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Epidemiology : 

2 Epidemiology WHO estimated that there are 31.7 million diabetic in India in 2000 By 2030 it may be increase to 71.4 million India has Largest number of diabetic in the world Indians have genetic susceptibility for diabetes and is precipitated by lifestyle changes (which you think modernization) Type II among Indians occur at younger age (decade earlier than) diagnosis is delayed, improper care-increased morbidity & mortality Abdominal obesity, ( waist to hip ratio) contribute High prevalence among first degree relatives

Normal glucose metabolism : 

3 Normal glucose metabolism A balance is preserved between Entry of glucose into circulation from the liver, Supplemented by intestinal absorption after meals Glucose uptake by peripheral tissue When intestinal glucose absorption decline gluconeogensis increased in liver by action of glucagons and adrenalin Gluconeogensis falls during prolonged starvation


4 PANCREAS The normal adult Pancreas contains about I million islets The core of each islet consists of beta cells that produce Insulin Cortex consists of Endocrine cells Alpha cells that produce other hormones including- glucagons Delta cells- Somatostatin And PP cells – Pancreatic Polypeptide

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Action of INSULIN (Anabolic effects) : 

6 Action of INSULIN (Anabolic effects) Suppresses gluconeogensis Promotes glycogen synthesis and storage It promotes the peripheral uptake of GLUCOSE, particularly in skeletal muscle And encourages storage in muscle as muscle glycogen Encourages protein synthesis It also promotes lipogenesis and suppresses lipolysis

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7 Increase insulin (Anabolic effects ) Carbohydrate metabolism Glucose transport to muscle and adipose tissue Glucose Phosphorylation Glycogenolysis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt Lipid metabolism Triglyceride metabolism Fatty acid synthesis (liver) Lipoprotein lipase activity (adipose tissue) Protein Amino acid trans port Protein synthesis Decrease Carbohydrate Gluconeogensis Glycogenolysis Lipid metabolism Lipolysis Lipoprotein lipase (muscle) Ketogenesis Fatty acid oxidation Protein Protein degradation

In absence of insulin (catabolic effects) : 

8 In absence of insulin (catabolic effects) These processes are reversed in absence of insulin Gluconeogensis increased- In adipose tissue Lipolysis – glycerol-gluconeogensis Triglycerides – non esterified fatty acids – oxidation – ketone bodies Ketone bodies are organic acids. Oxidized and utilized as fuel When Ketone bodies production exceeds their removal – leads to Ketoacidosis In Muscle Gluconeogensis takes place following ways Glycogenolysis – lactate –gluconeogensis Protein –pyruvate –gluconeogensis Proteolysis – glutamine (in Gut)- Alanine-gluconeogensis

DM-Metabolic disturbance : 

9 DM-Metabolic disturbance Deficiency of insulin leads to INCREASED CATABOLIC EFFECT DECREASED ANABOLIC EFFECT Lead to-DIABETES MELLITUS ABSOLUTE DEFICIENCY - TYPE 1 DM RELATIVE DEFICIENCY - TYPE 2 DM In type 2 - hyperglycemia can reduce insulin secretion In both type of DM the action of insulin are also impaired by insensitive target cells

Lack of insulin Increased in glucagons, cortisol, GH, catecholamine : 

10 Lack of insulin Increased in glucagons, cortisol, GH, catecholamine Decreased anabolism Hyperglycemia-fatigue Glycosuria- vulvitis & balanitis Osmotic diuresis – polyurea & polydipsia Salt and water depletion – tachycardia & hypotension Death Increased catabolism Glycogenolysis Gluconeogensis -wasting Lipolysis – loss of weight Hyperketonaemia Acidosis- hyperventilation and peripheral vasodilatation Hypotension & Hypothermia Diabetic Ketoacidosis

Slide 11: 

11 Type I Diabetes mellitus Immune mediated type 1 DM Environmental factors Idiopathic

Immune mediated type 1 DM : 

12 Immune mediated type 1 DM Highest incidence – Scandinavia and northen Europe – 37 per lakh/year Age group – 14 years or young United state 15 per lakh Migrating to these region incidence increases among migrants Lowest incidence in china 1 per lakh in china Global incidence increasing. 3% each year Susceptibility is due A. Genes in 1/3 cases. I.HLA-DR3 OR HLA-DR4 (HLA-DQB1 *0302). Protective gene HLA-DQB1 *0602, 5’ II. Polymorphic region of insulin gene. B. Environmental factors in 2/3 cases

Type 1 diabetes mellitus : 

13 Type 1 diabetes mellitus No insulin or severe deficiency Unrestrained gluconeogensis, lipolysis, Increased counter-regulatory hormones Unrestrained gluconeogenesis, lipolysis, ketogenesis Peripheral glucose utilization blocked Leads to Ketoacidosis Protein catabolism-muscle wasting and negative nitrogen balance Autoimmune injury starts many years before clinical diabetes develops

Continued : 

14 Continued It occurs at any age More common in children and young adults Peak incidence before school age and again at around puberty It is catabolic disorder – Insulin virtually absent Glucagon is elevated Pancreatic B cells fail to respond to all insulinogenic stimuli Exogenous insulin is therefore required to reverse catabolic state which Prevent ketosis Reduce the hyperglucagonemia and reduce blood glucose

Continued : 

15 Continued Early Screening for Circulating antibodies to facilitate in making diagnosis in people who are not affected and prone for Circulating antibodies Islet cells Insulin Glutamic acid decarboxylase And tyrosine phosphates Zinc transporter ZnT8 3% children likely to have if mother is type 1 DM 6% if father is DM

16 Environmental factors Number of different hypothesis Infection rubella, Coxsackie's B4 Consumption of cows milk Suffering from autoimmune disease –asthma Idiopathic Less than 10% have no evidence of pancreatic B cell autoimmunity Called type 1B Most patients are of Asian African origin

Type 2 DM : 

17 Type 2 DM Insulin resistance On liver and peripheral tissue Post prandial glucose uptake impaired-especially in skeletal muscle Increased glucagons Enhanced hepatic glucose output, impaired peripheral utilization Rarely Ketoacidosis

Continued : 

18 Continued Occurs predominantly in adults But it is now encountered in children and adolescents also Circulating insulin is sufficient to prevent Ketoacidosis But inadequate to prevent hyperglycemia due to insulin resistance (i.e. tissue insensitivity) Genetic and environmental factors cause Insulin resistance And Beta cell loss

Continued : 

19 Continued Whenever one twin gets type II DM, in 70% monozygotic twins over 40 years of age other will develop DM within a year So far 18 different genetic loci have been associated with increased risk of type 2 DM One of genetic loci with largest risk effect TCF7L2 Two loci affect fat mass and obesity risk are FTO & MC4R PPARG locus has been implicated in insulin resistance

Continued : 

20 Continued Early in the disease process hyperplasia of pancreatic B cells occur And we get exaggerated insulin and proinsulin response (hyperinsulinism) With time, progress to impaired B cell function due to ? Amyloid deposit and genetic defect Obesity is the most important environmental factor causing insulin resistance accumulation of fat in the omentum and mesenteric region correlate with insulin resistance (s c fat less asso) The daily vigorous exercise prevents this, despite >5000 kcal intake Abnormal levels of adipokines leptin, adiponectin, TNF-alpha and resistin contribute to insulin resistance Hyperglycemia per se can impair insulin action.

Continued : 

21 Continued Other specific types of DM MATURITY –onset diabetes of the young (MODY) Classified into 4 types Autosomal dominant inheritance Age of onset 25 years or younger, non obese Impaired glucose induced secretion of insulin MODY type 2 glucokinase gene defect. In rest 3 MODY mutation of nuclear transcription factor is the cause MODY TYPE 2 mild disease, slight fasting hyperglycemia and few micro-vascular complications MODY Type 3 is common among MODY

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22 MUTANT insulin rare subtype Mutant insulin receptors: rare type Mutation of mitochondria: sperm do not contain mitochondria, only mother transmit mitochondrial genes to her offspring Late 30s, hearing loss, many insulin dependent and many are over weight Wolfram syndrome: Autosomal recessive neurodegenerative disorder in childhood DI, Optic atrophy, deafness, Mutation of gene WFSI- impaired in insulin secretion to glucose stimulus, first decade life, DI develops in 2 decade. ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, peripheral neuropathy, psychiatric illness develop later

Pathogenesis : 

23 Pathogenesis Type 1 Diabetes is due to pancreatic islet B cell destruction Predominantly by an autoimmune process in-90% of cases, idiopathic – 10% These patients are more prone for Ketoacidosis Type 2 More prevalent form Results from insulin resistance There is compensatory increase in insulin secretion

Insulin resistance syndrome (syndrome X; metabolic syndrome) : 

24 Insulin resistance syndrome (syndrome X; metabolic syndrome) 25% of General they are non-obese, non-diabetic population has insulin resistance Incidence is as high as that of type II diabetes And are prone to develop type II DM Hyperglycemia, raised triglyceride levels, low HDL, hypertension, hyper uricemia, abdominal obesity, prothrombotic state with increased plasminogen activator inhibitor and pro-inflammatory state Called also Syndrome X (Insulin resistance syndrome) Management correct hyperglycemia, BP, dyslipidemia

Clinical findings : 

25 Clinical findings Major Manifestation of DM Hyperglycemia Detected on routine biochemical analysis of asymptomatic patients, pregnancy, steroid treatment stress hyperglycemia Chronic symptoms like thirst, polyurea, nocturia, tiredness, irritable, apathy, recent change in weight, blurring of vision, pruritus, balanitis, nausea, headache, polyphagia, predilection for sweets Emergency metabolic decompensation

Major Manifestation of DM : 

26 Major Manifestation of DM Polyurea----------------------- Weakness---------------------- Polyphagia with weight loss Recurrent blurred vision---- Vulvovaginitis---------------- Peripheral neuropathy------- Nocturnal enuresis----------- Symptomatic -----------------

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27 Type I Poly urea due to osmotic diuresis Hyperglycemia loss of glucose, water, and electrolytes in urine hyper osmolar state lead to blurred vision as lens exposed to hyper osmolar fluid Weight loss – depletion of water, glycogen and triglycerides. There after increased protein loss from muscle Postural hypotension – fluid loss-low plasma Weakness – potassium loss Paresthesias- temporary sensory dysfunction Anorexia, nausea, vomiting –ketosis lead to further dehydration and hyper osmolarity Consciousness levels vary- common in ketosis

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28 Type II May have polyurea and thirst Occasionally Neuropthic or cardiovascular complications like Chronic skin infection common – pruritis, vaginitis are frequent Large babies, polyhydramnios, pre-eclampsia, unexplained fetal loss. Obese fat in upper segment of body, relatively less fat on appendages waist: hip> 0.9 (men), 0.8 Mild hyper-tension, xanthoma And lipemia retinalis in familial hypertriglycemia

Investigations for diagnosis : 

29 Investigations for diagnosis Urine testing Glucose Dipstick Benedict Testing should be performed on urine passed 1-2 hours after meals. Confirmed by blood test Disadvantage- glycosuria in making of DM Individual variation in renal threshold-dysfunction of proximal renal tubules (Fanconi, chronic kidney disease) Low thresh hold, alimentary Glycosuria (benign), can occur after gastric surgery or hyperthyroidism, peptic ulceration, hepatic disease Pregnancy (increased load of glucose the tubules filtration increased )renal threshold falls –increased in glomerular filtration - always ask for blood glucose to rule out pregnancy induced DM

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30 KETONES Ketonuria may be found in normal people-by nitroprusside reaction-detect acetoacetate Ketone bodies may be found in normal people as in Starvation Strenuous exercise for long period Vomiting repeatedly. (Remember ketosis can induce vomiting) Low carbohydrate high fat diet Associated with glycosuria DM likely diagnosis PROTEINS – albumin>300mg. To identify renal disease in DM, infection Microalbuminuria – suggest risk of diabetic nephropathy, and/or macrovascular disease

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Blood testing : 

32 Blood testing Random blood glucose > 11 mmol/L GTT done Unrestricted carbohydrate diet for three days before test. Rest before test(30 mts), no smoking Fasting >7.0 mmol/L After 2 hours PP >11.1 mmol/L Self monitoring done by using glucometer. But give 10-15% lower value than laboratory

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Glycated haemoglobin (HbA1c ) : 

35 Glycated haemoglobin (HbA1c ) Haemoglobin becomes glycated between glucose and amino group on alpha and beta chins HbA1c abnormally elevated in diabetes with chronic hyperglycemia Since HbA1c circulate within red cell and reflect the state of glycemia over preceding 8-12 weeks as RBC survive for 120 days

Glycated haemoglobin (HbA1c ) : 

36 Glycated haemoglobin (HbA1c ) Glycated haemoglobin provides an accurate glycemic control over a period of weeks to months Normal in patients- impaired glucose tolerance The rate of formation of HbA1c is directly proportion to the blood glucose levels integrate to life span of RBCs Change is detectable within 2-3 weeks of raise in blood glucose. HbA1c in diminished in anemia, during pregnancy, uremia and haemoblobinopathies. HbA1c measured once or twice in a year. 5.0-6.5%

Blood lipids : 

37 Blood lipids Triglycerides measured in fasting condition Total cholesterol LDL cholesterol and HDL cholesterol In type I LDL cholesterol and serum triglycerides elevated In type II - In syndrome X High serum triglyceride (300-400mh/dL Low HDL (less than 30 mg/dL)- lead to macrovascular disease Qualitative change in LDL particles- smaller dense (atherogenic) correct Hyperglycemia exercise, diet, hypoglycemic control If inspite of treatment dyslipidemia persist, it could be due to lipid disorder

Secondary causes of hyperglycemia : 

38 Secondary causes of hyperglycemia Hyperglycemia due to tissue insensitivity to insulin Hormonal tumors( Acromegaly, Cushing, Glucagonoma, Pheochromocytoma ) Pharmacologic agents( corticosteroids, sympathomimetic drugs, niacin) Liver (Haemochromotosis, Cirrhosis) Muscle disorder (myotonic dystrophy) Adipose tissue disorder (lipodystrophy, truncal obesity) Insulin receptor disorder (acathosis nigricans) Hyperglycemia due to reduced insulin secretion Hormonal tumors somatostatinoma, Pheochromocytoma Pancreatic disorder pancreatitis, Haemochromotosis hemosiderosis, Drugs thiazides, diuretics, phenytoin, pentamidin

Treatment regimens : 

39 Treatment regimens Diet a well balanced nutritious diet Out of total calorie required is taken in form Carbohydrate 45-65% Fat 25-35% of which less than 7% in form of saturated fat in type II DM are given some fat in form monosaturated fats, which can lower triglycerides and increase HDL cholesterol is limited to 200-300 mg daily Protein 10-35% In diabetic nephropathy less protein (10% of cal)

Slide 40: 

40 Dietary fiber Increase intestinal transit time and retard nutrient absorption May give beneficial slower hyperglycemia & cholesterol levels Artificial sweeteners Aspartame 180 times as sweet as that of sucrose Not heat stable Other sweetener are saccharin, sucrolose, acesulfame- heat stable Fructose induces slight increase in plasma glucose levels But has adverse effect raise cholesterol-moderate intake advised

Slide 41: 

41 Sugar alcohol (made of sucrose, glucose and starch) sorbitol, xylitol, mannitol, isomalt, maltitol and hydrogenated starch not easily absorbed as sugar and used as sugar free food products However if consumed in large they will raise blood glucose and can cause bloating & diarrhea

Drugs for treating hyperglycemia : 

42 Drugs for treating hyperglycemia Drugs primarily stimulate insulin secretion-Sulfonylureas Drugs that alter insulin action Metformin-liver Drugs affecting glucose absorption Acarbose Prolong incretin action Exenatide Suppressing glucagon Pramlintide

Insulin secretagoguesInsulin secretagogues can be divided into 2 subclasses: Sulfonylureas and non-Sulfonylureas. : 

43 Insulin secretagoguesInsulin secretagogues can be divided into 2 subclasses: Sulfonylureas and non-Sulfonylureas. Sulfonylureas Repaglinide Nateglinide Biguanides Thiazolidinediones Acarbose Miglitol Insulin secretagogues Insulin sensitizers Inhibitors of CHO absorption

Drugs primarily stimulate insulin secretion : 

44 Drugs primarily stimulate insulin secretion A. Sulfonylureas, B. meglitinide analog and C. D-Phenylalanine derivatives A. Sulfonylureas: action Primary mechanism of action Specific receptors on the surface of pancreatic B cells bind Sulfonylurea. Resulting in depolarization of the B cells and activity promotes insulin release Not indicated in type I DM-(no functioning B cells) They are metabolized in liver. There metabolites are weakly active. Excreted in urine. Hence contra indicated in liver and kidney disease. Rare toxicity - rashes, leucopenia and thrombocytopenia Can cause weight gain

First generation Sulfonylurea : 

45 First generation Sulfonylurea Tolbutamide, Tolazamide, Acetohexamide, Chlorpropamide Tolbutamide: does 0.5-2 grams It is rapidly oxidized in liver. Duration of Action- 6-10 hours Given in doses of 500 mg before each meal and one at bed time. Can be used when liver function normal Prolonged hypoglycemia reported specially when patient is on sulfonamides, phenylbutazone or azole (antifungal) Tolazamide, Acetohexamide and Chlorpropamide (severe hypoglycemia, alcohol induced flushing and hyponatermia) are rarely used

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Second generation Sulfonylureas : 

48 Second generation Sulfonylureas Glyburide, glipizide, gliclazide and glimepiride are 100-200 times more potent than tolbutamide Should be used carefully in cardiovascular disease and older patients (hypoglycemia) Glyburide Dose 2.5 mg/day. Average maintenance dose 5-10 mg/day. Given in single dose in morning Metabolized in liver. Thus prolonged effect due to Metabolites and entry of drug into B cells Flushing with alcohol, not given in liver and kidney disease, elderly patients.

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49 Glipizide: Ingested 30 minutes before meals to prevent slow absorption in presence of food Dose 5to15 mg/d single dose before breakfast When higher dose required given in divided dose 90% metabolites are inactive. 10% excreted in urine unchanged Preferred in elderly – lower potency & shorter action. Extended release tablets available

Slide 50: 

50 Gliclazide: Intermediate acting 12 hours 40 to 80 mg starting dose maximum 320 mg Metabolized in liver. Conjugate derivatives in liver have hypoglycemic effect Glimepiride: 1 mg/day to a maximum 8 mg once daily Can be given along with insulin - if necessary cost effective Metabolized in liver, metabolites have hypoglycemic effect

Continued : 

51 Continued B. Meglitinide analogs: Repaglinide: Structurally similar to Glyburide Acts by binding to the sulfonylurea receptor It causes a brief rapid pulse of insulin Rapidly absorbed in intestines and metabolized in liver. Metabolites are inactive The starting dose 0.5 mg 8th hourly (max 16 mg) 15 minutes before each meal Can be used in combination with metformin Hypoglycemia side effect Weight gain Useful in kidney disorder

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52 C. D-Phenylalanine derivatives Neteglinide- it is rapidly absorbed from intestines, reaching plasma peak level within 1 hour Metabolized in liver And has Plasma half life of 1.5 hours It causes a brief rapid pulse of insulin When given before meal it reduces PP rise in glucose 60 mg who have mild elevation of HbA1c Maintenance dose can be 120 mg three times a day It can cause hypoglycemia and weight gain

2 drug which can alter insulin action : 

53 2 drug which can alter insulin action A. Metformin, B. Thiazolidinediones A. Metformin reduces the hepatic gluconeogenesis Half life being 1.5 to 3 hours Excreted unchanged in urine Drug of choice in obese. Does not cause wt gain Improves fasting as well as PP hyperglycemia and hyper- triglyceridemia in obese Not indicated in type I DM Contraindicated serum creatinine – 1.5 mg/dL, hepatic insufficiency, alcoholism and prone for tissue hypoxia Max dose 2.55 g. 500 mg tid is common schedule Extended release preparations available

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54 Side effects of metformin: GIT symptoms Persistent diarrhea can occur. Such cases extended release metformin given and has fewer GIT side effect Hypoglycemia does not occur Lactic acidosis rare. prone for lactic acidosis in tissue hypoxia Contraindicated in liver, kidney, alcoholics, heart disease and advanced age

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55 The reason we stop metformin is because there is an increased risk of lactic acidosis. The reason for this is that radio- contrast dyes are shown to cause acute renal failure. Since metformin is cleared virtually exclusively by renal mechanisms, this may cause increased concentrations of metformin, leading to lactic acidosis. The fact that the patient is a diabetic is irrelevant to whether you d/c the drug or not. If they take metformin, whether it be for diabetes, weightloss or anything else, you stop metformin 48 hours before and wait 48 hours after radio- contrast before reinitiating metformin therapy.

Slide 56: 

56 B. Thiazolidinediones Drugs sensitize peripheral tissue to insulin Regulate release resistin and adiponectin from adipocytes And adiponectin secretion is stimulated, which sensitizes tissue to the effect of insulin Resistin secretion inhibited which reduces insulin sensitization Observed effects to Thiazolidinediones Increased glucose trans port Decreased free fatty acid levels Decreases hepatic glucose output And increased differentiation of pre – adipocytes to adipocytes

Slide 57: 

57 Rosiglitazone and Pioglitazone are the preparations Can be given as monotherapy or in combination with Sulfonylureas or metformin or insulin Monotherapy lower HbA1c by 1-2% Lower reduction in insulin doses, when used in combination The dosage Rosiglitazone-4-8 mg daily and Pioglitazone 15-45 mg daily Thiazolidinediones and metformin combination does not cause hypoglycemia an advantage

Slide 58: 

58 Rosiglitazone can cause increase in total cholesterol, LDL cholesterol and HDL cholesterol. There is reduction in free fatty acids May increase the risk of IHD Pioglitazone lower triglycerides increase HDL cholesterol No increase the risk of IHD Both can cause edema, anemia, weight gain Contraindicated in liver disorders (raised ALT)

Drugs that affect absorption of glucose : 

59 Drugs that affect absorption of glucose α-Glycosidase inhibitors inhibit action of α-Glycosidase enzyme in gut Thus starch and sucrose are not metabolized into glucose Acarbose and Miglitol are the preparation available Acarbose: available in 50 mg and 100 mg tablets Initial dose 50 mg BD, gradually increased to 100 mg tid given along with food Flatulence, liver enzymes raised.

Slide 60: 

60 MIGLITOL: similar to acarbose Start with 25 mg tid increased to 50 mg tid Not indicated in end stage renal disease Flatulence is side effect

4. Incretin : 

61 4. Incretin Oral glucose releases gut hormone GLP-1, but not when glucose given iv GLP-1 induces insulin release In type II DM GLP-1 secretion impaired When infused it stimulate insulin secretion and lowers glucose levels And has lower risk for hypoglycemia as it has got modest insulin stimulatory effect at normoglycemic concentration it suppresses glucagon and patient feel less hungry

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62 Preparation are Exenatide and Sitagliptin Exenatide given as continuous infusion, half life 2.4 hours and glucose lowering effect 6 hours. Can cause weight loss, side effect nausea, ac pancreatitis Available in fixed dose pen 5 and 10 mcg Injected 60 minutes before breakfast and before dinner Initially 5 mcg BD for one month. If tolerated well increased to 10 mcg Careful in renal failure

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63 Sitagliptin100 mg once daily, careful in renal failure . Nasopharyngitis is side effect. Neutrophil count increased Anaphylaxis, allergic reaction, angioedema and exfoliative skin including Stevens- Johnson syndrome. Frequency of side effect not clear

5. Others : 

64 5. Others Pramlintide: is a synthetic analog of islet amyloid polypeptide When given subcutaneously before meal It delays gastric emptying Suppresses glucagon secretion Decreases appetite Can be used in both DM Hypoglycemia can occur Requirement of insulin decreased Nausea in 30%-50% Dose 15 mcg before each meal and titrated

Drug combination : 

65 Drug combination Many are available However it limits the clinician’s ability to optimal drug usage


66 INSULINS Indicated in both type. In Type II (when hyperglycemia is not controlled with diet and after use of OHA) Impure insulin can cause immunogenicity. However now highly purified insulin preparations are available and thereby decreases the incidence of complications Allergy Insulin resistance Lipoatrophy But we are not able to reproduce the physiological pattern

Insulin species : 

67 Insulin species Bovine (ox or cow) Porcine (pig) Human

Insulin preparations : 

68 Insulin preparations Human insulin is produced by recombinant DNA technique 5 analogs are in use Three rapidly acting LISPRO, INSULIN ASPART and INSULIN GLULISINE Two long acting : glargine, detemir Purified insulin where proinsulin contamination is less than 10 ppm and are potent. Potency is lost in extreme temperatures Before use check concentration of insulin units/ml

Insulin preparations : 

69 Insulin preparations Regular insulin is a short acting clear soluble crystalline zinc. Action starts within 30 minutes after sc use (can also used IV- diabetic ketosis, pre-operatively and in infections) Rapidly acting insulin analogs- produced by recombinant technology Insulin lispro Insulin aspart Insulin glulisin Action starts within 20 minutes duration of action 4 hours. Used commonly in insulin pumps

Slide 70: 

70 Long acting insulin preparations NPH insulin- Intermediate acting (neutral protamine hegedorn) Action starts at 2to 4 hours with peak response 8-10 hours Given twice daily Rarely Instable when refrigerated for long without using and if bottles are discarded after one year Long acting insulin analogs Insulin Glargine is clear solution When injected it forms microprecipitates that is slowly released. Action 24 hours. Given once daily. It cannot be mixed with other insulin. Fasting hyperglycemia well controlled Less nocturnal hypoglycemia Because of lack availability of safety data not used in pregnancy

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71 Long acting insulin analogs (continued) Insulin detemir - duration of action 17 hours. Used once or twice daily. Bioavailability is lower than other long acting insulin Mixed Insulin preparation

Methods of insulin administration : 

72 Methods of insulin administration Disposable syringes are available in 1 ml, 0.5 ml, and 0.3 ml sizes with length of 8 mm and 12.7 mm 0.3 ml syringes are more commonly used as most diabetic take about 30 units single injection In extreme insulin resistance high dose may be required 31 gauge needle cause reduce pain. Avoid reusing Any part of body with loose skin can be used. Recommended-abdomen. Rotation of site at same region to avoid delayed absorption fibrosis and lipodystrophy

Continued : 

73 Continued Insulin pen injector devices (reusable) – eliminate carrying vials are syringes. Cartridges 31 gauge needles are used-painless Insulin pumps – for SC delivery which are small and are easy to program Features To set number of different basal rates throughout the 24 hours and adjust the time over which bolus doses are given Pumps can be removed during bathing etc The patient is able to eat with less regard to timing Patient can manage glycemic excursion that occur with exercise

Technique of injection : 

74 Technique of injection Insulin is administered SC Injection must be given perpendicular to the skin with short hypodermic insulin needles, if patient lean into raised skin fold Factors affecting insulin bioavailability

Indications : 

75 Indications Long term and permanent insulin therapy IDDM or Type I NIDDM or Type II failure OHA Intermittent insulin therapy Type II during Acute infection Major surgery Acute MI or stroke Ketoacidosis, hyper osmolar coma, lactic acidosis, pregnancy and delivery

Adverse effects : 

76 Adverse effects Hypoglycemia Insulin edema Lipoatrophy Lipohypertrophy Insulin antibodies Allergy Weight gain Immunologic insulin resistance

Slide 77: 

77 Inhaled insulin: Exubera approved by FDA No longer available –lack of demand Was as effective as SC insulin controlling PP Physician reluctant use – following reasons Long time safety studies not available on lung function Awkward dosing schedule Cost Lack of insurance coverage Availability of other insulin delivery system

Transplantation : 

78 Transplantation Pancreatic trans plant Indicated only when all other insulin therapeutic approaches fail Who have frequent severe hypoglycemia Who have life-threatening complication related to their lack of metabolic control Islet cell transplant is a minimal invasive procedure. Studies shown encouraging results Cells were donated multiple donors Corticosteroids were not used to suppress immunity Percutaneous trans-hepatic transplant done in 20 subjects 2 years follow up studies showed decline in insulin secretion over the time

General consideration in treatment of DM : 

79 General consideration in treatment of DM Insulin treated patients can have full satisfying life However “free” diet and unrestricted activity are still not advised Multiple small feedings recommended Hypoglycemia being side effect safe jobs given Moderate exercise advised Personal hygiene - advice necessary Infections provoke release of catecholamine or glucagon which increase insulin requirement

Steps in management : 

80 Steps in management A. Diagnostic examination Identify visceral obesity Family history identified Type I or Type II Ketonuria ? With glycosuria H/o smoking, hypertension, hyperlipidemia which further increase cardiac risk GTT and HbA1c Total cholesterol, HDL cholesterol, ECG, kidney function test, peripheral pulses, neurological, and ophthalmic examination evaluated for further management

Slide 81: 

81 B. Patient education regarding self management It is life long disease, hence it is patient themselves and their families to manage the DM Teach them Nature of disease Chronic Hazards of disease. Their early recognisation and management Self monitoring of glucose. Proper testing of urine and blood glucose and recording the data Able to adjust the timing and quantity of their insulin dose, food and exercise To maintain personal hygiene. Foot care To give up smoking and alcohol consumption

Therapy : 

82 Therapy Type 2 diabetes mellitus In obese hyperglycemia is due to insulin resistance and beta cell failure Weight reduction Prescribe the diet To increase the physical activity to expend energy Cure can be achieved by reducing adipose stores However weight reduction and to maintenance is difficult Hypoglycemic drugs used when weight reduction and exercise does not control hyperglycemia

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83 Continued Choice of initial agent depends on number of factors Comorbid condition Adverse reactions to medication Ability of the patient to monitor hypoglycemia Drug cost And patient and physician preference Metformin is advantageous because apart from lowering glucose there is no risk of hypoglycemia Lowers triglycerides, weight loss. GIT side effect Cannot be used in end stage renal disease

Slide 84: 

84 Continued Thiazolidinediones Improve peripheral resistance, lower glucose without hypoglycemia However can cause fluid retention Contraindicated in heart patients Can cause weight gain and fracture risk in female Contraindicated when liver enzymes raised

Continued : 

85 Continued Sulfonylureas Hypoglycemia and weight gain The alpha glucosidase - GIT side effect Incretin Exenatide promotes given by injection –pancreatitis, not given in gaastroparesis Sitagliptin , no GIT side effect, can be given kidney failure. Serious allergy anaphylaxis, angioedema, stevens-jhonson syndrome

Continued : 

86 Continued For most obese patients with mild type II, metformin is the first line drug If inadequate Hyperglycemia after carbohydrate diet rich meal – metformin + short acting secretagogues before meal may suffice Patients with severe insulin resistance may be candidates for Pioglitazone Subjects concerned about weight gain benefit from use of Exenatide (incretin) If two agents are inadequate third agent is added Patients are more tolerant of sub - maximal dose of combination drugs

Slide 87: 

87 Insulin therapy should instituted if combination of oral agent if OHA show side effects if dose If Oral agent fail to restore euglycemia in type II Continue the oral combination add bed time NPH or long acting insulin analog If day time control is not achieved 70/30 NPH/regular mixture before breakfast and before dinner given If goals not achieved or if episodes of hypoglycemia occur –multiple insulin doses as in type I given

Slide 88: 

88 When we want institute insulin in type II Metformin (reduces hepatic glu output) + Pioglitazone (improves peripheral insulin resistance) + Insulin Regime is better choice

Non obese patients with type II : 

89 Non obese patients with type II These patients frequently have visceral adiposity Also called metabolically obese normal weight pt They need exercise and treatment as in obese Non obese and non central obesity patients Should be evaluated for other types of DM Like MODY and LADA and treat accordingly

Management of type I DM : 

90 Management of type I DM In these patient, information and counseling based on trial diabetes control and complication trial ( DCCT) According to these trials There is advantage of taking multiple insulin injection For attain euglycemia 3 to 4 injection/day needed There is advantage of self glucose monitoring

Continued : 

91 Continued Almost physiological state is achieved by combination therapy i.e. rapidly acting and long acting insulin Use of the rapidly acting insulin analog Is safer and much more convenient than using regular human insulin Improved post prandial glycemic control Patients had less episodes of hypoglycemia And it is convenient for patient to use However They have to be used in combination with long acting insulin With low carbohydrate diet may have post prandial hypoglycemia

Insulin regime : 

92 Insulin regime For example A patient consuming 75 g CHO break fast 60 g at lunch 90 g at dinner

Insulin regime : 

93 Insulin regime For example - 2 A patient consuming 75 g CHO break fast 60 g at lunch 90 g at dinner

Continued : 

94 Continued Continuous sc insulin infusion by portable battery operated “open loop” device available This device allows the setting of different basal rates administration of insulin By this method patient can delay or skip meals And patient can vary meal size and composition of food also Somogyi effect : insulin treated patient may show a rapid swing to hyperglycemia after episodes of hypoglycemia Due to release of antagonist of insulin Dawn phenomenon : it is hyperglycemia seen in the morning and is due to predawn surges in GH and other counter regulatory hormones mediating resistance to the action of insulin

Acceptable levels of glycemic control : 

95 Acceptable levels of glycemic control Aim of therapy to achieve euglycemia without provoking severe or frequent hypoglycemia 90 to 130 mg/dL of blood glucose Before meal And after an overnight fast acceptable 180 mg/dL one hour after meals 150 mg/dL after 2 hours of meals HbA1c 1% above normal range Control

Complications of Insulin therapy : 

96 Complications of Insulin therapy Hypoglycemia: when blood glucose falls around 54 mg/dL, patient starts to experience both sympathetic and parasympathetic symptoms Very important

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97 If these autonomic symptoms ignored and glucose levels fall further around 50 mg/dL Neuroglycopenic symptoms appear Irritability, Confusion, blurred vision, tiredness, headache and difficulty in speaking A further fall loss of consciousness, convulsions With repeated episodes of hypoglycemia there is adaptation and autonomic symptoms-not appear

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98 Until glucose levels are much lower, Then only Neuroglycopenic symptoms appear called “hypoglycemic” unawareness, blunted by ß blockers (used in angina and hypertension) Hence ß blockers used cautiously And ß1-selective blocking agents are preferred Causes for hypoglycemia in insulin treated patient as a consequence 1. Behavioral 2. Counter regulatory issue 3. Complication of diabetes

Behavioral issues : 

99 Behavioral issues Behavioral issues include Injecting too much insulin for the CHO ingested Drinking alcohol in excess, especially on empty stomach In type I during or even several hours after exercise Aggressive self treatment

Counter regulatory issue : 

100 Counter regulatory issue Impaired glucagon response Sympatho-adrenal response Cortisol deficiency Patient with DM of greater than 5 years duration lose their glucagon response to hypoglycemia This leads to blunting of Sympatho-adrenal response Occasionally Addison disease develop in type I DM When this happens insulin requirement fall significantly Unless insulin dose is reduced patients prone – hypoglycemia

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101 Prevention and treatment of insulin induced hypoglycemia Should carry glucose always Ingestion of 15g of carbohydrate enough After this check blood glucose in 15 minutes Parenteral glucagon kit 1 mg provided to all Family and friends should be instructed what to do in hypoglycemic state Once patient recovers conscious give CHO Medical person treating 50 ml of 50% glucose IV Or glucagon 1 mg IM

2nd complication- immunopathology : 

102 2nd complication- immunopathology Insulin antibodies IgA, IgD, IgE, IgG and IgM produced By using purified and human insulin immunological syndromes have come down Insulin allergy urticaria, anaphylaxis results treatment antihistamine, corticosteroid and even desensitization may be required Immune insulin resistance: develop circulating anti insulin antibodies which neutralizes insulin. Result in high insulin requirement

3rd complication lipodystrophy at injection site : 

103 3rd complication lipodystrophy at injection site Atrophy of fat at the site due immune reaction Lipohypertrophy ; insulin deposition at site when injection given at same locality

Chronic complications of DM : 

104 Chronic complications of DM Diabetic cataract Premature Cause non-enzymatic glycosylation of lens protein –high Diabetic retinopathy – Micro – aneurysms, Hemorrhages, Exudates and Retinal edema Cotton wool spots (small infarcted areas of retina)

Continued : 

105 Continued Proliferative or malignant retinopathy Newly formed vessels and Retinal detachment Retinopathy Does not occur first 3-5 years in type I DM In type II patient will have retinopathy at the time of diagnosis Annual consultation necessary (might have DM for many years) and require care Treatment available Xenon or argon photocoagulation Avoid smoking No contraindication in use of aspirin

Continued : 

106 Continued Glaucoma Occurs in 6% of patients Treatment as that of open angle disease Closed angle Glaucoma uncommon Cause Neo-vascularization Or after surgery

B. Diabetic Nephropathy : 

107 B. Diabetic Nephropathy 1/3 of all end stage chronic kidney disease are being treated for nephropathy Type I have 30 to 40% chances of having nephropathy after 20 years In type II it is 15 to 20%. But end stage nephropathy much more common improved glycemic control and more effective therapy and use of ACE inhibitor can reduce the incidence Diabetic nephropathy is initially manifested by proteinuria, subsequently kidney function decline

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108 Microalbuminuria – Radioimmunoassay more sensitive test for detecting Microalbuminuria 24 hours urine collection not advised (due to wide variability of albumin excretion) Early morning spot urine collection and estimating albumin/creatinine ratio is preferred Normal less than 15 mcg/minute 20 mcg or more considered as abnormal 30 mcg/L or more is abnormal after testing for 3 times at an interval of 3-6 months

Continued : 

109 Continued In Microalbuminuria it correlates with hypertension and increased LDL cholesterol frequency May have systolic hypertension And increased cardiovascular risk Even end stage nephropathy may not have some times Glycemic control and low protein diet(0.8 g/kg/d) may reduce Microalbuminuria Anti-hypertensive therapy also decrease Microalbuminuria ACE (CAPTOPRIL) reduce Microalbuminuria

Progressive diabetic nephropathy : 

110 Progressive diabetic nephropathy Progressive diabetic nephropathy consists of proteinuria of varying severity and may lead to “Nephrotic syndrome” Hypoalbuminemia, edema and increased in circulating LDL cholesterol And progressive azotemia Proteinuria continue to excrete 10-11 g daily and glycosuria appear

Continued : 

111 Continued Hypertension develop Atherosclerosis accelerated At this stage glycemic control is not beneficial At this stage ACE inhibitor shown beneficial effect-improve glomerular filtration. How not known (captopril ) Creatinine greater than 2 mg/dL and hyperkalemia- stop drug (hyporeninemic hypoaldosteronism ) Restriction of dietary protein to 0.8/ kg body/ day are recommended Dialysis has limited value Kidney transplant is the treatment of choice, if there are no contraindications

Diabetic neuropathy : 

112 Diabetic neuropathy A. Distal symmetrical polyneuropathy. Most common neuropathy Loss of function appears in a stocking – glove pattern (due to axonal neuropathy process) Longer nerves are vulnerable Motor and sensory nerve conduction delayed Ankle jerk absent Sensory : bilateral symmetric impairment of vibration, pain and temperature. Ulcers and Charcot arthopathy Pain and swelling at high pressure points, Jt instability (changes joint subluxation and periarticular fractures) Motor: small muscles of foot with joint deformities

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113 Treatment of Distal symmetrical polyneuropathy Ensure good vascular supply Treat infection if any Local application of platelet derived growth factor Patient who used this platelet derived growth (3 or more tubes) showed increased cancer death. Therapeutic foot wear help in preventing recurrence Daily inspection of feet for redness, blisters, abrasion and lacerations

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114 B. Isolated peripheral neuropathy Can be mononeuropathy or mononeuropathy multiplex (several nerves) Characterized by sudden onset and subsequent recovery of most functions (6-12 weeks time) Cause vascular ischemia or trauma Cranial (3,4, 6) and femoral are commonly involved Diabetic amyotrophy – sever pain front of thigh and weakness of quadriceps muscle.

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115 C. Painful diabetic neuropathy Hypersensitivity to touch and occasionally severe “burning” pain, particularly in night Causing physical and emotional problem to pt Amitriptyline 25 to 75 mg at bed time-helps or Desipramine 25-125 Pain relief in 48 to 72 hours anti-depressive 2-3 wks If no improvement after 5 days, discontinue Amitriptyline Diabetic neuropathic cachexia. Insulin & analgesics – prognosis good

Autonomic neuropathy : 

116 Autonomic neuropathy Postural hypotension and decreased response to Valsalva maneuver Gastro-paresis, alternating bouts of diarrhea and constipation Inability to empty bladder Impotence MANAGEMENT No effective treatment. Metoclopramide has been of some help. Effect is short time. Tardive dyskinesia and extrapyramidal effects occur

Continued : 

117 Continued Erythromycin bind to motilin receptor- helps in gastric emptying Refractory diarrhea loperamide 4-8mg or diphenoxylate with atropine provide relief Codeine also given in severe cases Constipation responds to laxative –senna Bethanechol 10-50 mg three times occasionally respond. Catheter decompression Hypotension a) elastic stocking. b) mineralocorticoid therapy- help

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118 Management of erectile dysfunction (Medical, mechanical and surgical treatment available) Cyclic 3, 5-Guanosine MonoPhosphate (cGMP)-specific phosphodiesterase type 5 inhibitors impair the breakdown of cGMP and improve function Sildenafil (Viagra), Vardenafil and Tadalafil shown to improve the function in response to sexual stimulation Sildenafil 50-100 mg and Vardenafil and Tadalafil-10 mg. headache, flushing, dyspepsia are side effects Priapism (if errection persist seek medical advice) Not to given if patient is on nitrates (potentiate). Ppt hypotension Caution IHD, STROKE, AF. Can develop VISUAL LOSS

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119 CONTINUED Intracorporeal injection of vaso-active drugs Papaverrine, papaverine+ phentolamine and alprostadil (prostaglandin E1 ) External vacuum therapy Surgical implants

Slide 120: 

120 D. Cardiovascular complications Heart disease and Peripheral vascular disease Microangiopathy congestive cardiomyopathies Coronary heart disease 3 to 5 times more common and in women after menopausal risk is due to hyperglycemia, hyperlipidemia, abnormal platelet adhesion, coagulation factors, hypertension, oxidative stress and inflammation By use of Ramipril 25% risk lowered ACE inhibitors Aspirin 81 to 325 mg daily

Continued : 

121 Continued Peripheral vascular disease- Atherosclerosis is markedly accelerated in the larger arteries, enhanced at bifurcation of larger vessels Prevention injury, no tobacco, no propranolol Ischemia, impotence and intestinal angina Gangrene of the feet Factors responsible Peripheral vascular disease- Peripheral neuropathy Loss of inflammatory response Secondary infection

Skin and mucous membrane : 

122 Skin and mucous membrane Pyogenic infection Eruptive xanthoma Necrobiosis lipoidica diabeticorum are oval or irregularly shaped plaques with shining surface Situated over anterior part of leg or dorsal surface of ankle Brownish, rounded, painless atrophic lesions of the skin called ‘shin spots’ Candidal infection produce erythema & edema over skin folds Vulvovaginitis

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123 Claw toes

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124 Prominent metatarsal heads and an ulcer

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125 Callus on planter surface

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126 Bunion on medial border of foot

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Slide 128: 

128 Charcot feet

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129 Nail deformity

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130 Neuropathic ulcer

Slide 131: 

131 Infected ulcer

F. Special situations. 1. surgery : 

132 F. Special situations. 1. surgery A prospective trial studies in surgical ICU patient reported that aggressive treatment of hyperglycemia reduces mortality and morbidity Keeping blood glucose values close to 100 mg/dL is advised in surgical and medical ICUs Patient when discharged target glucose values between 100mg/dL and 180mg/dL is appropriate Regular insulin 25 units in 250 mL normal saline is infused at the rate of 1-3/units/ hour Blood sugar monitored every 30 minutes and insulin dose adjusted Minor surgical problem if controlled with OHA insulin generally not required. Sugar monitored. Avoid iv sugar

During pregnancy : 

133 During pregnancy Tight control with normal HbA1c is very important Poor control Increases the risk of abortion Congenital malformation Polyhydramnios Preterm labor Still births Macrosomia

Slide 134: 

134 Increases maternal and fetal mortality & morbidity Retinopathy and preexisting retinopathy worsens Microalbuminuria – risk for preeclampsia Irreversible kidney failure during surgery if patient is in renal failure Gaastroparesis exacerbate nausea and vomiting It is better to control DM with insulin

Slide 135: 

135 Thank you Thank you

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