundt D Polonsky W. The relation- ship between nonroutine use of insulin food and exercise and the occurrence of hypoglyce- mia in adults with IDDM and varying degrees of hypoglycemic awareness and metabolic control. Diabetes Educ. 199723:55–8. 201. Cox DJ Gonder-Frederick L Antoun B Cryer PE Clarke WL. Perceived symptoms in the recognition of hypoglycemia. Diabetes Care. 199316:519–27. 202. Pennebaker JW Cox DJ Gonder-Frederick L Wunsch MG Evans WS Pohl S. Physical symptoms related to blood glucose in insulin-dependent diabetics. Psychosom Med. 1981 43:489–500. 203. Mitrakou A Mokan M Ryan C Veneman T Cryer P Gerich J. Influence of plasma glucose rate of decrease on hierarchy of responses to hypoglycemia. J Clin Endocrinol Metab. 199376:462–5. 204. Hepburn DA Deary IJ Frier BM Patrick AW Quinn JD Fisher BM. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care. 199114:949–57. 205. Pohl J Frohnau G Kerner W Fehm-Wolfsdorf G. Symptom awareness is affected by the subjects’ expectations during insulin-induced hypoglycemia. Diabetes Care. 199720: 796–802. 206. Guelfi KJ Jones TW Fournier PA. The decline in blood glucose levels is less with intermit- tent high-intensity compared with moderate exercise in individuals with type 1 diabetes. Diabetes Care. 200528:1289–94. 207. Bussau V A Ferreira LD Jones TW Fournier PA. A 10-s sprint performed prior to moderate- intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Diabetologia. 200750:1815–8. 208. Bussau V A Ferreira LD Jones TW Fournier PA. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care. 200629:601–6. 209. Cryer PE Davis SN Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 200326: 1902–12. 210. Pearson T. Glucagon as a treatment of severe hypoglycemia: safe and efficacious but under- utilized. Diabetes Educ. 200834:128–34. 211. Harris G Diment A Sulway M Wilkinson M. Glucagon administration – underevaluated and undertaught. Practical Diabetes Int. 200118:22–5. 212. George E Marques JL Harris ND Macdonald IA Hardisty CA Heller SR. Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM. Diabetes Care. 199720:1293–8.

slide 175:

Chapter 7 Fueling the Athlete with Type 1 Diabetes To Cure Diabetes Naturally Click Here Carin Hume 7.1 Introduction Evidence-based guidelines exist to advise athletes on the appropriate amount com- position and timing of food intake required to optimize training and performance 1–3. The nutrition goals and guidelines for training and competition for athletes with and without T1DM are similar yet there are special considerations for the athlete with T1DM. Maintenance of glycemic control remains an important goal for the athlete with T1DM so as to limit the progression of long-term complications from diabetes 4. A recent review by the American Dietetic Association shows that medical nutri- tion therapy can help to reduce the potential for complications of diabetes through improvements in glycemic lipid and blood pressure control 5. Tailored nutritional advice may also be able to have a significant influence both on athletic performance and glycemic control in active individuals with T1DM. In this chapter we will con- sider important features of the nutritional guidelines for athletes without diabetes and then discuss how these might need to be adjusted for athletes with T1DM. 7.2 Nutrition Guidelines for the Athlete Without T1DM A summary of nutrition guidelines for athletes without diabetes is presented below. These guidelines serve as a basis for nutritional advice to the athlete with T1DM but will need to be adjusted to accommodate the particular needs of this group. C. Hume B.Sc. M.Sc. Department of Nutrition and Dietetics Buckinghamshire Hospitals NHS Trust Queen Alexandra Rd. High Wycombe Buckinghamshire HP11 2TT UK I. Gallen ed. Type 1 Diabetes

slide 176:

DOI 10.1007/978-0-85729-754-9_7 © Springer-Verlag London Limited 2012 151

slide 177:

152 152 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 152 152 7.2.1 Carbohydrate • Athletes need to consume a diet containing adequate daily carbohydrate CHO to support training and maintain health. CHO in the athlete’s diet needs to be considered in terms of whether both the total daily intake and the timing of CHO consumption in relation to exercise maintain an adequate supply of CHO sub- strate for the muscle and central nervous system 3. CHO needs will change according to the training load and competition program and are therefore likely to vary from day to day. • An adequate CHO intake is required to meet the fuel requirements of training and to optimize the restoration of muscle glycogen stores between training ses- sions. This is essential for high-intensity and long duration training sessions. Daily CHO intake guidelines for athletes are expressed per kilogram body mass and range from 3–12 g/kg BM/day 3. Athletes partaking in moderate-intensity exercise for approximately 1 h per day should aim for a CHO intake of 5 to 7 g/kg BM/day. CHO recommendations for endurance athletes training at a mod- erate to high intensity level for 1–3 h per day are 6–10 g/kg BM/day. Athletes partaking in more extreme and moderate- to higher-intensity exercise for more than 4 h per day may require a CHO intake in the range of 8–12 g/kg BM/day. For athletes performing skill-based activities and recreational athletes not per- forming daily exercise a CHO intake of 3 g/kg BM/day is probably adequate. It is essential to have an understanding of the type of training undertaken by the athlete and the energy demands of the sport in order that these guidelines may be correctly applied. • “Carbohydrate loading” is the consumption of extra CHO in the time leading up to an event in order to maximize muscle glycogen stores. Evidence suggests that this may be beneficial for endurance events lasting longer than 90 min 6 in particular when the athlete’s daily diet provides 7–8 g CHO/kg BM/day. A CHO-loading regimen may involve 1–3 days of a high-CHO diet providing between 10–12 g CHO/kg BM/day 7 8. • During exercise the consumption of CHO provides an exogenous fuel source to the muscle and central nervous system. Current guidelines recommend a CHO intake of 30–60 g/h for sports of more than 60 min in which fatigue is likely to occur 1 2. This is a general guideline and must be adapted to the needs of the individual and sport. • In events lasting an hour or less small amounts of CHO can improve cognitive and physical performance most likely due to a central nervous system effect 9. Interestingly performance improvements have also been shown where athletes simply rinsed their mouth with a CHO drink during a 1-h cycling time trial 10. • In events lasting longer than 2.5 h it is suggested that the amount of CHO required to optimize performance ranges from 60–90 g/h and there appears to be a dose-response relationship between CHO intake and performance 11. When the hourly CHO intake is between 70–90 g/h it is advisable to use sports prod- ucts that contain a mixture of CHO sources i.e. glucose and fructose in order to maximize CHO oxidation and absorption from the gut 12.

slide 178:

153 153 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 153 153 • Where the recovery period is short i.e. 8 h between intense training sessions it is advisable to begin consuming CHO as soon as possible after a training ses- sion or competition event. In the immediate post-exercise period 0–4 h after exercise a CHO intake of 1.0–1.2 g/kg BM/h for the first 4 h is required to replace glycogen stores. CHO with a moderate to high glycemic index see below may be preferable when rapid restoration of glycogen stores is a priority 13. The combined ingestion of a small amount of protein 0.2–0.4 g/kg BM/h with smaller amounts of CHO 0.8 g/kg BM/h results in similar muscle glyco- gen synthesis compared to when larger amounts of CHO are ingested alone 14. The addition of protein to the post-exercise CHO is therefore beneficial when CHO requirements cannot be met. For athletes who rest for a day between intense training sessions the timing and quantity of CHO consumed immedi- ately post- exercise is of lesser importance and the focus should be on consum- ing sufficient CHO during the 24-h period after exercise 15. Nevertheless consuming a meal or snack within 60 min post-exercise is important as muscle glycogen synthesis rates are much higher in the immediate post-exercise period. 7.2.1.1 Glycemic Index GI The GI classifies CHO-rich foods based on their postprandial blood glucose response compared with a reference food usually white bread or glucose which has a GI value of 100 16. GI is calculated by measuring the incremental area under the blood glucose response curve after the ingestion of a reference food containing 50 g of available CHO and a test food also containing 50 g of available CHO. A high GI value indicates rapid absorption and delivery of the CHO into circulation. CHO-rich foods can be classified as high GI GI 71 moderate GI GI between 56 and 70 and low GI GI of 55 or less 16. 7.2.1.2 The GI and Exercise Performance in the Athlete Low-GI pre-exercise feedings 1–3 h before exercise have been shown to result in greater fat oxidation and lower muscle glycogen utilization during exercise com- pared to high-GI pre-exercise feedings 17. However it is debatable whether this apparent metabolic benefit translates into a performance benefit. A small number of studies have shown a performance benefit for a low-GI pre-exercise meal 18 but studies which have supplemented CHO during exercise indicate that the GI of the pre-exercise meal has little impact on athletic performance and show no differences in CHO and fat oxidation when a CHO beverage is ingested during exercise 19. Given that it is accepted practice for athletes to consume CHO during endurance events and exercise lasting more than 1 h the practical relevance of including the GI in the pre-exercise nutrition strategy is unclear. The GI may have a more important impact on post-exercise nutrition. If rapid restoration of glycogen is a priority due to short recovery periods 8 h between

slide 179:

154 154 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 154 154 training sessions a benefit has been demonstrated for higher-GI foods over lower- GI foods 20. However as discussed above the timing quantity and rate of CHO ingested after exercise are also all important for rapid glycogen synthesis. 7.2.2 Protein • The timing of protein intake is important. Foods or snacks containing high-qual- ity protein should be consumed regularly throughout the day and in particular soon after exercise to aid in the maintenance or gain of muscle and in the repair of damaged tissues. Consumption of 15–25 g of protein soon after all training sessions will maximize the synthesis of proteins 1. • A varied diet that meets energy needs will provide adequate protein for most athletes however for smaller athletes with lower energy intakes consideration needs to be given to ensure that adequate protein is consumed. 7.2.3 Hydration Being adequately hydrated is important for optimizing exercise performance. The American College of Sports Medicine ACSM position stand on exercise and fluid replacement 21 forms the basis for the following recommendations. • It is recommended to ingest 5–7 ml/kg of fluid at least 4 h before exercise. • During exercise athletes should drink enough fluid to limit dehydration to 2 of body weight. It is important to avoid excessive fluid ingestion which can result in hyponatremia and associated problems. Gaining weight during exercise is an important indicator that fluid ingestion is inappropriately high. • Rates of fluid loss are highly variable. The rate of fluid replacement required will be dependent on a number of factors such as the individual’s sweat rate exercise duration and opportunities to drink. Extra care needs to be given to avoiding dehy- dration when exercising in hot and humid environments and at high altitudes. • Sodium stimulates thirst and fluid retention and should be included in beverages at a level of 500–700 mg/l when sweat losses are high and when exercise lasts more than 2 h. • The CHO concentration of beverages should ideally not exceed 8 in order to maximize gastric emptying and minimize the chance of gastrointestinal upset. • In the post-exercise period rapid and complete recovery from excessive dehy- dration can be achieved by drinking 1.5 l of fluid for every kilogram lost. 7.2.4 Vitamin and Mineral Supplements • Vitamin and mineral supplements are typically not required if an athlete is con- suming adequate energy from a varied diet.

slide 180:

155 155 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 155 155 • Adequate calcium and vitamin D play an important role in bone health and in the prevention of stress fractures. Athletes who live at northern latitudes or who train predominantly indoors may be deficient in vitamin D and are therefore likely to benefit from supplementation with vitamin D 22. • In addition to vitamin D calcium supplementation may be required in athletes with amenorrhea and weight-conscious athletes with a low energy intake in order to prevent low bone density and the risk of stress fractures 23. 7.3 Specific Challenges in Diabetes As we have seen in Chap. 2 exercise presents particular metabolic challenges in T1DM with a significant risk of both hyper- and hypoglycemia depending on the situation. Maintaining blood glucose levels within an acceptable range requires the correct balance between insulin dosing the consumption of metabolic fuels par- ticularly carbohydrate and the energy requirements of the exercise. In practice the energy requirements are often relatively inflexible being determined by the training goals or demands of competition. This means that glycemic control is invariably maintained by making adjustments to insulin dosing or carbohydrate replacement. Insulin dosing has been considered elsewhere in this volume Chap. 3 in conjunc- tion with pre-exercise carbohydrate feeding and so this chapter will focus on nutri- tional advice specific to the athlete with T1DM and in particular the effects of CHO supplementation. 7.4 Macronutrient Recommendations for the Athlete with T1DM No specific macronutrient recommendations exist for the athlete with T1DM. Guidance is therefore drawn from both general nutrition practice recommendations for adults with diabetes 5 and recommendations for athletes without diabetes. 7.4.1 Carbohydrate • As noted above it is essential to consume adequate CHO to support training in order to optimize sporting performance. Daily CHO recommendations for ath- letes as presented earlier are also applicable to the athlete with T1DM. • In order to maintain glycemic control in T1DM this CHO intake needs to be matched with appropriate insulin doses given at the appropriate time. Individuals on MDI and CSII therapy are advised to adjust insulin doses to match CHO intake insulin-to-CHO ratios 24.

slide 181:

156 156 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 156 156 • Athletes without T1DM are advised to vary energy and CHO intake according to the periodized training load and daily fluctuations in training. For the athlete with T1DM it is important to consume adequate CHO on a daily basis to ensure that glycogen stores are replenished which should aid in reducing exercise- associated hypoglycemia. There is evidence to suggest that day-to-day consis- tency in distribution of CHO intake results in improved glycemic control although it is debatable whether this applies to individuals who adjust insulin to match CHO 25. At present therefore there is perhaps insufficient evidence to suggest that substantial day-to-day variation in CHO intake is beneficial for the athlete with T1DM and so a reasonably consistent daily CHO intake may be preferable. • CHO should be distributed fairly evenly throughout the day with a particular focus on ensuring that adequate CHO is consumed soon after training sessions to promote glycogen synthesis post-exercise. 7.4.1.1 GI in the Nutritional Management of Diabetes The use of the GI is recognized as playing an important part in the management of diabetes by various professional organizations including the Canadian Diabetes Association Diabetes UK and Diabetes Australia 26–28. Using continuous glu- cose monitoring a low-GI meal has been shown to reduce postprandial glucose excursions in children and adolescents treated with both MDI and CSII when com- pared with a high-GI meal 29 30. A low-GI diet has also been found to positively affect the daily mean blood glucose concentration 31. These differences probably explain why low-GI diets can help to lower HbA1c in people with diabetes and are therefore recommended in this group 32. A low-GI diet also has the potential to limit insulin requirements which may be particularly beneficial in the context of exercise. Lower insulin dosing will result in lower levels of circulating insulin which may help to reduce the risk of hypoglyce- mia both during exercise and in the early postprandial period and also post-exercise when insulin sensitivity is enhanced. Related to this it is interesting to note that nutrition recommendations for individuals with T1DM frequently focus on “carbo- hydrate counting” matching insulin to CHO but do not take the GI into account. Given that the above evidence suggests that lower-GI CHO requires less insulin than an equal amount of higher-GI CHO it seems that the GI of CHO should also be taken into account when deciding appropriate insulin dosing. It is also important to understand that the GI does not tell the whole story about some foods and so its use should be applied with appropriate consider- ation. For example while watermelon has a high GI the CHO load in a serving is relatively small and therefore there does not seem any reason to limit such a food in the diet even in the context of diabetes. In contrast adding fat to a high- GI food not only lowers its GI but also alters its overall nutritional value mean- ing that there may not be such a strong benefit from the lower-GI food in these circumstances.

slide 182:

157 157 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 157 157 7.4.1.2 GI and Exercise in the Athlete with T1DM As noted elsewhere in this volume Chap. 3 the findings of two recent studies have looked at the effect of low-GI compared to high-GI CHO in individuals with T1DM and have made recommendations for athletes with T1DM 33 34. Isomaltulose a low-GI CHO was compared with dextrose a high-GI CHO. Optimal timing of isomaltulose and ideal insulin dose reduction was also considered. The overall outcome was that taking low-GI CHO in the form of isomaltulose 30 min prior to running with a reduced bolus 25 of usual bolus of rapid-acting analogue insulin was protective against hypoglycemia. A more stable blood glucose response was also observed when compared with dextrose and a more normal metabolic response was seen with lipid oxidation maintained in spite of CHO ingestion. Care may be needed in applying these recommendations to individual athletes as 75 g of CHO as used in these studies is a large amount of CHO to ingest 30 min before an exercise such as running this is unlikely to be a problem for cycling and so the pos- sibility of gastrointestinal disturbance needs to be considered. Future studies using solid food mixed macronutrient meals and smaller pre-exercise CHO feedings are important for seeing how this research will translate into practice. Nonetheless the results are worthy of attention as they do suggest that the GI of the pre-exercise feeding may be important and is potentially a useful strategy for some individuals with T1DM. 7.4.2 CHO Intake Prior to Training or Competition Ideally individuals need to find a pre-event nutrition strategy that safeguards against hyperglycemia in the hours prior to exercise and hypoglycemia before and during exer- cise. The pre-event meal serves the purpose of maintaining or increasing muscle glyco- gen stores and liver glycogen content especially important for early morning events where the liver glycogen stores are depleted from an overnight fast. In order to achieve this the pre-event meal should be based on high-CHO foods that the individual athlete is comfortable with. In diabetes there is likely to be a benefit from consuming a low-GI CHO pre-exercise meal for endurance events or longer duration training sessions. The timing of the pre-event meal is individual a meal 2–4 h before the event is suitable for most athletes. For the individual with T1DM the benefit of consuming the pre-event meal at least 4 h before the event allows the athlete to start exercise with low circulating insulin levels which may be advantageous in endurance events and for individuals prone to hypoglycemia. When the pre-exercise meal is 2 h before the event or training session the meal insulin bolus may need adjusting according to the intensity and dura- tion of the exercise 35 and the individual’s glycemic response to competition. Blood glucose may be raised in the hours before competition through stress-associated increases in counterregulatory hormones and therefore some individuals may require a slightly larger insulin bolus than usual with the pre-exercise meal. Consumption of a low-GI CHO drink 30 min before the event or training session in conjunction with a significant reduction in the meal insulin bolus a reduction of

slide 183:

158 158 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 158 158 up to 75 of usual insulin bolus is another strategy which may be helpful. It remains to be seen whether ingestion of a solid meal containing similarly low-GI CHO at this point might have the same effect. The possibility of GI upset means this strategy may not be practical in all competition situations but it may be particularly useful in training especially where the individual chooses not to supplement with CHO during the exercise. The use of common sports drinks as a replacement for a pre-event meal may not be ideal in all circumstances due to the high GI of these products which will promote hyperglycemia in the hours before an event. Glycemic control must be assessed prior to training and events in order to make a decision whether CHO is required before exercise. The direction of the rate of change in BG is useful in this instance which has implications for blood glucose testing see below. If the pre-exercise BG is 5 mmol/l not rising and the exercise is primarily aerobic at least 15 g of CHO should be ingested. In contrast if the BG is 5–14 mmol/l and stable or increasing no CHO may be required before exercise. The preferred strategy in these circumstances might be to supplement CHO during exercise depend- ing on the exercise duration and experience of the glycemic response to exercise. It is common practice for athletes with T1DM who are prone to hypoglycemia during exercise to preload with high-GI CHO to ensure that blood glucose is suffi- ciently raised at the start of exercise. This practice is not encouraged as exercising in a hyperglycemic state poses problems with regard to performance through pos- sible effects on both coordination 36 and metabolism with hyperglycemia associ- ated with a shift toward CHO oxidation as the main fuel source compared to when exercising in euglycemia 37. Supplementing with high-GI CHO at regular inter- vals during exercise e.g. every 15–20 min will maintain a more stable and physi- ological blood glucose level than pre-loading with CHO. 7.4.2.1 CHO Loading The aim of CHO loading is to maximize muscle glycogen stores prior to endurance events. While CHO loading has been proven to have performance benefits in endur- ance events in the athlete without T1DM 6 this practice has not been researched in the athlete with T1DM. “Tapering” the reduction in training load immediately prior to an event may already pose a challenge with maintaining euglycemia in the days leading up to an event. A significant increase in CHO intake prior to an event may therefore exacerbate this challenge. For this reason CHO loading is currently not encouraged in the athlete with T1DM. 7.4.3 CHO Intake During Training and Competition CHO intake is known to increase performance during endurance and intermittent high-intensity exercise allowing for the maintenance of high levels of CHO oxidation throughout the exercise. In the athlete with T1DM supplementing with

slide 184:

159 159 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 159 159 CHO during exercise has been shown to prevent hypoglycemia and is a useful strat- egy for unplanned activities or when insulin adjustments are not an option such as in the late postprandial period. Guidelines on CHO supplementation during exer- cise for the athlete without T1DM are discussed earlier in this chapter. These guide- lines can be used for the athlete with T1DM but consideration needs to be given to various factors see below. Consideration must also be given to the type of CHO used. Exogenous CHO oxidation rates have been shown to be higher when ingesting a combination of CHOs that use different intestinal digestion and transport systems compared to when a single CHO source is used 12. This becomes particularly important in circumstances where more than 70 g CHO/h may be required such as when per- forming intense exercise during peak insulin action. The source of CHO consumed should be selected to maximize CHO oxidation and prevent gastrointestinal prob- lems. For example when a mixture of glucose and fructose is ingested during exer- cise in the athlete without T1DM exogenous CHO oxidation rates have been shown to be as high as 1.7 g/min 38. In contrast isomaltulose and fructose are oxidized at low rates 0.6 g/min and for this reason are not routinely recommended to be ingested during exercise. There are a number of important factors which need to be taken into account when adapting recommendations regarding CHO intake during exercise to the indi- vidual athlete: 1. The mode of insulin delivery and insulin regimen CSII gives the athlete a greater degree of flexibility for making basal rate adjust- ments before during and after exercise unlike other regimens i.e. MDI and twice daily insulin regimens. CHO needs for individuals on CSII may therefore be at the lower end of suggested recommendations if appropriate insulin adjustments are made. 2. The timing of exercise in relation to insulin administration CHO needs have been shown to vary according to the levels of circulating insu- lin. Francescato et al. found that 60 min of moderate-intensity exercise performed 1 h after insulin administration required approximately 1 g CHO/kg BM the sub- jects required approximately 0.5 g/kg BM and 0.25 g/kg BM of CHO when the same intensity exercise was performed 2.5 and 4 h after insulin administration respectively 39. When the pre-meal rapid insulin dose is adjusted for postprandial exercise see Table 1 of Rabasa-Lhoret et al. 35 the CHO needs are likely to be lower than suggested recommendations. 3. Time of day of exercise CHO needs when exercising in a fasted state are likely to be significantly lower than when exercising at other times in the day and therefore CHO supplementation during exercise at this time may not be required. 4. Blood glucose when commencing exercise The pre-exercise BG will influence the type of CHO and timing of CHO feeding during exercise. When BG is elevated prior to aerobic exercise for example above 10 mmol/l CHO feedings may need to be delayed until BG has lowered or solid foods e.g. banana cereal bar which have a lower GI can be ingested earlier on in

slide 185:

160 160 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 160 160 the exercise. In contrast when the pre-exercise BG is below 6 mmol/l high-GI CHO such as energy drinks and energy gels may need to be taken on board earlier in the exercise. Interestingly since performance improvements have been shown where athletes without T1DM simply rinsed their mouth with a CHO drink 10 this may be a strategy the athlete with T1DM wishes to try when competing with elevated BG. However it is important to recognize that this has not been investigated in the con- text of T1DM 5. The effect of antecedent hypoglycemia and/or prolonged moderate exercise Both these factors have been shown to blunt counterregulatory responses during subsequent exercise bouts thereby making the athlete more susceptible to hypogly- cemia. Davis et al. found that nearly threefold greater exogenous glucose infusion rates were required to preserve euglycemia during exercise following a day of ante- cedent hypoglycemia as compared to a day without hypoglycemia 40. The athlete therefore needs to be aware that after recent hypoglycemia CHO needs during sub- sequent training sessions may be greater than usual. 6. The type of exercise High-intensity e.g. sprints weight training and intermittent high-intensity exercise e.g. football hockey may result in hyperglycemia during and/or after the exercise therefore CHO feeding during exercise as per general sports nutrition recommendations will exacerbate the hyperglycemia. 7. Training status The level of fitness of the individual will affect the CHO needs. An untrained indi- vidual will require more CHO than someone who is physically fit. If an individual exercises different muscles to the usual muscles used CHO needs may also be greater. 8. Environmental conditions Training and competing in warm and humid conditions and at altitude may raise BG consideration must therefore be given to the environmental conditions espe- cially if they are different to usual conditions. By considering these factors in addition to using a trial and error approach an ath- lete with T1DM can develop their individual strategy for managing CHO supplementa- tion during exercise. A stable BG before during and after exercise suggests that the individual has made the appropriate insulin and CHO adjustments for the activity. 7.4.4 CHO and Protein Intake After Training and Competition Insulin sensitivity in the athlete with T1DM may last for 12–24 h post-exercise 41 42 predisposing the athlete to post-exercise late-onset hypoglycemia if muscle glycogen stores are not replenished after exercise. Post-exercise nutrition is also important to facilitate skeletal muscle repair and synthesis. In athletes without T1DM the co-ingestion of CHO 0.8 g/kg BM/h with a small amount of protein 0.2–0.4 g/kg BM/h post-exercise stimulates endogenous insulin release and results in similar muscle glycogen repletion rates to when only CHO 1.2 g CHO/kg BW/h

slide 186:

161 161 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 161 161 is ingested 14. It is speculated that greater postprandial insulin levels after protein co-ingestion may stimulate the storage of CHO in more insulin-sensitive tissues such as the liver and exercised skeletal muscle therefore promoting more efficient storage of CHO 42. The athlete with T1DM should consider administering a small insulin bolus with the post-exercise CHO to facilitate rapid glycogen synthesis. The consumption of approximately 20 g of intact protein which is the equivalent of 9 g of essential amino acids is sufficient to maximize muscle protein synthesis during the first few hours after exercise. When the athlete has multiple training sessions on the same day consuming moderate- to higher-GI CHO within the first few hours post-exercise will aid in replenishing muscle glycogen stores. Individuals on a MDI regimen who are prone to post-exercise late-onset hypoglycemia during the night may benefit from consuming a CHO and protein-containing snack at bedtime 43. 7.5 The Role of Blood Glucose Monitoring To Kill Diabetes Forever Click Here There are significant interindividual variations in BG responses to exercise but there is some stability of intraindividual responses which means that individuals can use knowledge of their BG responses to make informed decisions about the management of their diabetes for exercise. The gathering of relevant information is key to this process. Frequent BG monitoring before during and after exercise is useful as it provides information about how BG values change with exercise. A single reading is rarely helpful in itself. For this reason continuous glucose moni- toring is a useful alternative to finger prick testing and may be particularly benefi- cial for the recognition of post-exercise hypoglycemia. Seeing the pattern of how BG changes are affected by a particular type of exer- cise bout will provide the basis for the insulin and nutrition strategy for future simi- lar exercise bouts. It may also be useful to record the timing of the exercise duration and intensity of a training session or event the dose and timing of any insulin bolus and CHO intake before during and after exercise. Noting the injection site and incidence of hypoglycemia in the preceding 24 h is also likely to be helpful. 7.6 Weight Management for the Athlete with T1DM Weight control is often an issue for athletes and there are circumstances where it will be particularly relevant: long distance running where an athlete is required to carry their own weight cycling where appropriate weight may result in an increase in the power-to-weight ratio and sports which have weight categories such as lightweight rowing horse racing boxing and martial arts. Unfortunately controlling weight can be a particular challenge for the athlete with T1DM for a number of reasons. For example exercising with inappropriately high levels of circulating insulin will increase CHO needs during exercise and also suppress the use of endogenously stored fuel sources.

slide 187:

162 162 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 162 162 Losing weight requires setting realistic goals getting the fine balance between energy intake and expenditure correct and considering the macronutrient composi- tion and energy density of the diet. A number of strategies are available to the ath- lete with T1DM to aid with weight control either by reducing the amount of CHO required at the time of exercise or by affecting substrate utilization: • Exercise in the morning in a fasted state this is not advisable for key high- intensity training sessions or in the late postprandial period i.e. 4–5 h after the meal insulin bolus. • In the case of CSII reduce basal insulin infusion rate around exercise in order to minimize CHO requirements during exercise see Chap. 5. • If on an MDI regimen consider the time action profile of the basal insulin aim to exercise at a time when the basal insulin’s action is coming to an end. Using twice daily NPH may help in this instance. • Reduce the pre-meal insulin bolus when exercising within 90–120 min of the meal. • Exercise soon after a low-GI meal e.g. 30 min after meal. Due to the dampened postprandial blood glucose response produced by a low-GI meal the associated insulin bolus may be significantly reduced or even omitted if the pre-meal blood glucose is in a low to normal range and the exercise is predominantly aerobic. • Eat a low-GI diet—this may have a small but positive effect on weight control. • Ingest caffeine before exercise to help prevent hypoglycemia associated with exercise not advisable when exercising after midday. The dose of caffeine used in the research was 5 mg/kg BM 44. This large dose may not be practical for most athletes. • Start exercise in a euglycemic state BG of 5–9 mmol/l to maximize fat oxidation. • Abstain from heavy pre-loading with CHO and instead supplement with CHO during exercise as dictated by BG. 7.7 Hydration Recommendations regarding fluid intake for athletes with T1DM are similar to those for athletes without T1DM as outlined earlier. However it is worth noting that exercising with elevated BG will promote fluid loss and therefore fluid requirements will be greater than when exercising in a euglycemic state. When exercising during hyperglycemia water or CHO-free electrolyte sports drinks should be ingested instead of regular sports drinks. 7.8 Protein In individuals with T1DM with normal renal function a protein intake of 15–20 of daily energy intake is recommended 5. Guidance on the timing of protein intake as discussed earlier in this chapter should also be adopted by the athlete with T1DM.

slide 188:

163 163 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 163 163 7.9 Fat In contrast to CHO and protein recommendations there are at present no reference values for fat intake in exercise. 7.10 Summary A sound nutritional strategy is an important weapon in the armory of the athlete with T1DM. Many of the general recommendations made for all athletes apply to this population but there are special considerations which apply to T1DM of which both athletes with T1DM and their health professionals should be aware. The major- ity of the differences between recommendations for those with and without T1DM come in the consideration of appropriate CHO intake in the diet. References 1. Burke LM. The IOC consensus on sports nutrition 2003: new guidelines for nutrition for ath- letes. Int J Sport Nutr Exerc Metab. 2003134:549–52. 2. Rodriguez NR Di Marco NM Langley S. American College of Sports Medicine position stand. Nutrition and athletic performance. Med Sci Sports Exerc. 2009413:709–31. 3. Burke LM Hawley JA Wong SH Jeukendrup AE. Carbohydrates for training and competi- tion. J Sports Sci. 201129:S17–27. 4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treat- ment of diabetes on the development and progression of long-term complications in insulin- dependent diabetes mellitus. N Engl J Med. 199332914:977–86. 5. Franz MJ Powers MA Leontos C Holzmeister LA Kulkarni K Monk A et al. The evidence for medical nutrition therapy for type 1 and type 2 diabetes in adults. J Am Diet Assoc. 201011012:1852–89. 6. Hawley JA Schabort EJ Noakes TD Dennis SC. Carbohydrate-loading and exercise perfor- mance. An update. Sports Med. 1997242:73–81. 7. Bussau V A Fairchild TJ Rao A Steele P Fournier PA. Carbohydrate loading in human mus- cle: an improved 1 day protocol. Eur J Appl Physiol. 2002873:290–5. 8. James AP Lorraine M Cullen D Goodman C Dawson B Palmer TN et al. Muscle glycogen supercompensation: absence of a gender-related difference. Eur J Appl Physiol. 2001856: 533–8. 9. Jeukendrup A Brouns F Wagenmakers AJ Saris WH. Carbohydrate-electrolyte feedings improve 1 h time trial cycling performance. Int J Sports Med. 1997182:125–9. 10. Carter JM Jeukendrup AE Jones DA. The effect of carbohydrate mouth rinse on 1-h cycle time trial performance. Med Sci Sports Exerc. 20043612:2107–11. 11. Smith WM Zachwieja JJ Peronnet F Passe DH Massicotte D Lavoie C. Fuel selection and cycling endurance performance with ingestion of 13C glucose: evidence for a carbohydrate dose response. J App Physiol. 20101086:1520–9. 12. Jentjens RL Jeukendrup AE. High rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged cycling exercise. Br J Nutr. 2005934: 485–92.

slide 189:

164 164 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 164 164 13. Burke LM Collier GR Hargreaves M. Muscle glycogen storage after prolonged exercise: effect of the glycemic index of carbohydrate feedings. J Appl Physiol. 1993752:1019–23. 14. Howarth KR Moreau NA Phillips SM Gibala MJ. Coingestion of protein with carbohydrate during recovery from endurance exercise stimulates skeletal muscle protein synthesis in humans. J Appl Physiol. 20091064:1394–402. 15. Burke LM Collier GR Davis PG Fricker PA Sanigorski AJ Hargreaves M. Muscle glycogen storage after prolonged exercise: effect of frequency of carbohydrate feedings. Am J Clin Nutr. 199664:115–9. 16. Jenkins DJ Wolever TM Taylor RH Barker H Fielden H Baldwin JM et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981343:362–6. 17. Stevenson E Williams C Nute M. The influence of the glycaemic index of breakfast and lunch on substrate utilisation during the postprandial periods and subsequent exercise. Br J Nutr. 2005936:885–93. 18. Donaldson CM Perry TL Rose MC. Glycemic index and endurance performance. Int J Sport Nutr Exerc Metab. 2010202:154–65. 19. Burke LM Claassen A Hawley JA Noakes TD. Carbohydrate intake during prolonged cycling minimizes effect of glycemic index of preexercise meal. J Appl Physiol. 1998856:2220–6. 20. Blom PC Hostmark AT Vaage O Kardel KR Maehlum S. Effect of different post-exercise sugar diets on the rate of muscle glycogen synthesis. Med Sci Sports Exerc. 1987195:491–6. 21. Sawka MN Burke LM Eichner ER Maughan RJ Montain SJ Stachenfeld NS. American College of Sports Medicine position stand. Exercise and fluid replacement. Med Sci Sports Exerc. 2007392:377–90. 22. Nakagawa K. Effect of vitamin D on the nervous system and the skeletal muscle. Clin Calcium. 2006167:1182–7. 23. Nattiv A Loucks AB Manore MM Sanborn CF Sundgot-Borgen J Warren MP. American College of Sports Medicine position stand: the female athlete triad. Med Sci Sports Exerc. 20073910:1867–82. 24. DAFNE Study Group. Training in flexible intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating DAFNE ran- domised controlled trial. BMJ. 20023257367:746. 25. Wolever TM Hamad S Chiasson JL Josse RG Leiter LA Rodger NW et al. Day-to-day consistency in amount and source of carbohydrate intake associated with improved blood glu- cose control in type 1 diabetes. J Am Col Nutr. 1999183:242–7. 26. Canadian Diabetes Association. Guidelines for the nutritional management of diabetes melli- tus in the new millennium. Can J Diabetes Care. 200023:56–69. 27. Connor H Annan F Bunn E Frost G McGough N Sarwar T et al. The implementation of nutritional advice for people with diabetes. Diabet Med. 20032010:786–807. 28. Perlstein RWJ Hines C Milsavlevic M. Dietitians Association of Australia review paper: Glycaemic Index in diabetes management. Aust J Nutr Diet. 199754:353–5. 29. Ryan RL King BR Anderson DG Attia JR Collins CE Smart CE. Influence of and optimal insulin therapy for a low-glycemic index meal in children with type 1 diabetes receiving inten- sive insulin therapy. Diabetes Care. 2008318:1485–90. 30. O’Connell MA Gilbertson HR Donath SM Cameron FJ. Optimizing postprandial glycemia in pediatric patients with type 1 diabetes using insulin pump therapy: impact of glycemic index and prandial bolus type. Diabetes Care. 2008318:1491–5. 31. Nansel TR Gellar L McGill A. Effect of varying glycemic index meals on blood glucose control assessed with continuous glucose monitoring in youth with type 1 diabetes on basal- bolus insulin regimens. Diabetes Care. 2008314:695–7. 32. Thomas D Elliott EJ. Low glycaemic index or low glycaemic load diets for diabetes mellitus. Cochrane Database Syst Rev. 2009211:CD006296.

slide 190:

165 165 C. Hume 7 Fueling the Athlete with Type 1 Diabetes 165 165 33. West DJ Stephens JW Bain SC Kilduff LP Luzio S Still R et al. A combined insulin reduc- tion and carbohydrate feeding strategy 30 min before running best preserves blood glucose concentration after exercise through improved fuel oxidation in type 1 diabetes mellitus. J Sports Sci. 2011293:279–89. 34. West DJ Morton RD Stephens JW Bain SC Kilduff LP Luzio S et al. Isomaltulose improves postexercise glycemia by reducing carbohydrate oxidation in type 1 diabetes mellitus. Med Sci Sports Exerc. 2011432:204–10. 35. Rabasa-Lhoret R Bourque J Ducros F Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen ultralente-lispro. Diabetes Care. 2001244:625–30. 36. Martin DD Davis EA Jones TW. Acute effects of hyperglycaemia in children with type 1 diabetes mellitus: the patient’s perspective. J Pediatr Endocrinol Metab. 2006197:927–36. 37. Jenni S Oetliker C Allemann S Ith M Tappy L Wuerth S et al. Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus–a pro- spective single-blinded randomised crossover trial. Diabetologia. 2008518:1457–65. 38. Jeukendrup AE. Carbohydrate and exercise performance: the role of multiple transportable carbohydrates. Curr Opin Clin Nutr Metab Care. 2010134:452–7. 39. Francescato MP Geat M Fusi S Stupar G Noacco C Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism. 2004539:1126–30. 40. Davis SN Galassetti P Wasserman DH Tate D. Effects of antecedent hypoglycemia on subse- quent counterregulatory responses to exercise. Diabetes. 2000491:73–81. 41. MacDonald MJ. Postexercise late-onset hypoglycemia in insulin-dependent diabetic patients. Diabetes Care. 1987105:584–8. 42. Beelen M Burke LM Gibala MJ van Loon LJ. Nutritional strategies to promote postexercise recovery. Int J Sport Nutr Exerc Metab. 2010206:515–32. 43. Kalergis M Schiffrin A Gougeon R Jones PJH Yale JF. Impact of bedtime snack composi- tion on prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing inten- sive insulin management using lispro insulin before bed. Diabetes Care. 200326:9–15. 44. Gallen IW Ballav C Lumb A Carr J. Caffeine supplementation reduces exercise induced decline in blood glucose and subsequent hypoglycaemia in adults with type 1 diabetes T1DM treated with multiple daily insulin injection MDI. ADA 70th Scientific Sessions June 25−29 2010 1184−P.

slide 191:

Chapter 8 Diabetes and Doping Richard I.G. Holt 8.1 Introduction Want To Diabetes Free Life Click Here When humans are placed in a competitive setting particularly in the sporting arena they will attempt to gain an advantage over their opponent in order to win. When all legitimate methods have been exhausted and the athlete has reached their peak per- formance there is a temptation for some to seek out pharmacological methods to improve performance yet further. Doping not only damages the integrity of sport but may cause significant harm to athletes who use performance-enhancing drugs. The term doping is originally derived from the African Kaffir’s word “dop” an alcoholic drink made from grape skins that was used as a stimulant in battle. The use of the word became popular in the early twentieth century when racehorses were illegally drugged when the word was also used as a slang expression for opium. During exercise performance is dependent on the combustion of metabolic fuels such as glucose for short-term high-intensity activity and free fatty acids for more prolonged activity to release kinetic energy this process depends on an adequate supply of nutrients and oxygen to the muscle fibers. This process may be enhanced by drugs that increase fuel and oxygen delivery to exercising muscle increase mus- cle strength or any combination of these factors. Given the complexity of the meta- bolic and cardiovascular changes during exercise it is unsurprising that there is an extensive range of drugs that have been used by athletes. The earliest records of doping in sport come from ancient times but with the advent of modern pharmacology and the birth of the field of endocrinology in the

slide 192:

nineteenth century the number and quantity of drugs used to improve strength and overcome fatigue increased dramatically. At the time this practice was not illegal R.I.G. Holt M.A. M.B. B.Chir. Ph.D. FRCP FHEA Human Development and Health Academic Unit University of Southampton Faculty of Medicine IDS Building MP887 Southampton General Hospital Tremona Road Southampton Hampshire SO16 6YD UK e-mail: r.i.g.holtsouthampton.ac.uk I. Gallen ed. Type 1 Diabetes DOI 10.1007/978-0-85729-754-9_8 © Springer-Verlag London Limited 2012 167

slide 193:

168 168 R.I.G. Holt 8 Diabetes and Doping 168 168 and so there are good records of the regimens that athletes would take. Alongside the benefits however came the dangers and several fatalities followed. Gradually a code to ban performance-enhancing drugs was developed. This chapter will describe the history of doping and the most commonly abused performance-enhancing drugs including insulin. The potential beneficial and adverse effects will be discussed particularly in relationship to type 1 diabetes where the performance-enhancing drug may adversely affect the action of insulin and glycemic control. The chapter will finally discuss the therapeutic use exemption TUE which is required for all elite competitors with diabetes who use insulin. 8.2 History of Doping 8.2.1 Early History of Doping Despite the perception that doping is a modern phenomenon there are many examples of substance use dating back to ancient times when extracts derived from plants animals or even humans were taken 1 2. One of the first performance-enhancing substances to be tried was testosterone the effects of castration on animal behavior were well recognized and this may have provided the incentive for people living in ancient times to eat the testes of animals or humans to improve their own well-being. The importance of diet on performance was also recognized one of the earliest reports describes how dried figs were used to improve the performance of Charmis the Spartan winner of the stade race 200 yards 183 m at the Olympic Games of 668 B.C. The ancient Greeks also used concoctions of brandy and wine as stimulants as part of their training regimens while Roman gladiators took unspecified stimulants mostly derived from plants to overcome fatigue and injury. Examples include bufo- tenin a drug derived from the muscarine-containing mushroom fly agaric Amanita muscaria Cola acuminita and Cola nitida and coca leaves. 8.2.2 Developments in the Use of Stimulants and Anabolic Agents During the Nineteenth Century There was an escalation in the number and types of performance-enhancing drugs during the latter half of the nineteenth century in line with development in modern pharmacology and medicine. Stimulants were used to improve muscular work capacity while the anabolic effects of substances that were later classified as hor- mones began to be recognized. Caffeine was used to improve brain functioning while alcoholic beverages were considered a relief for stress. As there were no rules prohibiting such substances

slide 194:

169 169 R.I.G. Holt 8 Diabetes and Doping 169 169 athletes did not try to conceal the use of these compounds and as a result good records of doping exist for this time. Trainers also developed doping cocktails for their athletes using various combinations of stimulants such as strychnine tablets and mixtures of brandy and cocaine. The continuous “six-day” bicycle races began in the nineteenth century and a variety of medications were tried to improve the considerable physical strength and stamina needed for the race French cyclists are reported to have taken mixtures based on caffeine while the Belgians experimented with sugar cubes dripped in ether and others used alcohol-containing cordials the sprinters specialized in the use of nitroglycerine. As the race progressed the amounts of strychnine and cocaine added to the caffeine mixtures steadily increased sometimes with lethal conse- quences Arthur Linton an English cyclist who is alleged to have overdosed on “tri-methyl” a compound thought to have contained either caffeine or ether was the first such fatality in 1886 during a 600-km race between Bordeaux and Paris. There is some dispute over this as others suggest that Linton actually won the race and died 10 years later from typhoid fever. Mixtures of champagne brandy hot drops of morphine belladonna and strych- nine were used to maintain high levels of strength and energy during another endur- ance race the “ultramarathon” which was a walking and running race over 6 days and 6 nights with the winner being the person who covered the greatest distance. Around the same time in 1889 Charles Édouard Brown-Sequard a renowned physiologist and neurologist undertook a series of groundbreaking and controver- sial experiments that led to the birth of the field of endocrinology. Brown-Sequard reported to the Society of Biology in Paris in 1891 that he had experienced signifi- cant restoration of strength following a 3-week program of self-injection of “first blood of the testicular veins secondly semen and thirdly juice from a testicle… from a dog or a guinea pig.” One month after the last injection however he “expe- rienced almost a complete return of the state of weakness.” Although it is currently accepted that these findings were likely the result of a placebo effect the idea of hormone replacement was conceived as a result. It is perhaps unsurprising that the potential of this research was considered for athletic performance and in 1894 Oskar Zoth and Fritz Pregl investigated the effect of testicular extracts on muscular strength. Although with hindsight it seems improb- able that these testicular extracts contributed positively to athletic performance many athletes including the German Olympic team at the 1936 Berlin games alleg- edly began to take these extracts. 8.2.3 Twentieth-Century Doping At the beginning of the twentieth century scientists isolated characterized and synthesized testosterone which allowed a greater understanding of its anabolic effects. The first recorded case of the use of testosterone as a means of improving performance was an 18-year-old horse named Holloway who was reported to have

slide 195:

170 170 R.I.G. Holt 8 Diabetes and Doping 170 170 “declined to a marked degree in his staying power and during February of 1941 in several attempts at ice racing failed to show any of his old speed or willingness.” Following testosterone administration the horse won or was placed in a number of races and established a trotting record at the age of 19 years. The widespread use of testosterone and other anabolic steroids that followed resulted in bodybuilders with deformed body shapes and extremely large muscles. The use of stimulants such as amphetamines also began to increase in the mid- 1930s initially among servicemen fighting in the Second World War and college students but latterly by athletes. The use of stimulants was particularly prevalent in cycling during the 1960s and 1970s and the first televised doping fatality occurred during the 1967 Tour de France when the English cyclist Tom Simpson died with high circulating levels of methamphetamine. Doping moved to a new level around this time with suspicions abounding that several countries pursued state-sponsored doping. These concerns were subse- quently confirmed following the collapse of the Berlin wall when reports emerged from the former German Democratic Republic that PhD programs had been estab- lished to develop the ideal regimens to improve performance. In the 1980s anabolic steroids and cortisone remained the drugs most commonly abused but the number of drugs expanded dramatically and the current World Anti- Doping Agency WADA list of prohibited substances is several pages long and includes 12 categories of substances and methods including anabolic agents hor- mones diuretics and masking agents stimulants and narcotics as well as prohibited methods such as blood transfusion Table 8.1. 8.2.4 The Prevalence of Doping The true prevalence of doping is unknown and reports vary widely from 1 to 90 because of the current secrecy surrounding it. The huge financial rewards for profes- sional sportsmen and women corporate sponsors the TV broadcast and cable indus- tries and sport-governing bodies coupled with the ever-increasing pharmacopoeia of performance-enhancing substances the athlete’s drive to win and the challenges for doping control may all act to encourage athletes to use prohibited substances. 8.3 History of Anti-Doping Prior to the end of World War I doping was not considered to be cheating and so the use of performance-enhancing substances was neither prohibited nor discour- aged. In 1928 the International Amateur Athletic Federation IAAF became the first international sport body to ban the use of stimulating substances. Others fol- lowed the IAAF lead but the lack of effective tests failed to curb the use of drugs. Around the same time Otto Rieser in his work “Doping and Doping Substances”

slide 196:

171 171 R.I.G. Holt 8 Diabetes and Doping 171 171 Table 8.1 Drugs appearing on the 2011 WADA list of prohibited substances Substances and methods that are prohibited at all times in and out of competition Anabolic agents Anabolic androgenic steroids AAS Other anabolic agents clenbuterol selective androgen receptor modulators tibolone zeranol zilpaterol Hormones and related substances Erythropoiesis-stimulating agents e.g. erythropoietin EPO Gonadotropins e.g. LH hCG prohibited in males only Insulins Corticotrophins Growth hormone hGH insulin-like growth factors e.g. IGF-I fibroblast growth factors FGFs hepatocyte growth factor HGF mechano growth factors MGFs platelet-derived growth factor PDGF vascular-endothelial growth factor VEGF Beta-2 agonists Hormone antagonists and modulators Diuretics and other masking agents Methods to enhance oxygen transfer Gene doping Substances prohibited during competition Stimulants Narcotics Cannabinoids Glucocorticosteroids Substances prohibited in particular sports Alcohol Beta-blockers published in 1933 made the first attempts to educate athletes about the dangers of performance-enhancing drugs and discourage their use. The death of Danish cyclist Knud Enemark Jensen during the Rome Olympic Games in 1960 following the consumption of amphetamine provided a further incen- tive for sports authorities to introduce drug testing and in 1966 the International Cycling Union and International Federation of Association Football introduced tests for prohibited substances. The following year the International Olympic Committee IOC established its Medical Commission under the chairmanship of Prince Alexandre de Merode and voted to adopt a drug-testing policy for banned drugs. Tests were first introduced at the Olympic Winter Games in Grenoble and then at the Olympic Games in Mexico in 1968. The IOC began publishing its Prohibited Substances List which became extensive and remains enforceable at all Olympic events. Despite the example shown by the IOC many organizations were slow to follow because of the lack of the necessary protocols or equipment to enforce the bans for example the US National Football League only introduced anti-doping testing in 1982. Championed by Professor Manfred Donike the IOC Medical Commission devel- oped a worldwide network of top class laboratories staffed by chemists and

slide 197:

172 172 R.I.G. Holt 8 Diabetes and Doping 172 172 pharmacologists who were equipped to measure mainly steroids and stimulants in urine. The introduction of a reliable urinary test for anabolic steroids was seen as a major breakthrough in 1974 resulting in a marked increase in the number of drug disqualifica- tions in the late 1970s notably in strength-related sports such as throwing events and weightlifting. When combined with the introduction of out-of-competition testing the testing program provided a major disincentive for athletes to use these drugs. Following a series of high-profile scandals the IOC convened a World Conference on Doping in Lausanne in February 1999 during which it was recognized that an independent international agency with powers to set unified anti-doping standards and coordinate sporting organizations and public authorities was needed. As a direct result the World Anti-Doping Agency WADA was established on November 10 1999. The development and implementation of a uniform set of anti-doping rules the World Anti-Doping Agency Code together with a list of prohibited substances are credited as the most important achievements in anti-doping. 8.4 The World Anti-Doping Agency List of Prohibited Substances The WADA List of Prohibited Substances now runs to several pages and is updated annually as more information about the effects of performance-enhancing drugs becomes available. The list is divided into several sections covering drugs that can- not be used at any time drugs that cannot be used during competition and drugs such as alcohol and beta-blockers which are only banned in certain sports. An exhaustive list of prohibited substances is beyond the scope of this chapter and readers are recommended to refer to the latest list which is available on the World Anti-Doping Agency website http://www.wada-ama.org/. The main categories of performance-enhancing drugs are given in Table 8.1. 8.5 Drugs of Abuse and Diabetes While each of these drugs may cause harm to people with diabetes some drugs have specific relevance for people with type 1 diabetes because of their effects on insulin action and glycemic control. A more detailed description of these drugs is given below including information about prevalence of abuse where this is known how these drugs may enhance performance the potential for harm and the relevance for diabetes. 8.6 Anabolic Androgenic Steroids Anabolic androgenic steroids AAS are steroid hormones that have masculinizing and growth-promoting actions and are the most widely abused performance-enhancing drugs. Although the virilizing effects of the testis have been recognized for millennia

slide 198:

173 173 R.I.G. Holt 8 Diabetes and Doping 173 173 Attachment of methyl group at A1 Introduction of double bond Detachment of methyl group at C6 Esterification at C17 OH increases potency and prolongs duration of action Attachment of various groups at C2 Alkylation at C17 confers oral activity but associated C D with liver dysfunction Attachment of pyrazole ring to A ring O A B Attachment of Attachment of methyl group at C7 chlorine or hydroxyl group at C4 Fig. 8.1 Development of androgenic anabolic steroids. As the half-life of testosterone is short manipulations at the C17 position of the D ring have led to compounds that are either more potent and longer lasting esterification or orally acting alkylation marked in bold. Further alterations have been tried to alter the relative androgenic and anabolic actions Table 8.2 Formulations of testosterone available in clinical practice in the UK Oral Testosterone undecanoate 17-b-hydroxyl ester Buccal Testosterone Intramuscular 17-b-hydroxyl esters Testosterone enanthate Testosterone undecanoate Testosterone propionate Testosterone phenylpropionate Testosterone isocaproate Testosterone decanoate Implant Testosterone Transdermal Testosterone it was not until 1931 that the first androgenic steroid androsterone was isolated from urine. An anabolic effect separate from the androgenic effect was then shown in 1935. Following the discovery of testosterone it became apparent that testoster- one only has a short half-life regardless of its route of administration and so a large number of synthetic molecules were developed subsequently with modified phar- macokinetics. Synthetic androgens predominantly have one of two substitutions on the D ring of native testosterone either esterification at the 17-b-hydroxy group or alkylation at the 17-a position Fig. 8.1. Esterification typically results in more potent androgens with a longer duration of action Table 8.2 allowing them to be

slide 199:

174 174 R.I.G. Holt 8 Diabetes and Doping 174 174 Distance m 1948 1952 1956 1960 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 24 First reports of use of anabolic 22 steroids 20 18 16 Systematic doping of East German athletes IOC bans use of anabolic Introduction of out- of- competition testing Fall of communism steroids Introduction of test 14 for testosterone 12 Year Fig. 8.2 The winning distance in the women’s Olympic shot put since 1948 administered by intramuscular injection every 1–4 weeks. The alkylated forms are less potent but can be given orally however as they may cause serious liver injury they are only rarely used clinically. In the late 1990s topical preparations of testos- terone became available. Although more convenient these may induce skin rashes. Further manipulations of the basic steroid structure have been undertaken to alter the anabolic and androgenic actions Fig. 8.1. In addition to the AAS used in clinical practice there are others available on the “black market.” The purity and safety of these compounds is called into question not least because some of these have been discontinued previously by legitimate pharmaceutical manufacturers because of toxicity. 8.6.1 Prevalence of Anabolic Androgenic Steroid Abuse Reports of the inappropriate use of AAS first appeared in the 1930s their use became firmly established in weightlifting during the 1950s before spreading to other sports in the 1960s. For many years there were debates within the scientific literature about the performance effects of AAS with several articles and reviews commenting on the lack of scientific proof. Despite the skepticism shown by scien- tists the benefits were realized by athletes whose performance improved dramati- cally. For example between 1956 and 1980 the winning distance in the Olympic women’s shot put increased from 15.28 to 22.41 m Fig. 8.2. Since the introduction of effective testing in the early 1980s the winning distance in the women’s shot put

slide 200:

175 175 R.I.G. Holt 8 Diabetes and Doping 175 175 has fallen progressively to the point where the winner in Beijing in 2008 would not have made the final in Moscow in 1980. During the Cold War supported by sophisticated scientific research there was systematic state doping of East German athletes with AAS. Doping was not con- fined to East Germany and there have been plenty of examples of abuse of AAS in Western countries. Perhaps the most famous case was Ben Johnson who was dis- qualified from the 100-meter race at the 1988 Olympic Games in Seoul when stano- zolol was detected in his urine. Another example comes from US National Football League where in 2009 nearly 1 in 10 retired players admitted using AAS in a con- fidential survey. Following an undercover investigation by Lance Williams and Mark Fainaru- Wada two reporters working in San Francisco the Bay Area Laboratory Co-operative BALCO company headquarters was raided on September 3 2003. Officially BALCO was a service company for blood and urine analysis and food supplements but evidence was found that it had supplied performance-enhancing drugs includ- ing AAS to many high-profile American and international athletes. Its owner Victor Conte was imprisoned for 4 months for his role in the scandal. Designer AAS such as tetrahydrogestrinone THG norbolethone and desoxymethyltestosterone had been manufactured by Patrick Arnold an organic chemist and supplied to BALCO. THG is remarkable as a highly potent agonist for the testosterone and progesterone receptor which was undetectable at the time. After Don Catlin the former director of the Olympic Analytical Laboratory in Los Angeles succeeded in identifying the molecule and developing a test the complexity of the underlying chemistry shocked anti-doping agencies but testified to the lengths that some athletes and their support- ers would pursue to achieve a performance benefit. In addition to athletes AAS appear to be widely used in the general population most commonly for cosmetic purposes with only 20 of all users participating in competitive sports or bodybuilding. 0.5 of the adult US population admitted to using AAS regularly while 2.5 of boys and 0.6 of girls attending US high school reported having taken AAS at some point during their lives. Misuse is com- monest among young middle-class heterosexual men. The widespread and increas- ing use led President George Bush in the mid-1990s to pass the first Anabolic Steroid Control Act which made it illegal to possess or distribute AAS for non- medical purposes. In the UK AAS are regulated under the Misuse of Drugs Act which sets out three separate categories Class A Class B and Class C dependent on the drug’s capacity to cause harm with Class A being the most dangerous AAS are classified as Class C drugs alongside benzodiazepines among others. 8.6.2 Why Do Athletes Abuse Anabolic Androgenic Steroids Androgenic anabolic steroids increase muscle mass and strength through a number of mechanisms including the stimulation of protein synthesis inhibition of protein breakdown recruitment of satellite cells production of cytokines and increase in

slide 201:

176 176 R.I.G. Holt 8 Diabetes and Doping 176 176 androgen receptor number. Clinical trials have shown that AAS improve both muscle mass and strength in a dose-dependent manner and these effects are additive to resistance training alone. It appears that the arms and upper torso are more responsive to the effects of AAS than the lower limbs. The full potential of AAS however has almost certainly not been realized in these trials because of the limited doses used because of medical and ethical concerns about potential side effects. By contrast athletes are reported to take combinations of AAS in doses that are up to 30 times higher than the physiological replacement dose. There are many websites and printed manuals giving details about the use and supply of AAS. Steroid use usually involves techniques such as “cycling” and “stacking.” AAS appear to lose effectiveness with time through adaptation of the androgen receptor and athletes have learned to obtain a greater benefit through using the steroids intermittently in a cycle over 5–10 weeks. Stacking involves the use of two or more steroids concomitantly in order to obtain a synergistic effect. 8.6.3 Adverse Effects of Androgenic Anabolic Steroids 8.6.3.1 Endocrine Function The most marked side effect of AAS is virilization 3 4. In both men and women this manifests as acne an increase in body hair and male pattern baldness. The acne results from excess stimulation of sebaceous glands on both the face and the body. In men prostatic enlargement may occur leading to urinary hesitancy and poor flow and there are concerns about the long-term risk of prostate cancer. Gynecomastia may develop as excessive testosterone is converted to estradiol under the action of the aromatase enzyme. In women the virilizing effects may be even more marked including a decrease in breast size cliteromegaly and enlargement of the larynx causing a deepening of the voice. These changes can be permanent. The administration of AAS may reduce fertility through suppression of LH and FSH secretion from the anterior pituitary gland. In the absence of gonadotropin drive gonadal function declines. In men sperm count falls and testicular atrophy may occur. In women there is reduced endogenous estrogen production ovulation is impaired and irregular or absent menstrual cycles may ensue. These effects on reproductive function are prolonged taking many months to return to normal after AAS discontinuation. 8.6.3.2 Hepatotoxicity Orally administered AAS impair the filtration and excretion of metabolic waste products by the liver leading to cholestasis jaundice and hepatocellular necrosis. Nonalcoholic fatty liver may develop as a result of altered lipid metabolism. Peliosis hepaticus a rare condition characterized by hemorrhagic blood-filled cysts that are prone to rupture may also occur. With long-term use there is an increased risk of

slide 202:

177 177 R.I.G. Holt 8 Diabetes and Doping 177 177 hepatocellular carcinoma. Abnormal liver function usually returns to normal a few months after treatment discontinuation. 8.6.3.3 Cardiovascular Disease The incidence of myocardial infarction is increased in young men taking AAS. The mechanisms are not fully understood but echocardiography has shown abnormal cardiac enlargement and impaired function following AAS use. There is also evi- dence that AAS abuse may increase the risk of hypertrophic cardiomyopathy in genetically predisposed individuals. In addition to these structural changes AAS misuse is associated with the develop- ment of dyslipidemia. The concentration of high-density lipoprotein HDL choles- terol is reduced by 40–70 while low-density lipoprotein LDL cholesterol increases. These effects vary with dose and type of AAS but seem most marked with oral admin- istration. The changes in lipid profile are particularly relevant for people with diabetes who are already at increased risk of atherosclerotic cardiovascular disease. 8.6.3.4 Psychiatric Effects The use of AAS is associated with an increase in irritability aggressiveness and symptoms of mania. By contrast depression is also common affecting 10–40 of users. Depression may also occur after AAS withdrawal particularly when high doses have been used and may lead to suicide attempts. 8.6.3.5 Anabolic Androgenic Steroids and Diabetes The effect of AAS on diabetes appears to be dependent on the type and dose of AAS. Oral 17-a alkylated AAS seem to have the most marked effect by inducing insulin resistance inhibiting its actions on glucose and lipid metabolism. There are case reports of individuals developing diabetes during treatment with AAS although a causative link is uncertain 5 not least because athletes often take a cocktail of drugs including growth hormone which may have a much greater effect on glucose metabolism than AAS see below. Testosterone deficiency is often seen in men with the metabolic syndrome and type 2 diabetes and under these circumstances testosterone replacement is associated with improved lipid and glycemic control and reduced insulin resistance. These findings may not however be applicable to athletes taking supraphysiological doses. 8.7 Erythropoietin and Blood Transfusion Erythropoietin EPO is a hormone produced in the peritubular cells of the proximal tubules of the kidney and stimulates erythrocyte production by the bone marrow.

slide 203:

178 178 R.I.G. Holt 8 Diabetes and Doping 178 178 8.7.1 Prevalence of Erythropoietin Administration Blood doping is thought to have started during the 1970s and was first prohibited in the 1970s. Before the ban was introduced it was openly and commonly used by middle- and long-distance runners as well as cyclists. It is alleged that the US cycling team employed this method during the 1984 Olympics. Since its prohibition there have been a number of high-profile cases involving athletes who have used either EPO or blood transfusion. These include Niklas Axelsson who tested positive for EPO in 2000 and Tyler Hamilton who used a homologous blood transfusion in 2004. The Spanish Operación Puerto in 2006 investigated allegations of blood doping in hundreds of athletes while several mem- bers of the Astana Team in the 2007 Tour de France tested positive for homologous blood transfusion leading to the withdrawal of the team. The German speed skater and fivefold Olympic gold medalist Claudia Pechstein was banned for 2 years in 2009 for alleged blood doping. 8.7.2 Why Do Athletes Abuse Erythropoietin Exogenous EPO which is available as a recombinant protein or as an analogue is abused by endurance athletes as the increase in red blood cells improves oxygen transport to muscles. Its administration results in a slow and sustained increase in erythrocyte volume which is associated with improved performance. Endogenous EPO production can be induced by training at high altitude and this leads to a simi- lar increase in erythrocyte volume and performance. Only about 50 of competitive athletes respond to altitude training and it is notable that nonresponders do not improve their aerobic capacity 6. An alternative method used by athletes to expand erythrocyte volume is autolo- gous or homologous blood transfusion. Blood is removed and erythrocytes are har- vested stored and then reinfused at a later date. Handling of the blood is important as this can influence erythrocyte function and survival. In contrast to EPO adminis- tration following a blood transfusion the erythrocyte volume is only increased for a few weeks. In the future blood dopers may use oxygen-carrying molecules in place of hemoglobin. 8.7.3 Adverse Effects of Erythropoietin and Blood Transfusion The main adverse effect of an increased erythrocyte volume is an increased risk of thrombotic events. However there are also additional risks of infection associated with blood transfusion particularly when this occurs in an unregulated fashion.

slide 204:

179 179 R.I.G. Holt 8 Diabetes and Doping 179 179 8.7.4 Erythropoietin and Blood Transfusion and Diabetes The risks of EPO and blood transfusion appear to be similar for people with diabetes. However the response to EPO may differ in people with diabetes as both IGF-I and insulin augment the effect of EPO on erythroid progenitors. In some situations this has resulted in marked polycythemia in people with type 1 diabetes and end-stage renal disease receiving EPO 7. Whether this is relevant for athletes is unclear. 8.8 Growth Hormone hGH Growth hormone GH is a naturally occurring peptide hormone produced by the ante- rior pituitary gland. Studies of people with GH deficiency have shown that GH plays a pivotal role in maintaining body composition well-being physical performance and cardiovascular health in adults as well as children. These features make the hormone an attractive option for elite athletes wishing to improve their performance. 8.8.1 Prevalence of GH Abuse Exactly when and where GH was first used to enhance performance is unknown but “The Underground Steroid Handbook” written by Dan Duchaine in 1982 was the earli- est publication to advocate its use at least a decade before clinical endocrinologists began treating adults with GH deficiency. Since then a number of high-profile athletes have been caught or have admitted taking GH. Following the Seoul Olympic Games doping scandal Justice Charles Dubin led an inquiry into drug abuse in sport which concluded that despite the tight regulations surrounding its use GH was widely avail- able and was being used by athletes. In a more recent investigation US Senator George Mitchell found that GH was used extensively by Major League Baseball players to improve their performance and to assist their recovery from injury and fatigue the use of GH was believed to have risen because unlike AAS it was largely undetectable and was readily available for example through “antiaging” centers using prescriptions from physicians whom the athletes had never met. 8.8.2 Why Do Athletes Abuse Growth Hormone Despite its apparent widespread use there is little scientific evidence to support its use as an ergogenic aid 7. Nevertheless the actions of GH to increase muscle mass and reduce fat mass are attractive to athletes and two recent studies have suggested that GH may improve performance.

slide 205:

180 180 R.I.G. Holt 8 Diabetes and Doping 180 180 8.8.2.1 Delivery of Fuels Growth hormone is an insulin antagonist it increases fasting hepatic glucose out- put by increasing hepatic gluconeogenesis and glycogenolysis and decreases peripheral glucose utilization. Although the effect on peripheral glucose uptake may not appear advantageous for performance GH also increases the production of insu- lin-like growth factor-I IGF-I which in turn stimulates peripheral glucose uptake and utilization see below. Growth hormone stimulates lipolysis both directly and indirectly by increasing adipocyte sensitivity to other lipolytic factors such as catecholamines. Endogenous nocturnal or exercise-induced GH secretion leads to a rise in fasting free fatty acid FFA concentration which peaks around 2 h after the GH spike. Likewise following exogenous GH administration FFA rises and peaks with a similar pattern. Studies of fatty acid turnover in people with GH deficiency suggest that GH plays a crucial role in FFA delivery to exercising muscle. Overall the net effect of GH appears to increase the availability of glucose and fatty acids for exercising muscle and probably explains why endurance athletes as well as strength athletes have used GH. 8.8.2.2 Muscle and Bone Anabolism GH stimulates muscle and whole body protein synthesis partly through a direct local action and partly by the generation of IGF-I which in turn inhibits whole body protein breakdown and stimulates protein synthesis. The mechanism of action is different from AAS and so there are additive effects when these agents are used in combination. Insulin see below is also used with GH as it inhibits protein break- down and promotes anabolism. As well as muscle GH has profound anabolic effects on bone and soft tissue which may speed healing following an injury. 8.8.2.3 Cardiovascular Effects Growth hormone therapy in adults with GH deficiency increases left ventricular posterior wall thickness stroke volume and left ventricular ejection fraction during exercise thereby ensuring an adequate blood supply to muscle. It is unclear how- ever whether these cardiovascular effects are relevant for healthy young adults. 8.8.2.4 Thermoregulation Growth hormone is involved in the maintenance of body temperature during exer- cise as impaired thermoregulation occurs during heat exposure and exercise in

slide 206:

181 181 R.I.G. Holt 8 Diabetes and Doping 181 181 2 2 untreated adults with GH deficiency. By contrast a change in body temperature may be one of the mechanisms that induces GH secretion during exercise. 8.8.2.5 Effects on Whole Body Physiology The effects of GH on whole body physiology have been demonstrated through a series of randomized controlled trials of GH replacement in people with GH defi- ciency. In the absence of GH body composition changes with a loss of lean tissue and accumulation of fat in particular visceral fat. Skeletal muscle mass and strength is reduced with a consequent impairment of physical performance exercise capacity and VO max aerobic capacity or the maximum ability to take in and use oxygen. Following treatment with recombinant human GH rhGH there is an impressive normalization of body composition on average lean body mass mainly skeletal muscle increases by 6 kg while there is a concomitant loss of fat mass. These body composition changes are accompanied by improvements in quality of life particu- larly in the area of “increased energy” and performance enhancements. Although a meta-analysis found that short-term rhGH treatment had no effect on muscle strength a further meta-analysis demonstrated that maximal power output VO 2 max and maximum work rate all improved following GH replacement. 8.8.2.6 Effect of Growth Hormone in Healthy Adults Until recently most studies in normal young healthy subjects have not found a per- formance benefit following GH treatment. Although GH administration is frequently associated with increased lean body mass and decreased fat mass important exer- cise variables such as respiratory quotient maximal oxygen uptake bicycling speed power output energy expenditure or strength are not improved 8. These studies may not be suited to assess the effects of GH in individual athletes who often use higher doses than those used in the randomized controlled trials and who often combine GH with other performance-enhancing drugs. The first trial to show a performance benefit for GH in young healthy adults was undertaken in abstinent anabolic steroid users. As well as the previously observed changes in body composition 6 days of GH treatment lead to significant improve- ments in strength peak power output and maximal oxygen uptake. It is possible that unlike previous studies this study found a benefit because the prior use of steroids may have rendered the athletes particularly sensitive to the anabolic actions of GH. A more recent placebo-controlled RCT of 6-week treatment found that GH improved sprint capacity in both men and women. There was a further synergistic effect with testosterone in men but the effect on performance was short-lived and had disappeared by 6 weeks after GH discontinuation. Other performance mea- sures however including VO max and strength were unchanged.

slide 207:

182 182 R.I.G. Holt 8 Diabetes and Doping 182 182 Overall it appears that in recreational athletes GH has a modest performance- enhancing effect particularly when combined with testosterone but whether these effects can be extrapolated to elite athletes is unknown. 8.8.3 Adverse Effects of Growth Hormone The side effects associated with GH administration in adults with GH deficiency are well documented and may also affect any athlete abusing GH however as anec- dotal evidence suggests that many athletes are taking doses that are much than those used therapeutically it is reasonable to predict that athletes may develop features of acromegaly with prolonged use. The long-term effects may therefore include fluid retention causing ankle swelling hypertension and headache diabetes and a car- diomyopathy which is characterized by abnormalities in cardiac muscle structure and function. Although controversial there is a potential for increased risk of cer- tain cancers including colorectal thyroid breast and prostate cancer. All pharmaceutically available GH is now made by recombinant DNA technol- ogy but supplies of pituitary-derived GH are still available to athletes on the black market increasing the risk of the prion-induced Creutzfelt-Jacob Disease. 8.8.4 Growth Hormone and Diabetes Under normal physiological conditions insulin is the prime regulator of glucose metabolism but there is increasing evidence that GH and IGF-I play an important contributory role. A role for GH in glucose metabolism was first postulated in the 1930s when Houssay and Biasotti found that hypophysectomy reduced the hyper- glycemia seen in canine models of diabetes. The diabetogenic factor isolated from pituitaries was also found to have growth-promoting activity and named “growth hormone.” The experimental administration of GH to animals and humans con- firmed its diabetogenic properties but it was only after the development of reliable GH assays that the importance of GH in glucose metabolism was fully appreciated in both healthy subjects and people with type 1 diabetes. Pituitary GH secretion is increased in individuals with diabetes leading to con- centrations that are up to 2–3 times higher than healthy subjects. Portal insulin con- centrations play a key role in the regulation of hepatic IGF-I generation in the absence of portal insulin a state of acquired hepatic GH resistance develops with reduced IGF-I production and negative feedback at the pituitary gland. GH admin- istration to people with type 1 diabetes has little effect on serum IGF-I concentra- tion while residual insulin secretion as reflected by plasma C-peptide concentration determines the degree of GH hypersecretion. Nocturnal GH hypersecretion may play a role in the early morning worsening of insulin sensitivity and plasma glucose as people with type 1 diabetes and GH

slide 208:

183 183 R.I.G. Holt 8 Diabetes and Doping 183 183 deficiency do not exhibit the “dawn phenomenon” while even a single bolus of GH to these individuals decreases morning insulin sensitivity. 8.8.4.1 Growth Hormone and the Microvascular Complications of Diabetes In 1953 Poulsen presented the case of a woman with type 1 diabetes and back- ground diabetic retinopathy which regressed after she developed panhypopituitar- ism after postpartum pituitary necrosis. This observation led to the use of pituitary ablation in the 1960s to treat diabetic retinopathy until the development of the safer photocoagulation. A role for GH in development of microvascular complications is also suggested by the decreased incidence of retinopathy in people with type 1 dia- betes and GH deficiency. This area is controversial as there is no evidence that GH replacement therapy causes an increased incidence of retinopathy in GH-deficient adults with or without diabetes. Furthermore the role of GH is complicated by the many other growth factors which have been implicated in the development of microvascular complications. In conclusion it would appear that GH is likely to be less effective as a perfor- mance-enhancing drug in people with type 1 diabetes because of the GH-resistant state it is also likely to be associated with additional harm through impaired glyce- mic control and possible worsening of diabetic complications. 8.9 Insulin-Like Growth Factor-I Insulin-like growth factor-I is a single chain peptide which has structural homology with proinsulin. Although IGF-I is synthesized widely the majority of circulating IGF-I is produced in the liver under the regulation of GH insulin and nutritional intake. It has profound effects on cell proliferation and differentiation in many tis- sues as well as metabolic effects which are broadly similar to those of insulin including actions on glucose metabolism. 8.9.1 Prevalence of Abuse with IGF-I The prevalence of IGF-I abuse is probably much lower than for GH because unlike GH there is no readily available natural source and therefore all IGF-I is manufactured through recombinant DNA technology. As the tests for detecting GH abuse develop however there are anecdotal reports that athletes for example weightlifters are increasingly turning to IGF-I as an alternative performance- enhancing agent 9.

slide 209:

184 184 R.I.G. Holt 8 Diabetes and Doping 184 184 Two therapeutic preparations of IGF-I have been approved since 2005 for the treatment of growth failure in children with severe primary IGF-I deficiency or with GH gene deletion who have developed neutralizing GH antibodies. The first product is recombinant human IGF-I Mecasermin and the second is a combination of rhIGF-I and its major binding protein IGFBP-3 Mecasermin Rinfabate. Although these drugs are still in relatively short supply IGF-I is manufactured for cell culture and other uses and this laboratory grade material is available to athletes. The widening availability of IGF-I together with an appreciation of the efforts to detect GH abuse is likely to increase illicit use of IGF-I despite its inclusion on the WADA List of Prohibited Substances. 8.9.2 Why Do Athletes Abuse IGF-I IGF-I has a number of effects on carbohydrate lipid and protein metabolism in a wide range of target tissues some of which may prove beneficial to the competing athlete. Although a positive correlation between serum IGF-I concentration and physical fitness has been observed there is no published evidence that rhIGF-I administration improves physical performance or indeed alters body composition. Recent studies undertaken in Southampton however suggest that IGF-I increases the maximal uptake of oxygen in healthy recreational athletes. The actions of IGF-I have been demonstrated in people with rare inherited defects of the GH receptor. The condition is characterized by severe postnatal growth failure and rhIGF-I therapy leads to substantial improvements in linear growth. There are signifi- cant increases in protein synthesis rates with increased lean body mass and decreased adiposity. Rates of lipolysis and lipid oxidation increase with rhIGF-I therapy. More recently important effects of rhIGF-I on intermediate metabolism have been shown in healthy individuals. 8.9.2.1 Protein Metabolism IGF-I infusion in healthy individuals results in the insulin-like property of inhibiting proteolysis inhibition and the GH-like property of stimulating protein synthesis. The intracellular pathways of IGF-I action are not fully understood but it appears that IGF-I acts at least in part by stimulating amino acid uptake into cells. The combined actions of IGF-I GH and insulin could result in synergistic effects on protein metabo- lism and may explain why athletes take cocktails of these potent hormones 10. 8.9.2.2 Carbohydrate Metabolism IGF-I has direct actions on glucose metabolism that are similar to insulin and causes hypoglycemia by increasing peripheral glucose uptake and decreasing hepatic glu- cose production when administered to healthy volunteers. A single intravenous dose of 100 mg . kg −1 results in the rapid onset of symptomatic hypoglycemia and is

slide 210:

185 185 R.I.G. Holt 8 Diabetes and Doping 185 185 equipotent to 0.15 IU . kg −1 of insulin. A continuous intravenous infusion of IGF-I causes a 50 fall in C-peptide concentration despite the maintenance of euglyce- mia. The onset of hypoglycemia is slower with subcutaneous IGF-I administration than with insulin because of the presence of circulating IGF binding proteins which buffer the IGF-I action. IGF-I infusion also inhibits GH secretion through negative feedback which may contribute to the improvements in insulin sensitivity. The potential benefit to the athlete is the stimulation of muscle glycogen synthe- sis replenishing nutrient supplies physical endurance at high work intensities relies on skeletal muscle glycogen stores and so IGF-I may improve performance and accelerate recovery in endurance sports such as long-distance running or cycling. 8.9.3 Adverse Effects of IGF-I The side effect profiles of the commercial preparation of rhIGF-I include hypoglyce- mia jaw pain headache myalgia and fluid retention. The combined rhIGF-I- rhIGFBP-3 Mecasermin Rinfabate is associated with less hypoglycemia because the IGFBP-3 appears to buffer the acute effects of IGF-I and increase its half-life. Side effects of Mecasermin Rinfabate include local injection-site erythema and lipohyper- trophy though headaches and altered liver function tests have also been reported. There are limited long-term data about the safety of IGF-I. Tonsillar and adenoi- dal tissue hypertrophy was reported in nearly a quarter of children with GH insen- sitivity syndrome treated with rhIGF-I for up to 12 years. In addition there were changes in the facial appearance in some children although these regressed par- tially after therapy was withdrawn. By contrast rhIGF-I treatment in adult patients with severe insulin resistance for 16 months did not result in changes in physical appearance. The clinical features of acromegaly are however possible with pro- longed use. Epidemiological studies have linked certain cancers with increased serum IGF-I concentration and like GH it is possible that the administration of uncontrolled doses of IGF-I may increase the risk of cancer. There are also concerns about the use of laboratory grade IGF-I because of the reduced purity. 8.9.4 IGF-I and Diabetes Serum IGF-I is reduced in people with type 1 diabetes because of the acquired hepatic GH resistance. Intensive insulin treatment by subcutaneous injection does not completely normalize IGF-I but when insulin is given to people with type 1 diabetes by continuous intraperitoneal infusion directly into the portal circulation as occurs normally in vivo using an implantable pump portal insulin concentra- tion increases and there is near-normalization of IGF-I. There has been interest in treating type 1 diabetes with IGF-I at a replacement dose to correct the derangements of the GH-IGF axis and exploit its hypoglycemic actions. When a single dose of IGF-I 40 mcg/kg was administered to adolescents

slide 211:

186 186 R.I.G. Holt 8 Diabetes and Doping 186 186 with type 1 diabetes hepatic insulin sensitivity increased and the glucose production rate fell. Over 7 days IGF-I increased peripheral glucose uptake and reduced prote- olysis despite a reduced insulin requirement to maintain euglycemia. After 3 months treatment with rhIGF-I at night insulin sensitivity and glycated hemoglobin improved in adolescents with type 1 diabetes in association with a fall in insulin requirement 11. Although these improvements were not sustained over the 6 months of the study it was thought that the deterioration in control was related to poor concordance with the multi-injection regimen rather than a reduction in the biological effect of IGF-I. The improvement in metabolic control is achieved through both reduced GH secretion and through a direct hypoglycemic action of IGF-I. Despite these early promising findings the development of IGF-I as a treatment for diabetes was halted because of concerns that increased serum IGF-I concentra- tions are associated with progression of retinopathy in people with diabetes. Overall there is no published evidence that IGF-I improves performance although metabolic studies suggest it has features that may be beneficial to athletes. The administration of IGF-I to people with type 1 diabetes may affect insulin require- ment and increase the risk of hypoglycemia. There are also concerns that it may increase the incidence and progression of retinopathy. 8.10 Insulin Insulin is a 51-amino-acid peptide hormone comprising two polypeptide chains the A and B chains which are linked by disulfide bridges. Insulin is synthesized in the b-cells of the islets of Langerhans in the pancreas. It has major effects on intermedi- ate metabolism and may be considered as the hormone that signals the “post-meal” fed state. During this period it is pivotal in the regulation of cellular energy supply and macronutrient balance and directing anabolic processes. Autoimmune destruction of the b-cells leads to the development of type 1 diabe- tes. Insulin is used therapeutically to treat all people with type 1 diabetes and some people with type 2 diabetes. It was first isolated from the pancreas in 1921 by Banting and Best and the first person with diabetes was treated in 1922. Initially the only source of insulin was from animals and both bovine and porcine insulin are still used albeit in diminishing amounts. The advent of recombinant DNA technol- ogy led to a major advance in the production of insulin the insulin coding sequence is inserted into bacteria such as Escherichia coli allowing large quantities of insulin including animal insulin to be produced in a highly purified manner. The half-life of intravenous soluble insulin is only 4 min but apart from the treat- ment of diabetic emergencies insulin administered in clinical practice is by subcu- taneous injection. When soluble insulin is injected subcutaneously it forms a hexamer which delays its absorption from the injection site. It therefore acts more slowly than endogenously secreted insulin and so the pharmacokinetic profile does not match endogenous requirements periods of both hypoglycemia and hypergly- cemia can therefore ensue. In order to address this problem attempts have been

slide 212:

187 187 R.I.G. Holt 8 Diabetes and Doping 187 187 made to shorten the onset and duration to provide a suitable mealtime insulin and also to lengthen the profile to provide a more appropriate background insulin. The first modifications were the addition of protamine and zinc in the 1930s and the 1950s respectively to form isophane insulin which has a prolonged duration of action. Recombinant DNA technology first permitted the production of human sol- uble insulin and then the development of both short- and long-acting insulin ana- logues. The shortest-acting insulin analogues appear in the circulation within 5–10 min of injection and are cleared within 4–6 h while the latest long-acting insu- lin analogues in development are present for over 24 h. 8.10.1 Prevalence of Insulin Abuse There are only sketchy details about the use of insulin by professional athletes 10. It is alleged that short-acting insulin is used to increase muscle bulk in body build- ers weightlifters and powerlifters. After concerns raised by the Russian medical officer at the Nagano Olympic Games the International Olympic Committee IOC immediately banned its use in those without diabetes. Athletes with insulin-requir- ing diabetes may use insulin with a medical exemption. 8.10.2 Why Do Athletes Abuse Insulin Insulin has major anabolic actions on intermediate metabolism affecting glucose lipid and protein metabolism with the most important insulin-sensitive tissues being the liver skeletal muscle and adipose tissue. 8.10.2.1 Glucose Metabolism Under normal physiological conditions insulin together with its principal counter- regulatory hormone glucagon is the prime controller of glucose metabolism and plasma glucose concentration. It is involved in the regulation of carbohydrate metabolism at many steps increasing glucose uptake into cells promoting glycoly- sis and glycogen synthesis while inhibiting glycogen breakdown and gluconeogen- esis. These actions would allow an athlete to replenish muscle glycogen stores after a bout of exercise in a similar manner to that described for IGF-I. 8.10.2.2 Lipid Metabolism Insulin increases the rate of lipogenesis in several ways in adipose tissue and liver and controls the formation and storage of triglyceride. The critical step in lipogenesis

slide 213:

188 188 R.I.G. Holt 8 Diabetes and Doping 188 188 is the activation of the insulin-sensitive lipoprotein lipase in the capillaries which releases fatty acids from circulating chylomicrons or very low-density lipoproteins to be taken up by adipose tissue. Fatty acid synthesis is increased while fat oxida- tion is suppressed. Lipogenesis is also facilitated by the glucose uptake because its metabolism by the pentose phosphate pathway provides NADPH which is needed for fatty acid synthesis. Triglyceride synthesis is stimulated by esterification of glycerol phosphate while triglyceride breakdown is suppressed by dephosphoryla- tion of hormone-sensitive lipase. 8.10.2.3 Protein Metabolism Insulin stimulates the uptake of amino acid into cells thereby promoting protein synthesis in a range of tissues however the major action of insulin is to inhibit protein breakdown. The similarities between IGF-I and insulin suggest that these proteins act in a coordinated manner to regulate protein turnover. Furthermore many of the intracellular signaling mechanisms of insulin and IGF-I such as IRS-I are shared. There are differences however in their respective dose-response curves. Low physiological insulin concentrations inhibit protein breakdown and increase glucose disposal into skeletal muscle while higher nonphysiological concentrations are required to stimulate protein synthesis. In contrast increases in IGF-I that have no effect on glucose uptake stimulate protein synthesis while higher concentrations are required to inhibit protein breakdown. The precise mechanism by which these similar but divergent pathways interact is not fully understood. 8.10.3 Adverse Effects of Insulin The side effects of insulin are well documented from the extensive experience in treating people with diabetes. The commonest side effect is hypoglycemia but weight gain is also a problem in people with diabetes. This may be less problematic for athletes whose diet and training regimen is closely monitored. There is evidence that hyperinsulinemia per se may induce insulin resistance which has been impli- cated in the development of cardiovascular disease this remains contentious but argues that people with diabetes should not receive more insulin than is needed to control their hyperglycemia. 8.10.4 Insulin and Diabetes Unlike the other hormones described in the preceding sections insulin forms an essential part of the treatment of an athlete with diabetes. The main issue for an athlete with type 1 diabetes is the need to obtain a therapeutic use exemption which is described below.

slide 214:

189 189 R.I.G. Holt 8 Diabetes and Doping 189 189 8.11 Antihypertensives Beta-blockers which may be used in people with diabetes as antihypertensive agents are prohibited in competition in certain sports during competition Table 8.1. The main concern about these drugs in diabetes is that they may mask the symptoms of hypoglycemia they may also worsen glycemic control particularly if combined with thiazide diuretics. 8.12 Therapeutic Use Exemption Like all individuals athletes may develop illnesses or conditions that require them to take prescribed medications. When these appear on the WADA Prohibited List as is the case for insulin an athlete must apply for a Therapeutic Use Exemption TUE to allow them to take the medicine before and during competition. The International Standard for Therapeutic Use Exemptions ISTUE is regulated by WADA to ensure that the process of granting TUEs is coordinated across sports and countries. There are a number of criteria that must be fulfilled before a TUE is granted: • The athlete would experience significant health problems without taking the pro- hibited substance or method. • The therapeutic use of the substance would not produce significant enhancement of performance. • There is no reasonable therapeutic alternative to the use of the otherwise prohib- ited substance or method. In the case of type 1 diabetes the first and third criteria are clearly fulfilled as insu- lin is an essential part of the treatment of diabetes without which the athlete would die rapidly from diabetic ketoacidosis. However it is important to obtain accurate medical records to demonstrate the diagnosis and this may be difficult if the diag- nosis was made several decades previously. The second criterion is more difficult to prove as insulin may be performance enhancing however the decision to award a TUE must balance this possibility with the severity of the condition and the appro- priateness of the medication. The athlete may be required to provide evidence of recent blood glucose monitoring and other measures of glycemic control. TUEs may be granted by either International Sporting Federations which admin- isters applications from all international level athletes or National Anti-Doping Organizations for national level athletes. Both types of body are required by WADA to have an established process to administer TUE applications. It is important that an athlete should submit an application to only one organization and not to WADA. The TUE application is usually fairly simple and involves the athlete submitting an electronic or paper application to the relevant International Federation or National Anti-Doping Organization. WADA has developed the Anti-Doping Administration and Management System ADAMS a web-based database management system to

slide 215:

190 190 R.I.G. Holt 8 Diabetes and Doping 190 190 simplify the process. It is easy to use and is freely available in English French Spanish German Japanese Russian Italian Dutch and Arabic. ADAMS stores data on laboratory results TUEs and information on Anti-Doping Rule Violations ADRVs and facilitates the sharing of information between relevant organizations. All TUE applications should be supported by a physician’s statement and other supporting documentation confirming that the criteria for a TUE are met. The appli- cation should be submitted at least 30 days before participating in an event. Following the submission of an application it is assessed by an independent panel of physi- cians known as the Therapeutic Use Exemption Committee. If a TUE is denied by the committee an athlete has the right to appeal to WADA or ultimately to the Court of Arbitration for Sport. A TUE is granted for a specific medication with a defined dose and for a specific period of time and may contain conditions that should be adhered to. During a dop- ing control procedure the athlete should declare the medication being used and although not mandatory it is helpful to show the doping control officer the TUE approval form. As the WADA-accredited laboratories are blinded to the athlete’s identity during testing and medical information disclosed in a TUE application is kept strictly con- fidential they may report an adverse analytical finding to the doping control author- ity however as long as the TUE is still in effect and that the results of the analysis are consistent with the TUE granted i.e. the nature of medication route of admin- istration dose time frame of administration are deemed appropriate the result of the test will be recorded as negative. Acknowledgments I would like to thank Michael Stow of UK Anti-Doping for his helpful com- ments on the chapter. References 1. Holt RI Erotokritou-Mulligan I Sonksen PH. The history of doping and growth hormone abuse in sport. Growth Horm IGF Res. 2009194:320–6. 2. Yesalis CE Bahrke MS. History of doping in sport. In: Bahrke MS Yessalis CE editors. Performance-enhancing substances in sport and exercise. 1st ed. Champaign: Human kinetics 2002. p. 1–20. 3. Wilson JD. Androgen abuse by athletes. Endocr Rev. 198892:181–99. 4. Bagatell CJ Bremner WJ. Androgens in men–uses and abuses. N Engl J Med. 1996 33411:707–14. 5. Geraci MJ Cole M Davis P. New onset diabetes associated with bovine growth hormone and testosterone abuse in a young body builder. Hum Exp Toxicol. 20113012:2007–12. 6. Sawka MN Muza SR Young AJ. Erythrocyte volume expansion and human performance. In: Fourcroy JL editor. Pharmacology doping and sports. a scientific guide for athletes physi- cians scientists and administrators. Abingdon: Routledge 2009. p. 125–34. 7. Fernandez-Reyes MJ Selgas R Bajo MA Jimenez C Del PG Sanchez MC et al. Increased response to subcutaneous erythropoietin on type I diabetic patients on CAPD: is there a syner- gistic effect with insulin Perit Dial Int. 1995156:231–5.

slide 216:

191 191 R.I.G. Holt 8 Diabetes and Doping 191 191 8. Liu H Bravata DM Olkin I Friedlander A Liu V Roberts B et al. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med. 200814810:747–58. 9. Guha N Sonksen PH Holt RI. IGF-I abuse in sport: current knowledge and future prospects for detection. Growth Horm IGF Res. 2009194:408–11. 10. Holt RI Sonksen PH. Growth hormone IGF-I and insulin and their abuse in sport. Br J Pharmacol. 20081543:542–56. 11. Acerini CL Patton CM Savage MO Kernell A Westphal O Dunger DB. Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. Lancet. 1997 3509086: 1199–204. Further Reading Books Fainaru-Wada M Gotham LW. Game of shadows: Barry Bonds BALCO and the steroids scandal that rocked professional sports. 1st ed. 2006 pp. 352. ISBN-10: 9781592401994. Fourcroy JL. Pharmacology doping and sports: a scientific guide for athletes coaches physicians scientists and administrators. 1st ed. Routledge 2008 pp. 240. ISBN-10: 0415578221. Themed Journal Issues McGrath I Cowan D Guest Editors. Drugs in sport. Br J Pharmacol. 2008 1543. Sonksen PH Holt RIG Guest Editors. The abuse of growth hormone in sport and its detection: a medical legal and social framework. Growth Hormone IGF Res. 20094. Useful Websites UK Anti-Doping: http://www.ukad.org.uk/ US Anti-Doping Agency: http://www.usantidoping.org/ World Anti-Doping Agency: http://www.wada-ama.org/

slide 217:

Chapter 9 Synthesis of Best Practice Ian Gallen In the preceding chapters we have seen elegant discussions of the hormonal and metabolic responses to exercise and how these responses are altered by type 1 diabetes and insulin therapy. In Chap. 1 we have seen how exercise exerts a great demand on the capacity of the human body to maintain blood glucose homeostasis. The normal physiological counterregulatory hormone response generated by exercise produces a coordinated endocrine response which switches the physiological state from the post- absorptive to the exercise state enabling release of the nutrients required to support increased work. Increased glucose utilization by skeletal muscle proportionate to the duration and intensity of exercise is counteracted by a complex and well- coordi nated endocrine response. Hepatic glucose production through increased glycogenolysis and gluconeogenesis mediated through increased glucagon and a fall in insulin concentrations in the portal vein are important stimulators of hepatic glucose production during low- and moderate-intensity exercise. Further counterregulatory cat- echolamine responses during high-intensity exercise are important in intense exercise and with modest hypoglycemia in nondiabetic intervals. It is perhaps surprising that even in nondiabetic individuals preexercise hypoglycemia is associated with blunted counterregulation during subsequent exercise and prior exercise blunts the counter- regulatory response to subsequent hypoglycemia. There are further age- gender- and obesity-related difference in these responses. It is therefore entirely predictable that diabetes and insulin treatment is likely to have very significant effects on the ability to perform exercise though changes in glycemic and counterregulatory responses. In Chap. 2 we read how a number of endocrine disturbances can influence glu- cose regulation during exercise making the management of glycemia challenging

slide 218:

for patient and caregiver. While aerobic exercise frequently results in a reduction in blood glucose concentration intense and anaerobic exercise can promote transient hyperglycemia. I. Gallen B.Sc. M.D. FRCP Diabetes Centre Wycombe Hospital High Wycombe UK e-mail: ian.gallenbuckshealthcare.nhs.uk I. Gallen ed. Type 1 Diabetes DOI 10.1007/978-0-85729-754-9_9 © Springer-Verlag London Limited 2012 193

slide 219:

194 194 I. Gallen 9 Synthesis of Best Practice 194 194 In diabetes we have seen the effect of relative overinsulinization during exercise which when combined with the impaired physiological response of the counterregu- latory hormones results in impaired endogenous glucose production coupled with increased glucose utilization. The net effect of these variations in normal physiology leads to the classical glycemic response during endurance exercise of progressive falling blood glucose values and risk of hypoglycemia 1 2. In contrast short bursts of intense exercise may produce a relative excess counterregulatory hormone response relative to available insulin which may lead to hyperglycemia during exercise 3 4. We have seen how this exercise-induced state may protect against hypoglycemia following shorter periods of endurance exercise 5 6. However for both forms of exercise particularly if the exercise is intermittent increased glucose disposal into skeletal muscle as a result of increased expression of GLUT4 transporters 7 8 and resultant improvement in insulin sensitivity can lead to increased insulin sensitivity in the late postexercise period 2 9. This is particularly important when combined with the reduction in counterregulatory hormone response to hypoglycemia seen following exercise particularly in men as it may predispose to severe nocturnal hypoglycemia 10–16. Given the well-recognized and strong tendency to dysglycemia with exercise how can the practicing clinician best advise their patient The routine clinical review appropriately focuses on glycemic control on the adverse consequences of insulin treatment hypoglycemia and weight gain on the surrogate markers for complica- tions of diabetes HbAlc blood pressure microalbuminuria eGFR and lipids and on examination to detect signs of the complications of diabetes. This leaves little time for dealing with questions about how to manage exercise and these may not routinely be given the attention that they might deserve. Having said this patients with diabetes are encouraged to perform regular exercise and it is therefore incum- bent on the clinician to equip himself or herself with the skills that are necessary to advise their patient 17. Over the last decade we have developed a specialist diabetes and sports clinic for young people who are outstanding athletes from throughout the UK. The skills and practice gained from this clinic when combined with the excellent clinical research described in the previous chapters offer us the opportunity of suggesting a clinic model to health-care professionals to help people manage diabetes and exer- cise more effectively. We have found that patients attending the service complain of three main groups of symptoms: 1. Seemingly inexplicable dysglycemia during and immediately following exercise 2. Unexpected and severe hypoglycemia particularly at night 3. Excessive fatigue impaired physical performance and increased muscle weak- ness and cramps when compared to their prediabetic state or with peers this is probably the most subtle of the three groups of symptoms To deal with these issues we conduct a standardized clinical interview. The aim of the interview is to reduce day-to-day variation in insulin therapy and to improve insulin dosage relative to carbohydrate intake. A focus on detail is extremely

slide 220:

195 195 I. Gallen 9 Synthesis of Best Practice 195 195 important as we frequently find that much of the apparently inexplicable variation in glycemic control is not due to exercise but due to these factors: 1. General history of the person’s diabetes in which the duration treatment and complications of diabetes along with control are assessed. 2. A detailed review of injection technique particularly focusing on needle length site of injection and inspection of injection sites for lipohypertrophy and sclerosis is made. Care is taken in identifying suitable sites for injection of basal and bolus insulin doses particularly in the context of the proposed exercise. When NPH insulin is used a review of the technique of resuspension is frequently required. 3. A careful review of calorie intake and techniques for dose adjustment carbohydrate counting is made along with a review by our specialist dietician as to the appropri- ate calorie intake for the individual’s estimated energy expenditure. Patients coming to our service frequently report insufficient calorie intake to support their exercise which will increase the risk of late hypoglycemia and cause fatigue and impaired performance. In contrast where patients are overweight and desirous of weight loss reducing energy intake can be helpful and estimating energy expenditure allows appropriate dietary advice to be given. Carbohydrate intake should be spaced throughout the week avoiding carbohydrate preloading prior to exercise for which there is no evidence of benefit in diabetes. Advice to ensure the accuracy of the carbohydrate intake and appropriate insulin is also given. 4. A detailed history of the sporting/exercise program is made. Particular attention is paid to the timing duration intensity and type of exercise on each day of the week. This allows the exercise to be characterized so that the anticipated effect on blood glucose levels can be identified. In general the exercise is classified as endurance in which case blood glucose can be predicted to fall high intensity where blood glucose is likely to rise or mixed exercise such as team sports where the effect may be variable from day to day depending on the intensity of each event although the general effect tends to be a fall in blood glucose levels which is attenuated when compared with pure endurance exercise. Importantly the timing of each event in relation to the bolus dose of insulin is identified as well as any adjustments which are made to this dose. 5. Particular care and attention is paid to symptoms suggestive of hypoglycemic unawareness. Severe hypoglycemia particularly in young adults who are sleeping on their own is of special concern and where found requires specific attention 18. The risk of exercise-induced nocturnal hypoglycemia is carefully explained and avoidance of alcohol on days following exercise emphasized. We recommend that people with diabetes set alarms to wake in the early hours of the morning to check blood glucose. When possible we seek other members of the household to advise on signs of severe hypoglycemia and the appropriate use of glucagon. If exercise is planned to occur after an episode of hypoglycemia we advise that it is delayed or reduced in intensity and takes place in a safe environment. 6. In our interviews we also focus on measures of physical performance and fatigue. Identification of variability in performance such as slowing during timed endurance events or variability in ability to deal with opponents during team

slide 221:

196 196 I. Gallen 9 Synthesis of Best Practice 196 196 games. This is an area which may not be familiar to diabetes teams but is readily assessable on questioning. Open questions about perceived excess fatigue or poor performance suggest problems with antecedent hyperglycemia prior to or during exercise 19–22 or insufficient food intake. There is also good evidence that fuel oxidation is markedly variable in type 1 diabetes during exercise 23– 27 and it is likely that this will contribute to impaired physical performance particularly during endurance sport but this is amenable to management. 9.1 Potential Strategies There are limited strategies currently available to improve glycemic control and per- formance. These are centered on variation in the timing and dosage of insulin therapy and adjustment in carbohydrate intake. Our experience is that it is not possible to manage most patients who are performing regular physical activity on premixed twice-daily insulin without frequent exercise-induced hypoglycemia or conversely hyperglycemia on nonexercise days. For those using such a regimen we transfer the majority of our patients on to a multiple daily injection regime using rapidly acting analogue injection insulin aspart Novo Nordisk lispro Eli Lilly or glulisine Sanofi-Aventis 28. The basal component of the multiple daily injection regimens uses human NPH insulin Insulatard Novo Nordisk or Humulin I Eli-Lilly or analogue insulin glargine Sanofi-Aventis or insulin detemir Novo Nordisk. Short-acting insulin analogues enable more predictable postprandial glucose con- trol with reduced risk of late postprandial hypoglycemia in the context of increased calorie intake seen in subjects performing regular exercise. Longer-acting basal ana- logue insulin therapy has become a mainstay of insulin therapy for many people with type 1 diabetes. The longer duration of action of these therapies while advantageous during routine treatment may result in relative excess insulin during exercise. As a result both insulin glargine and detemir may increase the tendency to hypoglycemia during endurance exercise. There is some evidence to suggest that insulin detemir and NPH insulin may be less likely to cause hypoglycemia with exercise than insulin glargine 28 29. Ongoing studies are needed to demonstrate if these differences in this tendency between the two types of insulin are to be confirmed. Reducing basal insulin on the day preceding endurance exercise leads to pro- longed preexercise hyperglycemia and late postexercise hyperglycemia both of which add substantially to impaired glycemic control. We therefore do not advise preexercise reductions of basal insulin on the night preceding exercise 30. However we have found that for some patients who are performing prolonged endurance exercise e.g. marathon running on one or two days in the week par- ticularly in the morning it may be advantageous to have those patients managed on twice-daily NPH insulin. Normal morning NPH insulin dose can be significantly reduced or omitted on the day of the endurance exercise. This reduces the risk of hypoglycemia and the requirement for additional carbohydrate ingestion without causing the antecedent nocturnal hyperglycemia which would occur if the nocturnal

slide 222:

197 197 I. Gallen 9 Synthesis of Best Practice 197 197 basal insulin dose was reduced. It may be necessary to give a reduced dose of basal insulin following exercise to avoid later postprandial hyperglycemia. For patients treated using multiple daily insulin injections if exercise occurs within 90 min of the insulin injection it is possible to markedly reduce the prepran- dial insulin dose 31–33. This will reduce the tendency to exercise-induced hypo- glycemia albeit at the cost of preexercise hyperglycemia 33. However if the exercise is more than 2 h after the bolus dose of insulin this strategy is not benefi- cial. If patients are of normal body weight and weight control is not an issue late postprandial exercise can be successfully managed by ingestion of carbohydrate before and during exercise 9 22 34–37. Evidence from the preceding chapters does suggest that complex carbohydrates with low glycemic index may be success- ful at reducing hypoglycemia during exercise without causing late postexercise hyperglycemia but these carbohydrates are not currently widely available. More simple forms of carbohydrate such as glucose can be ingested in regularly accessi- ble form during exercise and we recommend ingestion during endurance up to the dose of approximately 1 g/kg/h of exercise so that typically a 70-kg adult may be ingesting 20 g of glucose every 20 min during exercise. There is considerable evi- dence that the ability to absorb glucose during exercise is limited to as little as 60 g/h 38. This implies that excess carbohydrate above this value will not assist in the avoidance of hypoglycemia but merely add to postexercise hyperglycemia. We advise that where exercise is under 1 h duration simple carbohydrates are taken. When exercise is more prolonged there is the opportunity to ingest more palatable complex foods. The strategy of ingesting frequent small quantities of glucose dur- ing the exercise where possible is effective at maintaining euglycemia 39. This may not be practical for some exercises and where this is the case ingestion of the low-glycemic-index carbohydrate isomaltulose is also effective in maintaining eug- lycemia without antecedent hyperglycemia 40. If exercise is intermittent i.e. less than every other day we advise reduction in basal insulin dose on the night following exercise of between 10 and 20. Clearly this may lead to the potential of hyperglycemia in the morning and where this is present additional blood sugar monitoring at 2–3 a.m. is useful to ensure that there is no nocturnal hypoglycemia. For patients performing exercise frequently such dose reductions once they have occurred do not need to be repeated. For patients who are trying to use exercise to lose weight calculated dietary intake needs to be significantly lower than the energy expenditure and alternates to carbohy- drate ingestion during exercise need to be pursued. We find that a brief burst of high- intensity exercise prior to endurance effort and adding intermittent high-intensity exercise during endurance exercise both protect against hypoglycemia following exer- cise without ingesting extra carbohydrate 4–6. However when compared to endur- ance exercise alone adding intermittent high-intensity exercise during endurance exercise increases the risk of nocturnal hypoglycemia 18. Ingestion of sympathomi- metic agents including caffeine or b2-adrenoreceptor agonist may potentially offer an additional treatment option for people who wish to do exercise in the late postprandial period and would like to reduce or avoid taking additional carbohydrate. Acute caf- feine ingestion 30 min before prolonged endurance exercise reduced hypoglycemia

slide 223:

198 198 I. Gallen 9 Synthesis of Best Practice 198 198 duration and following exercise in type 1 diabetes 41. Terbutaline may also protect nocturnal hypoglycemia in children following exercise. Continuous subcutaneous insulin infusion CSII enables reduction or suspension of normal basal insulin infusion rates before and during exercise. This reduction may restore some of the physiological response to exercise and reduce the need for carbo- hydrate ingestion. CSII infusion rates can be restored or increased prior to or follow- ing the end of exercise to deal with postexercise glycogenic peak. Nocturnal basal CSII infusion rates can also be reduced if exercise is infrequent. CSII treatment seems an attractive option for people with diabetes who are exercising regularly or who have complex or variable exercise programs which are less amenable to adjust- ment of MDI regimes. At present guidance on how CSII infusion rates are to be adjusted is dependent on clinical experience with little significant evidential base. The advent of commercially available continuous glucose monitoring CGMS equipment may seem at first sign a significant advance in the management of exer- cise and type 1 diabetes. These devices measure subcutaneous interstitial glucose values following calibration with synchronous capillary glucose measurement 42 43. Blood glucose values change very rapidly during exercise and unfortunately there is little reliable correlation between the CGMS and capillary glucose which means that CGMS is not a useful tool for identifying significant glucose changes particularly hypoglycemia in real time. However CGMS may have a role in alerting the user as to the trajectory and speed of glucose responses 44–46 and the high frequency of nocturnal hypoglycemia 47 and is often useful to an individual for identifying the pattern of glucose change which occurs when they are exercising. 9.2 Safety Clearly prior to assessment the status of diabetic complications needs to be assessed. Regular physical exercise does not appear to cause deterioration in either early dia- betic retinopathy or diabetic nephropathy 48–51 although it seems sensible to caution again intense physical exercise in patients with preproliferative retinopathy and in particular in those with intraretinal and other neovascular abnormalities. A detailed inspection of the feet is required. While early peripheral neuropathy does not preclude regular physical exercise detailed advice on foot care needs to be given with regular foot inspections. However for patients with foot shape abnor- mality and marked reduction in peripheral sensation or peripheral vascular disease upright physical exercise with increased workload on the feet and legs is unlikely to be appropriate. For patients who are seeking advice on how they might increase physical exer- cise who have had a long duration of diabetes and who have risk factors for vascular disease such as hypertension smoking history or hypercholesterolemia it is sensi- ble to seek detailed cardiological investigations. An exercise ECG or a stress echocardiogram is likely to be necessary before advising people to embark on a new program of exercise.

slide 224:

199 199 I. Gallen 9 Synthesis of Best Practice 199 199 Where exercise is to be outside it is sensible to advise on personal safety during exercise. People with diabetes need to carry with them readily accessible simple carbohydrates ensure adequate hydration and ideally avoid exercising alone. Where this is not practical ideally a mobile phone should be carried at all times. Furthermore others should be informed where they will be and in particular when they should be expected to return. The skills to assist the health-care professionals to manage type 1 diabetes and exercise are transferable to any diabetes service and if applied will reduce dysgly- cemia and improve physical performance and quality of life for those people. References 1. Gallen I. Exercise in type 1 diabetes. Diabet Med. 200320:2–5. 2. Lumb AN Gallen IW. Diabetes management for intense exercise Review 44 refs. Curr Opin Endocrinol Diabetes Obes. 2009162:150–5. 3. Mitchell TH Abraham G Schiffrin A Leiter LA Marliss EB. Hyperglycemia after intense exercise in IDDM subjects during continuous subcutaneous insulin infusion. Diabetes Care. 198811:311–7. 4. Guelfi KJ Ratnam N Smythe GA Jones TW Fournier PA. Effect of intermittent high-inten- sity compared with continuous moderate exercise on glucose production and utilization in individuals with type 1 diabetes. Am J Physiol Endocrinol Metab. 20072923:E865–70. 5. Bussau V A Ferreira LD Jones TW Fournier PA. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care. 2006293:601–6. 6. Bussau V A Ferreira LD Jones TW Fournier PA. A 10-s sprint performed prior to moderate- intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Diabetologia. 2007509:1815–8. 7. Kennedy JW Hirshman MF Gervino EV Ocel JV Forse RA Hoenig SJ Aronson D Goodyear LJ Horton ES. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects With type 2 diabetes Miscellaneous article. Diabetes. 199948:1192–7. 8. Kraniou GN Cameron-Smith D Hargreaves M. Effect of short-term training on GLUT-4 mRNA and protein expression in human skeletal muscle. Exp Physiol. 200489:559–63. 9. McMahon SK Ferreira LD Ratnam N Davey RJ Youngs LM Davis EA Fournier PA Jones TW. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab. 2007923:963–8. 10. Galassetti P. Reciprocity of hypoglycaemia and exercise in blunting respective counterregula- tory responses: possible role of cortisol as a mediator Review 70 refs. Diabetes Nutr Metab Clin Exp. 2002155:341–7 discussion 347–8 362. 11. Galassetti P Tate D Neill RA Morrey S Davis SN. Effect of gender on counterregulatory responses to euglycemic exercise in type 1 diabetes. J Clin Endocrinol Metab. 20028711: 5144–50. 12. Galassetti P Tate D Neill RA Morrey S Wasserman DH Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes. 2003527:1761–9. 13. Galassetti P Tate D Neill RA Morrey S Wasserman DH Davis SN. Effect of sex on counter- regulatory responses to exercise after antecedent hypoglycemia in type 1 diabetes. Am J Physiol Endocrinol Metab. 20042871:E16–24.

slide 225:

200 200 I. Gallen 9 Synthesis of Best Practice 200 200 14. Galassetti P Tate D Neill RA Richardson A Leu SY Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab. 20062906:E1109–17. 15. Sandoval DA Guy DL Richardson MA Ertl AC Davis SN. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 dia- betes. Diabetes. 2004537:1798–806. 16. Sandoval DA Guy DL Richardson MA Ertl AC Davis SN. Acute same-day effects of ante- cedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab. 20062906:E1331–8. 17. American College of Sports Medicine and American Diabetes Association joint position state- ment. Diabetes mellitus and exercise. Med Sci Sports Exerc. 19972912:i–vi. 18. Maran A Pavan P Bonsembiante B Brugin E Ermolao A Avogaro A Zaccaria M. Continuous glucose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-intensity exer- cise in nontrained patients with type 1 diabetes. Diabetes Technol Ther. 20101210: 763–8. 19. Almeida S Riddell MC Cafarelli E. Slower conduction velocity and motor unit discharge frequency are associated with muscle fatigue during isometric exercise in type 1 diabetes mel- litus. Muscle Nerve. 2008372:231–40. 20. Baldi JC Cassuto NA Foxx-Lupo WT Wheatley CM Snyder EM. Glycemic status affects cardiopulmonary exercise response in athletes with type I diabetes. Med Sci Sports Exerc. 2010428:1454–9. 21. McKewen MW Rehrer NJ Cox C Mann J. Glycaemic control muscle glycogen and exercise performance in IDDM athletes on diets of varying carbohydrate content. Int J Sports Med. 192020:349–53. 22. Tamis-Jortberg B Downs Jr DA Colten ME 5. Effects of a glucose polymer sports drink on blood glucose insulin and performance in subjects with diabetes. Diabetes Educ. 199622:471–87. 23. Chokkalingam K Tsintzas K Snaar JE Norton L Solanky B Leverton E Morris P Mansell P Macdonald IA. Hyperinsulinaemia during exercise does not suppress hepatic glycogen con- centrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study. Diabetologia. 2007509:1921–9. 24. Chokkalingam K Tsintzas K Norton L Jewell K Macdonald IA Mansell PI. Exercise under hyperinsulinaemic conditions increases whole-body glucose disposal without affecting muscle glycogen utilisation in type 1 diabetes. Diabetologia. 2007502:414–21. 25. Harmer AR Chisholm DJ McKenna MJ Hunter SK Ruell PA Naylor JM Maxwell LJ Flack JR 11. Sprint training increases muscle oxidative metabolism during high-intensity exercise in patients with type 1 diabetes. Diabetes Care. 200831:2097–102 Erratum appears in Diabetes Care. 2009323:523. 26. Jenni S Oetliker C Allemann S Ith M Tappy L Wuerth S Egger A Boesch C Schneiter P Diem P Christ E Stettler C. Fuel metabolism during exercise in euglycaemia and hyperglycae- mia in patients with type 1 diabetes mellitus – a prospective single-blinded randomised cross- over trial. Diabetologia. 2008518:1457–65. 27. Robitaille M Dube MC Weisnagel SJ Prud’homme D Massicotte D Peronnet F Lavoie C 1. Substrate source utilization during moderate intensity exercise with glucose ingestion in type 1 diabetic patients. J Appl Physiol. 2007103:119–24. 28. Yamakita T Ishii T Yamagami K Yamamoto T Miyamoto M Hosoi M Yoshioka K Sato T Onishi S Tanaka S Fujii S. Glycemic response during exercise after administration of insulin lispro compared with that after administration of regular human insulin. Diabetes Res Clin Pract. 2002571:17–22. 29. Arutchelvam V Heise T Dellweg S Elbroend B Minns I Home PD. Plasma glucose and hypoglycaemia following exercise in people with Type 1 diabetes: a comparison of three basal insulins. Diabet Med. 20092610:1027–32. 30. Tsalikian E Mauras N Beck RW Tamborlane WV Janz KF Chase HP Wysocki T Weinzimer SA Buckingham BA Kollman C Xing D Ruedy KJ. Diabetes research in children network

slide 226:

201 201 I. Gallen 9 Synthesis of Best Practice 201 201 DirecNet Study Group: Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 20051474:528–34. 31. Bracken RM West DJ Stephens JW Kilduff LP Luzio S Bain SC. Impact of pre-exercise rapid-acting insulin reductions on ketogenesis following running in Type 1 diabetes. Diabet Med. 201128:218–22. 32. Mauvais-Jarvis F Sobngwi E Porcher R Garnier JP Vexiau P Duvallet A Gautier JF. Glucose response to intense aerobic exercise in type 1 diabetes: maintenance of near euglycemia despite a drastic decrease in insulin dose. Diabetes Care. 2003264:1316–7. 33. Rabasa-Lhoret R Bourque J Ducros F Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen ultralente-lispro. Diabetes Care. 2001244:625–30. 34. Francescato MP Geat M Fusi S Stupar G Noacco C Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism. 2004539:1126–30. 35. Francescato MP Zanier M Gaggioli F. Prediction of glucose oxidation rate during exercise. Int J Sports Med. 2008299:706–12. 36. Ramires PR Forjaz CL Strunz CM Silva ME Diament J Nicolau W Liberman B Negrao CE. Oral glucose ingestion increases endurance capacity in normal and diabetic type I humans. J Appl Physiol. 1997832:608–14. 37. Riddell MC Bar-Or O Hollidge-Horvat M Schwarcz HP Heigenhauser GJ. Glucose inges- tion and substrate utilization during exercise in boys with IDDM. J Appl Physiol. 2000884:1239–46. 38. Jeukendrup AE Jentjens R. Oxidation of carbohydrate feedings during prolonged exercise: Current thoughts guidelines and directions for future research. Sports Med. 2000296: 407–24. 39. Perrone CA Rodrigues CA Petkowicz RO Meyer F. The effect of 8 and 10 carbohydrate drinks on blood glucose level of type 1 diabetic adolescents during and after exercise. Med Sci Sports Exerc Abstract. 200436:S272. 40. West DJ Morton RD Stephens JW Bain SC Kilduff LP Luzio S Still R Bracken RM. Isomaltulose improves postexercise glycemia by reducing CHO oxidation in T1DM. Med Sci Sports Exerc. 2011432:204–10. 41. Gallen IW Ballav C Lumb A Carr J. Caffeine supplementation reduces exercise induced decline in blood glucose and subsequent hypoglycaemia in adults with type 1 diabetes T1DM treated with multiple daily insulin injection MDI. Diabetes Care. 201059:184-P. 42. Davison R Aitken G Charlton J McKnight J Kilbride L. Comparison of patient blood glu- cose monitoring with continuous blood glucose monitoring during exercise. Diabetic Medicine Conference: Diabetes UK Annual Professional Conference 2010 Mar 3–5 Liverpool UK 43. Aitken G Charlton J Davison R Hill G Kilbride L McKnight J. Reproducibility of the glu- cose response to moderate intensity exercise in people with type 1 diabetes exercise. Diabetologia Conference: 45th EASD Annual Meeting of the European Association for the Study of Diabetes Vienna Austria Conference 2009 Sep 29–Oct 2 Vienna Austria 44. Cauza E Hanusch-Enserer U Strasser B Kostner K Dunky A Haber P 12. Strength and endurance training lead to different post exercise glucose profiles in diabetic participants using a continuous subcutaneous glucose monitoring system. Eur J Clin Invest. 200535:745–51. 45. Cauza E Hanusch-Enserer U Strasser B Ludvik B Kostner K Dunky A Haber P 9. Continuous glucose monitoring in diabetic long distance runners. Int J Sports Med. 200526:774–80. 46. Kapitza C Hovelmann U Nosek L Kurth HJ Essenpreis M Heinemann L. Continuous glu- cose monitoring during exercise in patients with type 1 diabetes on continuous subcutaneous insulin infusion. J Diabetes Sci Technol. 201041:123–31. 47. Iscoe KE Corcoran M Riddell MC 3. High rates of nocturnal hypoglycemia in a unique sports camp for athletes with type 1 diabetes: Lessons learned from continuous glucose moni- toring systems. Can J Diabetes. 200832:182–9.

slide 227:

202 202 I. Gallen 9 Synthesis of Best Practice 202 202 48. Svarstad E Gerdts E Omvik P Ofstad J Iversen BM. Renal hemodynamic effects of captopril and doxazosin during slight physical activity in hypertensive patients with type-1 diabetes mellitus. Kidney Blood Press Res. 2001241:64–70. 49. Tuominen JA Ebeling P Koivisto V A. Long-term lisinopril therapy reduces exercise-induced albuminuria in normoalbuminuric normotensive IDDM patients. Diabetes Care. 1998218:1345–8. 50. Viberti G Pickup JC Bilous RW Keen H Mackintosh D. Correction of exercise-induced microalbuminuria in insulin-dependent diabetics after 3 weeks of subcutaneous insulin infu- sion. Diabetes. 198130:818–23. 51. Kruger M Gordjani N Burghard R. Postexercise albuminuria in children with different dura- tion of type-1 diabetes mellitus. Pediatr Nephrol. 1996105:594–7.

slide 228:

Chapter 10 The Athlete ’s Perspective To Cure Diabetes Naturally Click Here 10.1 Chris Pennell Professional Rugby Player How and when were you diagnosed with type 1 diabetes CP: “From the age of nine I became very passionate about Rugby Union. I feel extremely privileged to be in a position where Rugby is my profession and liveli- hood. I was diagnosed with Type 1 Diabetes aged 19 following a routine blood test at the rugby club. Now aged 24 I currently captain The Worcester Warriors in the Aviva Premiership after earning promotion in the 2010/2011 season.” I. Gallen ed. Type 1 Diabetes

slide 229:

DOI 10.1007/978-0-85729-754-9_10 © Springer-Verlag London Limited 2012 203

slide 230:

204 204 I. Gallen 10 The Athlete’s Perspective 204 How do you train CP: “I am on multiple daily insulin injections. I can effectively breakdown my insu- lin treatment into three categories which I can slide between when required: 1. Fully fit this is when my insulin dependency is quite low. My metabolism is fast as I am active most days and competing in my sport on weekends. My basal dosage drops to 8–10 units. My bolus dosage will change depending on the format of my training day. I will only need 1–2 units with a large bowl of porridge along with sip- ping sports drinks during my morning training. My Blood glucose levels will stay consistently between 5 and 8 mmol/L during this training period. Depending on the intensity of the afternoon session I may not take any bolus insulin with my meal despite eating a small portion of carbohydrate. These sessions tend to commence 1-½ hours after eating. In this afternoon session I can regulate my blood glucose by sipping sports drinks over the training period in accordance with the type of training session and its intensity. If I have no training I will take 1 unit per 30 grams of car- bohydrate and continue this dosage for any further food until dinner. At 8pm I will take my basal insulin. I like to go to bed at a level between 6 and 7 mmol/L and tend to wake up between 4.5 and 6 mmol/L. Regular blood testing allows me to spot if I need any extra carbohydrate during training sessions. Glucose tablets work very well in pushing my levels up during more demanding sessions. 2. Injured. Being injured presents a huge challenge as a diabetic especially when there is a sudden change from being fully fit to bed ridden. During this time unsurprisingly my insulin requirements shoot up. I very quickly increase my basal dosage to 16–20 units. My bolus dosage goes up to 1 unit per 15 grams of carbohydrate. Again regular testing allows small amendments to be made and prevents any serious hypoglycemic or hyperglycemic episodes. 3. Transition. This is the period of time between beginning to exercise after injury and returning to full fitness. During this period I have found a steady change in my insulin dependency in direct correlation to my activeness during training. In the early stages of recovery where training intensity remains fairly low my insulin requirement stays high. Through the natural progression of returning to fitness my insulin requirements drop accordingly. During this time I test very regularly and make small adjustments over the weeks until I return to full fitness. I have become acute to the different requirements of different training ses- sions and I have learned to adjust the amount of glucose I intake through sports drinks depending on the type of training and its intensity. This method has allowed me to control my blood glucose levels whilst coping with a different variety of training intensities and periods.” CP: “Over the last 5 years my HbA1c results have come down from 7.0 to the most recent being 5.4 a normal reading for a non-diabetic. I largely put this down to keeping active but also sticking to a strict diet. I have always enjoyed eating health- ily and staying in shape. However the main changes in my diet have been around the choices of carbohydrates I eat and the balance of food on my plate. I have an even measure of protein fibrous carbohydrate and starchy carbohydrate. This bal- ance of food provides me with all the nutrients and fuel I need to maintain a regular body fat percentage and weight. Instead of eating white pasta white rice white potato and white bread I have swapped for whole meal pasta rice and bread. I

slide 231:

205 205 I. Gallen 10 The Athlete’s Perspective 205 believe this small change in choice has been the reason my HbA1c has come down to that of a non-diabetic. The steady drip of glucose into my blood stream forms a smooth blood glucose curve throughout the day.” What kind of problems have you encountered during training and how were they solved CP: “The nature of my sport and position means I must have the ability to perform in both an aerobic and anaerobic capacity to a very high level. In a fully fit state I am able to adjust my glucose intake without changing my insulin requirements. During aerobic training my glucose requirement goes up and additional supplementation is sometimes needed on top of the sports drinks to avoid hypoglycaemia. This is often in the form of glucose tablets. During anaerobic training I have found little or no need to top up my glucose levels due to the hormone response from the body. I have however found need to monitor my blood glucose levels after very intense anaerobic training something I only really experience during preseason.” CP: “Match day is another time when things change slightly for me. My body’s response to playing in big matches in front of big crowds of course makes my glu- cose levels shoot up. In the early stages I would go into matches having done every- thing the same as a training day. I would go into a game with my blood glucose level between 6 and 8 mmol/L and sip glucose drinks during stoppages. I stopped drink- ing the sports drinks and stuck to water. This had very little effect. I then injected 1 unit 5 minutes before kick-off and 1 unit again at half time but because of my sen- sitivity to insulin I was worried that I would simply induce hypoglycaemia. However this had the desired result and I would finish games between 6 and 9 mmol/L.” 10.2 Jen Alexander Marathon Swimmer

slide 232:

206 206 I. Gallen 10 The Athlete’s Perspective 206 How and when were you diagnosed with type 1 diabetes JA: “I’ve had type one diabetes since 1988 and have swum for most of my life. I live and train in Halifax Nova Scotia Canada swimming outdoors April-November. I’ve swum 18+ hours on a couple of occasions. In 2008 I was awarded the Diabetes Exercise and Sports Association’s ‘Athlete of the Year’ award. I use an insulin pump.” How do you train JA: “Swim-specific diabetes management starts 5 hours before the scheduled start. I don’t eat anything. I recognize that this isn’t the greatest strategy for preserving muscle glycogen but it works for me in terms of managing my diabetes. I swim with a waterproof insulin pump. My general strategy is to run my basal rate high enough that I don’t need to bolus for carbs. I turn my basal rate up to 150 and test my blood glucose just before I am about to jump into the water. From this blood test and until the swim ends we react to each blood test in the same way: • If my blood glucose is 6 mmol/L I get 40 grams of carbs. • If my blood glucose is 6–8 mmol/L I get 30 grams of carbs. • If my blood glucose is 8–10 mmol/L I get 15 grams of carbs. • If my blood glucose is 10 mmol/L I get water. I test and feed every 30 minutes with 50 grams of flavored sugar crystals/Gatorade in 750 ml of water to give a solution that’s 6.7 carbohydrate. I receive three feeds of flavored crystals and then one feed of Gatorade. I don’t have the same need to replace electrolytes because I’m not sweating much if at all. We’ll mix in liquid acetaminophen every 4–6 hours for pain and we deduct this from my carb allowance. If my blood glucose level has trended downward or upward for two consecutive tests my crew prompts me to adjust my basal rate. Even though I start my swims at 150 I’ll titrate down to about 50. Severe nausea can be part of open water swimming and I’ve dealt with this by turning my pump off for 30 minutes and con- suming ginger chews. Other than this I don’t consume solids during my swim. This plan works extremely well for me until hypothermia begins to affect my blood sugar as acute hypothermia elevates glucose levels due to catecholamine-induced glyconeogenesis. 1 ” What kind of problems have you encountered during training and how were they solved JA: “The ‘standard’ challenges of blood glucose levels affecting performance still apply. Hypoglycemia causes me to pull through the water less strongly. Both hypoglycaemia and hyperglycemia reduce my stroke rate. Furthermore swimmers with diabetes face additional risks: hypothermia complicates hypoglycaemia. Core 1 Granberg. Human endocrine responses to the cold. Arct Med Res. 199554:91–103.

slide 233:

207 207 I. Gallen 10 The Athlete’s Perspective 207 body temperature falls during hypoglycaemia 2 and recovery from hypoglycaemia is impaired at low body temperatures. 3 Conversely hypoglycaemia complicates hypo- thermia: a small study of people without diabetes suggests that blood glucose levels under 2.5 mmol/L suppress both shivering and the sensation of being cold. 4 A swim- mer unable to shiver to generate body heat risks advancing through the stages of hypothermia. Therefore swimming safely demands careful diabetes management.” JA: “Tight control over blood glucose levels is critical and finding a way to test blood while swimming was an exceptional challenge Open water swimmers around the world adhere tightly to the code of England’s Channel Swimming Association: the swim is disqualified if the swimmer touches the boat or a crew member touches the swimmer. Neither continuous glucose monitors nor heart rate monitors transmit properly in the salt water so blood glucose levels must be mea- sured by finger stick. Additional challenges included waves sea spray wind blow- ing so loudly that I couldn’t hear my meter beep test results being skewed by water on my finger and the daunting challenge of being able to squeeze enough blood from a finger vasoconstricted by hypothermia. To get my test kit to me we’ve constructed a ‘fishing pole’ of sorts. On the boat my crew has an aluminum painter’s extension pole. Instead of twisting a paint roller onto its end however we’ve twisted the marine version of a carabineer onto the pole then twisted a cap on top of that to ensure the hook doesn’t move. We roll 25 meters of rock-climbing rope around a kite-string winder then thread the rope through the carabineer. My crew attaches items to the rope extends the pole and then unwinds the rope to lower the items to me. This is ‘legal’ in the open water world as long as the rope remains slack. We use a waterproof container made of transparent plastic to house two meters a facecloth and a lancing device stuck to the side of the container with Velcro. During the early hours of a swim we use a standard lancing device but switch to larger disposable lancets and then blades as needed. When it’s time to test my crew prepares my test kit by putting a strip in each meter and then activating the finger flashlight. The boat pulls close and my crew dangles my test kit over my head using the pole and rope. I grab the kit open the lid and dry off my finger with the facecloth. I lance my finger and apply blood to each strip until the finger flashlight turns off which confirms enough blood has been applied. Sometimes there is too much seaspray to see clearly into the container and sometimes the wind blows too loudly to hear the meters beep to signal they have enough blood so watching the finger flashlight turn off is the only way I know the tests are work- ing. I reseal the plastic container drop it into the water and resume swimming. My crew then pull the test kit back on the boat and read the results.” 2 Gale Bennett Green and MacDonald. Hypoglycaemia hypothermia and shivering in man. Clin Sci. 198161:463–9. 3 Ibid. 4 Ibid.

slide 234:

208 208 I. Gallen 10 The Athlete’s Perspective 208 10.3 Mark Blewitt Long-Distance Swimmer How and when were you diagnosed with type 1 diabetes MB: “I was diagnosed with Type 1 Diabetes in 1980 at the age of thirteen. In the mid 1990s after reading an article on the profile of athletes competing in the London Marathon I decided to get fit. My fitness regime started with a casual visit once a week to my local swimming pool. The following summer I would partake in my first open water swimming race and I was hooked and would return to this venue several years’ later and win the four mile men’s race outright.” How did you train MB: “I started to think about taking part in the longest annually held race in the British swimming calendar one length or 10.5 miles of Windermere in the annual British Long Distance Swimming Association championship. When undertaking longer swims I had realised that I needed less and less insulin and more food. All my insulin was given by multiple daily injections MDI which consisted of three fast-acting injections and one slow-acting injection. In 1998 at the time of my Windermere swim I was most probably taking Actrapid and Ultratard.”

slide 235:

209 209 I. Gallen 10 The Athlete’s Perspective 209 MB: “I had only been able to get to the start line of such a swim though hours of training and competition. I am also sure that the highs and insulin-driven lows that are found with MDI drove me to eat through the lows resulting in my carrying the little extra weight. The key is to feed appropriately for the sport you are undertaking and whether on MDI or pump therapy you are in a position to change your insulin amounts to match the food intake you need and exercise that you are undertaking and target weight you need to be at.” MB: “In 1988 I completed my inaugural Windermere swim fourth in the men’s race. Later I realised that my finishing time would make me eligible for selection in the world’s longest annually held swimming race the race around Manhattan Island New York. I would complete the length of Windermere a further ten times over the next few years including the Two-Way 21 mile swims on three separate occasions in 2003 I smashed the breaststroke record for the course.” What kind of problems did you encounter during training and how were they solved MB: “An attempt on the English Channel was made in the July of 2002 but despite reduced insulin injecting during the swim in the water my attempted ended in the southern shipping lane. I found my blood glucose level low but in defeat I had learned a lot and decided in the few hours that it took to get back to Dover that I would be having another go. With support from my consultant Dr Ian O’Connell at Wigan Infirmary and nurse Judith Campbell who would be in my escort boat we worked out a new insulin and feeding regime. Judith is a diabetes nurse and had asked around for advice on what we were trying to achieve and was usually told in no uncertain terms that it would not be possible. However this time my swim was successful. I stumbled up the beach before clearing the water line 16 hours and 20 minutes after leaving Shakespeare Beach Dover.” MB: “Later I would learn that the a few hours from the end of the swim the escort pilot was concerned about the way I was swimming. Judith asked ‘Do others non-diabetics show such fatigue at this point in a swim’ And when the reply came in the affirmative Judith persuaded them that all I needed was tiny amount of insulin to pick me up. A compromise was reached. Collectively they would let me carry on swimming and no insulin would be administered. On completing the swim my Blood Glucose levels were monitored every hour for the next twelve hours through the night. The following day I resembled a Cabbage Patch Kid R as my face was swollen with jelly fish stings and my eyes sunken.”

slide 236:

210 I. Gallen 10.4 Russell Cobb Long-Distance Runner 10 The Athlete’s Perspective 210 210 To Kill Diabetes Forever Click Here How and when were you diagnosed with type 1 diabetes RC: “I was originally diagnosed with Type 1 diabetes whilst training to be a Royal Air Force pilot in 1984. My main performance sport is running although I play golf and sail dinghies as well.” How do you train RC: “I run to keep in good shape and health. I enter at least two half marathons a year and also compete in 2 or 3 10ks whilst training for these. Typically I run 3 to 4 times a week of which 2 or 3 are short runs before work and one longer run of 8–10 miles on a weekend.

slide 237:

211 I. Gallen 10.4 Russell Cobb Long-Distance Runner 10 The Athlete’s Perspective 211 211 My ‘fear’ during sport is that I will have hypoglycemia so for much of the time this is the focus but it is vital to keep blood sugars within an effective range in order to perform. Anything above 10 or 11 mmol/L and the ‘leaden’ effect takes over and affects performance. Anything under 5 mmol/L and I can sense that the ‘tank’ is nearly empty. Both affect performance. In a race getting blood sugar right is vital if I want to run a good time. On my PB at the Silverstone Half Marathon in 2008 I started and finished the race with 6 mmol/L blood glucose. This clearly links good control with good performance. Timing of the race matters to strategy. A late morning race and you can eat break- fast normally with normal dosage and then just before the race ‘fuel up’ with a bottle of Powerade and a Mars bar. I also reduce basal to about 25 for the first hour. This means I start with a good blood sugar can establish a good pace early and then in the second half of the race start to step it out. Leave too long between fuelling and the start and blood sugar rises and affects performance until you have ‘run it off.’ For an early race I will not eat breakfast at home but take a banana sandwich or something similar to the race with me and then eat this about 30 to 45 minutes before the start without any bolus and then rely on the lack of bolus insulin in my body to enable me to get round on this fuel with blood sugar at a good level. I will typically test once whilst running and adjust either basal rate up or down depending on the result and I carry ‘Go-gel’s’ with me if I need to top up.” What kind of problems have you encountered during training and how were they solved RC: “Training requires less thought in advance but if you don’t think ahead it can also catch you out. I have had low blood sugars by heading off for a quick run without taking any carbohydrate on board or adjusting basal down and then gone slightly further than intended and suddenly I know I am down to less than 4 mmol/L and with a mile or so to home this is no fun Running in the morning with no remaining bolus insulin present generally means if you do get it wrong and end up low then it will generally be ‘gentle’ and a single Go-gel and slowing the pace down will sort it out. Spontaneous runs around two hours after a normal meal with normal bolus are typically the ones that will catch me out even if I do have additional carbohydrate and stop basal so I try to avoid these and plan my runs.” RC: “In golf I have linked high blood sugars with poor play. For a three-and-a- half-hour round carrying clubs on a hilly course I will eat normally whether break- fast or lunch approx 50/60 carbohydrates but reduce bolus by 50 provided blood sugar is in normal range beforehand and also reduce basal to about 65 for approx 90 minutes. Get this right and keep blood sugar stable within 7–9 range this removes high blood sugar as a detriment to a poor round.”

slide 238:

212 212 I. Gallen 10 The Athlete’s Perspective 212 212 10.5 Sebastien Sasseville Ironman Competitor and Mountain Climber Click Here For Best Diabetes Treatment How and when were you diagnosed with type 1 diabetes SS: “When I first trekked to Mount Everest base camp in 2001 I promised myself that one day I would come back and climb Everest all the way to the top. What was initially a dream quickly became a project and I went back to Nepal four times in the following seven years. Along the way I was given the gift of diabetes and I say that with no irony whatsoever. Both the obstacle that I chose Everest and the one I didn’t choose diabetes made me stronger.” How did you train SS: “Climbing in high altitude is a demanding and risky endeavor. Add managing type one diabetes to the mix and it becomes a monumental challenge. I believe three key words can make everything a lot simpler and safer: education preparation and experimentation. In that order and in a continuous circle.”

slide 239:

213 213 I. Gallen 10 The Athlete’s Perspective 213 213 SS: “Education. To complete my journey it has been crucial to take ownership of my diabetes and proactively educate myself about it. Two minutes in my doctor’s office three times a year wasn’t going to cut it. I decided to learn as much as I could about type one diabetes from as many sources as possible. When exercising under- standing how everything works is fundamental. When insulin peaks how long it is

slide 240:

214 214 I. Gallen 10 The Athlete’s Perspective 214 214 active for understand the concept of insulin on board how blood glucose monitors works their limitations know how to count carbohydrates know how different types of carbohydrates absorb understand how my pump works etc. The list goes on indefinitely. Preparation. Climbing Mount Everest is a 60-day expedition. Needless to say a lot went into planning my diabetes strategy. I packed about 15 blood glucose moni- tors 2 pumps 12 months worth of insulin insulin pens 1500 test strips and a LOT of treatment for hypoglycemia. Having a back up plan is one thing but the strategy doesn’t stop there. Transportation storage and repartition of the supplies are all very important. For example no matter how much insulin I have if it’s all in the same place and freezes I’m in trouble. During the expedition I broke down my insulin stock in three thermos. I kept one on me at all times one at base camp and one in a clinic in Katmandu. No matter how short you exercise for always have something to treat hypoglycaemia. When prepared properly hypoglycemia is simply a discom- fort. On the other hand if unprepared hypoglycemia can be catastrophic if not life threatening. Experimentation. Every time I do something new I learn a lot. It took me 5 years of preparation to feel my diabetes strategy was ready to scale Mount Everest. I started with weekend camping trips then went for short expeditions then started climbing more seriously then added altitude in the mix went on several 30-day expeditions and eventually felt ready. By building slowly but surely the next step is always just a little bit higher and seems achievable.” What kind of problems did you encounter during training and how were they solved SS: “The Ironman race is grueling a 2.4 mile swim 112 mile bike ride and a 26 mile marathon. Needless to say that training for such an event with type one diabe- tes is a challenge. Starting slow is key. You need to figure out what to do on a 30 minute run before going on a 2 hour run. The more you measure something the more you understand it. I could not imagine testing my blood glucose fewer than ten times a day. I test pre and post meals before during and after exercise and whenever I’m not sure of what my blood glucose is. From this you can figure out why you are high low or within range. Identify what you have done right and what needs to be changed. In a race that can be as long as 17 hours preventing a low blood sugar often starts hours before the race. On the flip side my current blood sugar impacts how I will perform in several hours.” SS: “One thing is crucial to understand and to accept: diabetes is different for everyone and different every day. What works one day isn’t likely to work the next day. Instead think of diabetes and exercise as an equation with variables that con- stantly change. Some variables are obvious duration and intensity for example. I have listed several different variables that impact on my diabetes during exercise. Some variables don’t have an actual impact on my blood glucose but they impact my strategy and the way I prepare for the outing. Time of the day type of activity overall goal recreation weight loss or performance stress insulin on board recov- ery risk of disappointment risk to safety and temperature are just a few. Every day the equation adds up to a different strategy.”

slide 241:

215 215 I. Gallen 10 The Athlete’s Perspective 215 215 10.6 Fred Gill Rower To Stop Diabetes In Few Days Click Here How and when were you diagnosed with type 1 diabetes FG: “I was diagnosed with Type 1 Diabetes aged 21 at the start of my 3rd year at Newcastle University. While I had been a very keen sportsman in almost every sport at school it took me until my first year at Newcastle to find a sport that I was natu- rally good at in rowing. I was very tall and fit and progress was rapid until the start of my third year where it tailed off drastically. After losing 5 kilos and with an insa- tiable thirst I went for a blood test and that was the start of my diabetic challenge.” “I had of course heard of Steve Redgrave winning his 5th Olympic Gold aged 38 as a diabetic so there was never any question as to whether I would continue my rowing or not. However having been diagnosed on the Monday and taking a few days to get to terms with the life change my coach then Angelo Savarino rung me up on the Wednesday demanding why I was not at training and telling me that he had known ‘hundreds’ of diabetic athletes in Italy and I should stop feeling sorry for myself and start training properly again straight away. This proved to me the perfect mindset for me as I attacked my training just as I had before and within a month was producing scores similar to those prior to my diagnosis.” “That year I had also managed to make an application to Cambridge University and was lucky enough to be accepted. The training program at Cambridge however was completely different to the one I had come from and was far more based on training at low intensity and for long periods of time. For instance our two main ergometer sessions in the week were 70–80 mins at a low rate and intensity with one short break at half way. This is the method of training employed at most nation levels

slide 242:

216 216 I. Gallen 10 The Athlete’s Perspective 216 216 where athletes can train full time and thus spend longer periods training and recovering.”

slide 243:

217 217 I. Gallen 10 The Athlete’s Perspective 217 217 How did you train FG: “The training implemented at Newcastle was an Italian-style program where all training was to maximum intensity. Through the winter we would do long low-rate work such as 3–4 x 6k 3–5 x 4k 8–10 x 3k and our least favourite 14–16 x 1500 metres. All these pieces were started with one minute flat out before coming down onto a low rate that was carried on through the rest of the distance. I did not know it at the time but it was these one minute high intensity starts that staved off any hypos. I have only recently heard of the maximal sprint technique as a defense against hypos and have brought it into my current training. Therefore because of these one minute flat out starts to all the pieces in my time at Newcastle I did not have a single session ruined by hypoglycemia. At the end of that first season I won four gold medals at the British Universities’ regatta and for the first time in the club’s history won the Student fours at Henley Royal Regatta. My pairs partner and I also managed to achieve a 6th place finish at the national trials which meant we were in the Great Britain under 23 eight that came 5th at the under 23 World Championships later that summer.” What kind of problems did you encounter during training and how were they solved “At Cambridge the training program was completely different being far more based on training at low intensity and for long periods of time. For instance our two main ergometer sessions in the week were 70–80 mins at a low rate and intensity with one short break at half way. This is the method of training employed at most nation levels where athletes can train full time and thus spend longer periods training and recovering. However with no one minute flat out start and the low intensity of the training I was hypoing almost every time we would do these sessions. I would be exhausted with 10 mintues of the workout and subsequently used to dread them and not understand why I was so exhausted and everyone else was far less fatigued at the end of the ergo sessions. I found out that it is the low intensity use of large muscle areas such as quads glutes and back that lead to lowering blood sugar and hypogly- cemia after sustained periods such training with no glucose.” “I struggled through my first year a Cambridge constantly exhausted falling asleep in lectures and producing very inconsistent performances throughout. Some of my high-intensity work was at the top end of the squad and I was therefore given a good chance of being in the ‘Blue Boat’ for the boat race but after some bad per- formances and a spectacularly bad 5 k ergo score I was named in the reserve boat. It was after losing the reserve boat race in 2009 that lead me to plan a new insulin regime where I would take half my normal amount of insulin if I was training within one hour of eating and take glucose in the form of drinks and gels every 20 or so minutes throughout low intensity training to keep my blood sugar levels stable.” “My new regimen worked almost immediately so that through the summer I was able to train hard and effectively and attack the new year with renewed gusto. I was far more consistently producing scores near the top end of the squad and started being regarded as a genuine boat blue candidate and even potential stroke man which carries with it added glory and responsibility. I hypoed far less in training and

slide 244:

218 218 I. Gallen 10 The Athlete’s Perspective 218 218 the coaches faith in me was shown as they named me in the stroke seat of the provi- sional blue boat 3 months before the boat race.” “In the week leading up to the Race our training decreased as we tapered towards the big day and with it my insulin sensitivity. My blood sugar cycled throughout the day and night as I found it hard to live and eat with non-diabetics and carry out a different routine to the one I had got used to in training. However with help from the club doctor I kept to a personalised diet of low glycemic indexed GI foods and was able to regain some control in the days before the race. I was obviously extremely worried about what might happen if I hypoed or hypered during the race but tried to ignore it and put my energy into organising exactly what I would do hour by hour on the day so I would arrive on the start line with stable blood sugars.” “As it turned out even the best plans do not play out how they should. My blood sugar was quite high in the hours before the race and were about 13–14 mmol/L at the start. As it turned out my control was just about good enough as I stroked Cambridge around the outside of the Surrey bend a length down to then come through to take the inside of the last bend and win by a length. Since the boat race in 2010 I have continued my rowing with the aim of making the senior team. Having come 9th in both national trial regattas in 2011 I have not made the team for the forthcoming Olympics in London but will continue with rowing and hopefully make the team for the next Olympiad and Rio 2016.” 10.7 Monique Hanley Professional Cyclist To Cure Diabetes Naturally Click Here

slide 245:

219 219 I. Gallen 10 The Athlete’s Perspective 219 219 Photo credit to Mark Suprenant

slide 246:

220 220 I. Gallen 10 The Athlete’s Perspective 220 220 How and when were you diagnosed with type 1 diabetes MH: Monique Hanley was diagnosed with type 1 diabetes in 1998. Based in Melbourne Australia she became 2007 State track champion in the individual pur- suit and points score. She raced with the US-based cycling team Team Type 1 as a professional cyclist from 2007 to 2009. She was the only female member of Team Type 1’s eight-person team which won the 2007 Race Across AMerica RAAM and set a new world record. MH: “My life on the bike began shortly after a stern lecture from my endocri- nologist. I was 22 at the time and had just ‘retired’ from playing basketball. I played at Australian Women’s National Basketball League WNBL level but struggled with form and passion following my diagnosis with type 1 diabetes two years ear- lier. I lacked a lot of understanding on how type 1 diabetes could affect my on-court performance and received little sympathy from teammates and coaching staff. At the end of a disappointing second season and with all passion for the sport gone I walked away and never returned.” MH:“The impacts on my life were immediate. With more time to work and party life moved from being centered around exercise and performance. My conditioning fell away rapidly and my weight blossomed with an A1c shooting up past 8. Cycling met my needs replaced my mode of transport and offered me a door into another life. And it still remains the best fun I have ever had while exercising” How did you train MH: “I first completed a number of recreational cycling challenges including riding across Canada 7800 km and around France 2700 km. I followed le Tour on my own with a one man tent and a month’s supply of test strips and insulin. I was fas- cinated to discover that after four days of heavy exercise and constant reduction of insulin needs the fifth day onwards I would require slightly more. It seemed to take the four days to get the body adjusted to the new regime and from there it would say ‘okay got the hang of this. I actually need a little bit more to keep going’. Racing became my next goal. Starting with local road races I progressed to open women’s racing and eventually moved onto the track which resulted in finding my true passion in the sport and achieving success at an elite level in Australia. During this time I was invited to race for Team Type 1 in their 2007 and 2008 Race Across AMerica teams. We competed in the eight person team category and I was the only female member. We won the event in 2007 and in the process set a new world record for the crossing. I spent three years in the USA racing on the professional women’s circuit specializing in criterium racing.” What kind of problems did you encounter during training and how were they solved MH: “These are my key management strategies. I use a pump and CGM. I switched to the pump in 2004 and found it far more useful for training and racing. When you need to be flexible as life often is the pump is there to move with you I have to admit that I still find long races difficult to master and I struggle with being able to guess my blood sugar after two hours on the bike. A continuous glucose monitor is the best thing for bike racing and recovery.

slide 247:

221 221 I. Gallen 10 The Athlete’s Perspective 221 221 I reduced basal rate for criterium racing. It was easier to develop my diabetes ‘formula’ in criteriums thanks to trialing it every weekend in local races. I am resis- tant to complete removal of my pump during races or to reduce insulin rate in the lead up to the start of a race. Races can be delayed due to crashes in a previous race sudden change in weather we were once delayed by a hail storm or simply at the discretion of officials. A 50 basal reduction to cover the length of the race on the start line with some top up fuel ready to go usually 20–25 g high GI food in my back pocket is ideal for me. Usually the adrenaline of a criterium start will spike my blood glucose early on and as long as I eat around the 40 minute mark of a race my levels will be okay until the sprint finish this is assuming a one hour race no racing or heavy strain in the previous days and general cycling good fortune. I reduced basal rate for Racing Across AMerica. Every shift during this crazy race required a different basal rate. Combining the intense physical output short bursts at almost maximum effort with next to no sleep meant the body had no real chance to recover. A ‘good’ sleep was three hours. During one shift when I was hurting at my very worst my basal needs increased but typically my basal reduc- tion was between 50–80. Constant glucose monitoring was essential. After five and a half days it was an experience like no other. Try to Manage your mind. Mental preparation is essential in track racing and I quickly learnt the price you pay from adrenaline-induced high blood sugars. My performances are impacted the further north my meter reading is from 10 mmol/L. My challenge became how to focus on the racing goal while at the same time open to ‘variations’ in the event such as a puncture or reschedule. This helped me mini- mize the surge in blood glucose levels from adrenaline. Engaging a sports psycholo- gist was extremely beneficial. I learnt how to visualize performance goals and adopted breathing techniques which made a huge difference. Start at a low base. Once I realized just how much my blood sugars soared from adrenaline I adopted a new strategy: if I start at a low base the adrenal jump wouldn’t land me into the evil realms of life above 13 mmol/L. The trick was to ensure that the blood sugar wasn’t too low. It was a fine line to walk and it required plenty of monitoring during warmup. If it did drop too low there was always sports drink or lollies on hand to get it up enough for race time. Manage your hypos. It is extremely important to manage post-exercise hypos. During preparation for the Australian track season I encounter a fair share of extreme hypos. They usually happen following a heavy training period but never immediately following the conclusion of training and so tend to ‘sneak up’ on me. Anywhere up to 48 hours afterwards I am subject to severe lows and with my focus on keeping my blood sugar relatively low for track performance I am especially vulnerable. You can never test enough.”

slide 248:

Index To Kill Diabetes Forever Click Here A AAS. See Anabolic androgenic steroids AAS Aerobic exercise definition 31 hyperglycemia 33–34 hypoglycemia 32 33 Alpha-/beta-adrenergic blockade 118 Anabolic androgenic steroids AAS adverse effects of AAS and diabetes 177 cardiovascular disease 177 endocrine function 176 hepatotoxicity 176–177 psychiatric effects 177 athletes abuse 175–176 development of 173 prevalence of 174–175 testosterone formulations of 173–174 Anaerobic exercise 34–35 Anti-doping history of 170–172 World Anti-Doping Agency prohibited substances 171 172 Anti-doping administration and management system ADAMS 189–190 Antihypertensives 189 Athletes abuse AAS 175–176 EPO 178 growth hormone 179–182 insulin 187–188 insulin-like growth factor-I 184–185 carbohydrate intake after training and competition 160–161 intake during training and competition 158–160 intake prior to training 157–158 loading 158 with type 1 diabetes 155–157 without type 1 diabetes 152–154 nutrition guidelines without type 1 dia- betes carbohydrate 152–154 hydration 154 protein 154 vitamin and mineral supplements 154–155 with type 1 diabetes blood glucose monitoring 161 carbohydrate 155–161 fat 163 hydration 162 protein 162–163 weight management 161–162 Autonomic symptoms hypoglycemia 116–117 B Basal insulins 52 Beneficial effects physical activity cardiovascular benefits 79–80 psychological well-being 77–79 Blood transfusion adverse effects of 178 and diabetes 179 prevalence of 178 I. Gallen ed. Type 1 Diabetes DOI 10.1007/978-0-85729-754-9 © Springer-Verlag London Limited 2012 219

slide 249:

220 220 Index Index 220 C Caffeine dosage 110 in hypoglycemi 108 uses 168 Carbohydrate athletes intake after training and competition 160–161 intake during training and competition 158–160 intake prior to training 157–158 loading 158 with type 1 diabetes 155–157 without type 1 diabetes 152–154 childhood diabetes amount of 89 exercise types 88 ingestion 88 management 90 pre-exercise meal/snack suggestions 89 type of 89–90 ingestion of 64–65 post-exercise hypoglycemia 60–61 pre-exercise timing 61–63 Cardiovascular benefits physical activity 79–80 CGM. See Continuous glucose monitoring CGM Childhood diabetes assessment 75–76 carbohydrate 88–90 cardiovascular benefits 79–80 competition and travel 94–95 diabetes management 82–83 endurance sports 94 energy requirements 86–88 fat 91 fluid hydration and thermoregulation 91–92 fluid management 92 glucose and glycemic control 80–82 management of 84–86 nutrition and exercise 83 patterns 76–77 physical activity and developmental changes 74–75 power/strength sports 94 protein 90–91 psychological well-being 77–79 supplements and ergogenic aids 93 team sports 94 training/competitive sports 86 unplanned and spontaneous 83–84 vitamins and minerals 93 Clamp procedure 51 Continuous glucose monitoring CGM challenges 105 limitations 105–106 and nocturnal hypoglycemia 106–107 uses 105 Continuous subcutaneous insulin infusion CSII therapy basal insulin infusion 104 in children 103 and nocturnal hypoglycemia 106–107 Counterregulatory responses and glucose ingestion 15–18 hypoglycemia 12–14 recovery 132–133 CSII therapy Continuous subcutaneous insulin infusion CSII therapy D Dietary reference values DRVs 84 Doping early history 168 origin of 167 prevalence of 170 stimulants and anabolic agents use of 168–169 twentieth-century doping 169–170 E Early post-exercise hyperglycemia 35 Endurance sports 94 Endurance training 39 Erythropoietin EPO athletes abuse and adverse effects of 178 and diabetes 179 prevalence of 178 Exercise CGM 104–106 characteristics of 47–48 counterregulation 117–118 CSII therapy basal insulin infusion 104 in children 103 and nocturnal hypoglycemia 106–107 endocrine and metabolic responses aerobic exercise 31–34 anaerobic exercise 34–35

slide 250:

221 221 Index Index 221 blood glucose responses 30 early post-exercise hyperglycemia 35 energy metabolism and fuel utilization 2–5 exercise and hyperinsulinemia 5–7 gender differences 14–15 glucose ingestion 15–18 glucose metabolism hormonal regulation of 8–11 hypoglycemia 12–14 insulin action 7–8 late post-exercise hypoglycemia 35–36 endurance training 39 fuel utilization abnormalities in 36–37 hypoglycemia see Hypoglycemia type 1 diabetes individual effects 37–38 endurance exercise-induced hypoglycemia 48 intermittent exercise 49–50 post-exercise hypoglycemia see Post-exercise hypoglycemia resistance exercise 50–51 safety factors 64–66 sprint exercise 49 F Fatigue 15 G Glucokinase 128–129 Glucose ingestion 15–18 Glycemic control in childhood diabetes 80–82 potential strategies 196–198 resistance exercise 50 variational factors 195–196 Glycemic index GI and exercise performance 153–154 157 in nutritional management 156 post-exercise hypoglycemia 60–61 Growth hormone GH adverse effects 182 athletes abuse cardiovascular effects 180 fuel delivery 180 in healthy adults 181–182 muscle and bone anabolism 180 thermoregulation 180–181 whole body physiology 181 and diabetes 182–183 features 179 prevalence of 179 H HAAF. See Hypoglycemia-associated autonomic failure HAAF Hepatic glycogenolysis 9 Hexokinase II HKII 7 Hyperglycemia aerobic exercise 33–34 early post-exercise hyperglycemia 35 Hyperinsulinemia 5–7 Hyperinsulinization 115–116 Hypoglycemia acute hypoglycemia treatment 138–139 aerobic exercise 32 33 autonomic symptoms 116–117 counterregulation and hypoglycemia awareness 132–133 counterregulatory responses to 12–14 impaired cascade of events 118–119 late post-exercise hypoglycemia 35–36 normal cascade of events 116–117 post-exercise hypoglycemia see Post-exercise hypoglycemia prevention strategies for 107–108 risk factors age 121–122 AMP-activated protein kinase 129 corticotrophin-releasing factor 130 exercise duration and intensity 120–121 gamma-aminobutyric acid 129–130 glucokinase 128–129 glucose-sensing neurons 128 HAAF and hypoglycemia unawareness 123–127 impaired symptom identification 123 insulin sensitivity 122–123 insulin uptake and action 120 lactate 130–131 temperature 121 severe hypoglycemia prevention of intermittent high-intensity exercise 137–138 record keeping 137 strategies reducing risk 134–136 symptom identification improvement 134 137 Hypoglycemia-associated autonomic failure HAAF 123–127

slide 251:

222 222 Index Index 222 I Impairment mechanism AMP-activated protein kinase 129 corticotrophin-releasing factor 130 gamma-aminobutyric acid 129–130 glucokinase 128–129 glucose-sensing neurons 128 lactate 130–131 Insulin adverse effects 188 athletes abuse glucose metabolism 187 lipid metabolism 187–188 protein metabolism 188 and diabetes 188 prevalence of 187 synthesis 186 Insulin-like growth factor-I adverse effects 185 athletes abuse carbohydrate metabolism 184–185 protein metabolism 184 and diabetes 185–186 prevalence of 183–184 Intermittent exercise 49–50 Interval sprint training 39 K Ketogenesis 55 L Late post-exercise hypoglycemia 35–36 Leg glucose exchange during exercise 4 5 M MSNA. See Muscle sympathetic nerve activity MSNA Muscle sympathetic nerve activity MSNA 116 N Neurogenic symptoms hypoglycemia 116–117 Nocturnal hypoglycemia 106–107 P Phosphocreatine PCr 3 Physical activity. See also Exercise childhood diabetes assessment 75–76 carbohydrate 88–90 cardiovascular benefits 79–80 competition and travel 94–95 diabetes management 82–83 endurance sports 94 energy requirements 86–88 fat 91 fluid hydration and thermoregulation 91–92 fluid management 92 glucose and glycemic control 80–82 management of 84–86 nutrition and exercise 83 patterns 76–77 physical activity and developmental changes 74–75 power/strength sports 94 protein 90–91 psychological well-being 77–79 supplements and ergogenic aids 93 team sports 94 training/competitive sports 86 unplanned and spontaneous 83–84 vitamins and minerals 93 definition 73 Post-exercise hypoglycemia carbohydrate intake and exercise 57–60 glycemic index 60–61 pre-exercise carbohydrate consumption and insulin administration 61–63 pre-exercise insulin dose efficacy basal insulins 52 rapid-acting insulins 52–55 preparatory insulin and carbohydrate strategies 63–64 rapid-acting insulin dose safety strategies 55–57 Power/strength sports 94 Protein athletes insulin 188 insulin-like growth factor-I 184 with type 1 diabetes 162–163 without type 1 diabetes 154 in childhood diabetes 90–91 Pyruvate dehydrogenase complex PDC 6–7 R Rapid-acting insulins description 52–55 reduction of 65 safety strategies 55–57 Resistance exercise 50–51

slide 252:

223 223 Index Index 223 S Skeletal muscle acute exercise effect on insulin action 7–8 exercise and hyperinsulinemia stimulate glucose uptake 5–7 fiber types 3 Sodium/glucose co-transporter 1 SGLT1 57 Splanchnic glucose exchange during exercise 4 5 Sprint exercise 49 T Therapeutic use exemption TUE 189–190 Total daily energy expenditure TEE estimation 87 Type II fast-twitch fibers 3 Type I slow-twitch fibers 3 U Unplanned and spontaneous physical activity 83–84

authorStream Live Help