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Two very different types of diabetes: 

Two very different types of diabetes • TYPE I ('childhood') • Autoimmune destruction of the insulin- producing pancreatic islet cells • Requires lifetime administration of insulin • TYPE II ('Adult onset') • Associated with insulin resistance, obesity • Treated initially by weight loss, exercise, drugs

Evolution favors predisposition toward obesity (thrifty genotype): 

Evolution favors predisposition toward obesity (thrifty genotype)

The United States is a large country: 

The United States is a large country 1995 2003

Obesity Trends* Among U.S. AdultsBRFSS, 1985: 

Obesity Trends* Among U.S. Adults BRFSS, 1985 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1986: 

Obesity Trends* Among U.S. Adults BRFSS, 1986 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1987: 

Obesity Trends* Among U.S. Adults BRFSS, 1987 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1988: 

Obesity Trends* Among U.S. Adults BRFSS, 1988 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1989: 

Obesity Trends* Among U.S. Adults BRFSS, 1989 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1990: 

Obesity Trends* Among U.S. Adults BRFSS, 1990 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1991: 

Obesity Trends* Among U.S. Adults BRFSS, 1991 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1992: 

Obesity Trends* Among U.S. Adults BRFSS, 1992 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1993: 

Obesity Trends* Among U.S. Adults BRFSS, 1993 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1994: 

Obesity Trends* Among U.S. Adults BRFSS, 1994 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1995: 

Obesity Trends* Among U.S. Adults BRFSS, 1995 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1996: 

Obesity Trends* Among U.S. Adults BRFSS, 1996 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1997: 

Obesity Trends* Among U.S. Adults BRFSS, 1997 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1998: 

Obesity Trends* Among U.S. Adults BRFSS, 1998 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 1999: 

Obesity Trends* Among U.S. Adults BRFSS, 1999 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 2000: 

Obesity Trends* Among U.S. Adults BRFSS, 2000 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsBRFSS, 2001: 

Obesity Trends* Among U.S. Adults BRFSS, 2001 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

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Source: Mokdad et al., Diabetes Care 2000;23:1278-83. Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1990

Slide22: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1993-94 Source: Mokdad et al., Diabetes Care 2000;23:1278-83.

Slide23: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1995-96 Source: Mokdad et al., Diabetes Care 2000;23:1278-83.

Slide24: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1995 Source: Mokdad et al., Diabetes Care 2000;23:1278-83.

Slide25: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1997-98 Source: Mokdad et al., Diabetes Care 2000;23:1278-83.

Slide26: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 1999 Source: Mokdad et al., Diabetes Care 2001;24:412.

Slide27: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 2000 Source: Mokdad et al., J Am Med Assoc 2001;286:10.

Slide28: 

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS 2001 Source: Mokdad et al., J Am Med Assoc 2001;286:10.

Insulin is the principal regulator of blood sugar (glucose) levels: 

Blood Glucose Liver Muscle (fat) Islet cells of the Pancreas Insulin Inhibits glucose production Enhances glucose uptake Insulin is the principal regulator of blood sugar (glucose) levels Secretion triggered by rise in blood glucose

Glucose transport (GLUT) protein:Catalyzed “downhill” movement of glucose into or out of a cell. : 

Glucose transport (GLUT) protein: Catalyzed 'downhill' movement of glucose into or out of a cell.

Insulin regulates glucose uptake by altering the distribution of GLUT4 within the fat and muscle cell.: 

Insulin regulates glucose uptake by altering the distribution of GLUT4 within the fat and muscle cell.

Insulin resistance often leads to diabetes: 

Insulin resistance often leads to diabetes • Insulin production by the pancreas, in response to reduction in blood glucose, initially is normal • But muscle responds less than normal to insulin in taking up glucose from the blood • And liver does not respond normally to insulin by reducing production of glucose from small molecules. • Net result is an elevation in the level of glucose in the blood.

Type II Diabetes Mellitus and Obesity: 

Type II Diabetes Mellitus and Obesity Most diabetic patients are also obese. Insulin resistance, a hallmark and a cause of type II diabetes, and obesity are part of the metabolic syndrome (also known as Syndrome X). Syndrome X also includes hypertension and atherosclerotic disease.

Adipose tissue: a producer of many important hormones that regulate sugar and fat metabolism: 

Adipose tissue: a producer of many important hormones that regulate sugar and fat metabolism • Tumor necrosis factor-a (TNF- a) • Leptin • Acrp30/Adiponectin • Resistin

Acrp30/ Adiponectin - A Major Adipocyte- Specific Hormone: 

Acrp30/ Adiponectin - A Major Adipocyte- Specific Hormone • Enhances uptake of glucose from the blood by muscle • Enhances muscle 'burning' of fatty acids and glucose for energy • Inhibits glucose production by liver • Causes weight reduction in obese mice fed a cafeteria diet • Linked genetically to development of Type II diabetes • Reduced levels in serum correlated with obesity and diabetes

Slide36: 

Electron micrographs of Acrp30/ adiponectin 142 Å

Slide37: 

Acrp30/ adiponectin enhances fatty acid oxidation in isolated muscle 4 0 4 5 5 0 5 5 6 0 6 5 7 0 Oleate oxidation (nmol/g) EDL 2.5µg ACRP30 p = 0.03 p = 0.04 control control Soleus 2.5µg ACRP30

Slide38: 

0 2 4 6 8 µg glycogen/mg protein Control Acrp30 Insulin Insulin + Acrp30 Insulin and Acrp30/ adiponectin stimulate glycogen accumulation in differentiated C2C12 muscle cells * pandlt;0.05 vs. Control † pandlt;0.05 vs. Insulin * † *

Slide39: 

AMP- activated protein kinase (AMPK): a cellular 'fuel gauge' Hardie

Slide40: 

Functions of Acetyl CoA carboxylase (ACC) Acetyl CoA Malanoyl CoA ACC1 (adipose, liver) Cytosolic ACC2 (muscle, heart, liver) Associate with CPT-1 Malanoyl CoA Use to synthesize fatty acids, triglycerides, phospholipids, cholesterol, etc. Allosteric inhibitor of CPT-1 Inhibit fatty acid oxidation AMPK

Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/ adiponectin for 30 min. led to two-fold increases in AMPK activity and phosphorylation of AMPK on Thr 172 and acetyl CoA carboxylase (ACC) on Ser-79. : 

MALONYL CoA CONCENTRATION P- ACC P-AMPK AMPK ACRP30: - + Pandlt; 0.05 AMPK ACTIVITY Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/ adiponectin for 30 min. led to two-fold increases in AMPK activity and phosphorylation of AMPK on Thr 172 and acetyl CoA carboxylase (ACC) on Ser-79. Pandlt; 0.05

Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/Adiponectin (2.5 µg/ml) for 30 minutes activates both AMPK and ACC phosphorylation: 

Acrp30 trimer: - + min: 30 15 5 p44/42 MAPKinase pAMPK pACC p38 MAPKinase Acrp30 trimer: - + min: 30 15 5 pACC pAMPK p38 MAPKinase E.Coli Acrp30 Mammalian Acrp30 Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/Adiponectin (2.5 µg/ml) for 30 minutes activates both AMPK and ACC phosphorylation

Slide43: 

Human APM1 (Acrp30/Adiponectin): quantitation by ELISA Arita Y., et al BBRC 1999, 257, 79-83

APM1 (Acrp30) is decreased in individuals with type II diabetes and coronary artery disease: 

APM1 (Acrp30) is decreased in individuals with type II diabetes and coronary artery disease Nondiabetic Diabetic Diabetic with coronary     artery disease Hotta et al., Arterioscler. Thromb. Vasc. Biol., June 2000, 1595-1599 12 10 8 6 4 2 0 pandlt;0.001 pandlt;0.001 pandlt;0.001 pandlt;0.001 Men Women Plasma APM1 (g/ml)

Fat tissue from obese mice or humans is resistant to insulin: 

Fat tissue from obese mice or humans is resistant to insulin • Reduced response to insulin in taking up glucose from blood • Reduced levels of the insulin receptor, many other cellular proteins necessary for insulin function • Reduced production of adiponection WHY ??

Why is fat tissue from obese mice or humans is resistant to insulin?: 

Why is fat tissue from obese mice or humans is resistant to insulin? • Adipose (fat) tissue is invaded by macrophages • Macrophages produce nasty inflammatory hormones such as Tumor Necrosis Factor alpha (TNF-a) and Interleukin 1 (IL-1). • TNF-a and IL-1 induce insulin resistance in adipose (fat) cells.

Physiological Relevance of TNF-a: 

Physiological Relevance of TNF-a TNF-a is highly induced in adipose tissues of obese animals and human subjects TNF-a induces insulin resistance both in cell culture and in experimental animals The absence of either TNF-a or its receptors improves the action of insulin in mice

The Role of TNF-a in Inducing Insulin Resistance: 

The Role of TNF-a in Inducing Insulin Resistance • Autocrine (local action): • Blocks expression of many adipocyte genes important for insulin action and triglyceride (storage fat) synthesis • Endocrine (action on muscle and liver): • Blocks synthesis and secretion of Acrp30/ adiponectin • Causes lipolysis (conversion of storage fat to fatty acids), increased serum free fatty acids

TNF-a treatment of adipocytes leadsto downregulation of GLUT4 glucose transporter and Acrp30/ adiponectin messenger RNAs: 

TNF-a treatment of adipocytes leads to downregulation of GLUT4 glucose transporter and Acrp30/ adiponectin messenger RNAs Insulin TNF-a Insulin + TNF-a Messenger RNA level ACRP30/ adiponectin GLUT4 Control

TNF- administration to rats leads to induction of insulin resistance: insulin tolerance test: 

TNF- administration to rats leads to induction of insulin resistance: insulin tolerance test Ruan et. al. Diabetes 51 (11): 3176-3188 , 2002 * * * * * * n Saline O TNF-a

Slide51: 

AMPK- a cellular 'fuel gauge' Hardie