1. Clinical Presentation of Type 2 Diabetes 1

2. Risk Factors for Prediabetes and Type 2 Diabetes Family history of diabetes mellitus Cardiovascular disease Being overweight or obese Sedentary lifestyle Nonwhite ancestry Previously identified impaired glucose tolerance, impaired fasting glucose, and/or metabolic syndrome Hypertension Increased levels of triglycerides, low concentrations of high-density lipoprotein cholesterol, or both History of gestational diabetes mellitus Delivery of a baby weighing more than 4 kg (9 lb) Polycystic ovary syndrome Antipsychotic therapy for schizophrenia and/or severe bipolar disease 2 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

3. Development of Type 2 Diabetes Depends on Interplay Between Insulin Resistance and β-Cell Dysfunction Insulin resistance Abnormal β -Cell Function Relative insulin deficiency 3 Gerich JE. Mayo Clin Proc. 2003;78:447-456. Type 2 diabetes Normal β -Cell Function Compensatory hyperinsulinemia No diabetes Genes & environment

4. Etiology of β-cell Dysfunction Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366. 4 Genetic predisposition Lean phenotype Obese phenotype IGT, IFGElevated FFA Oxidative stress and glucotoxicity Cellular lipid synthesis and glucolipotoxicity Progressive  -cell failure and type 2 diabetes Initial glucolipoadaptation (increased FFA usage) Hyperglycemia Glucolipotoxicity and glucotoxicity

5. NGT=normal glucose tolerance; IGT=impaired glucose tolerance; EMBS=estimated metabolic body size. Weyer C et al. J Clin Invest. 1999;104:787-794. Progression to Type 2 Diabetes: “Falling Off the Curve” 5 0 100 20 0 300 400 500 012345 Glucose disposal (insulin sensitivity) (mg/kg EMBS/min) Acute insulin response (  U/mL) DIA IGT NGT Progressors NGT Nonprogressors

6. Pathophysiology of T2DM Organ SystemDefect Major Role Pancreatic beta cellsDecreased insulin secretion MuscleInefficient glucose uptake Liver Increased endogenous glucose secretion Contributing Role Adipose tissueIncreased FFA production Digestive tractDecreased incretin effect Pancreatic alpha cellsIncreased glucagon secretion KidneyIncreased glucose reabsorption Nervous systemNeurotransmitter dysfunction DeFronzo RA. Diabetes. 2009;58:773-795 6

7. Natural History of Type 2 Diabetes Figure courtesy of CADRE. Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25; Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258 Fasting glucose Type 2 diabetes Years from diagnosis 0 5 –10–5 10 15 Prediabetes Onset Diagnosis Postprandial glucose Macrovascular complications Microvascular complications Insulin resistance Insulin secretion  -Cell function Incretin effect 7

8. Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data. Data points from obese UKPDS population, determined by HOMA model. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. Type 2 Diabetes  -Cell Function (%) Years from Diagnosis 25 – 100 – 75 – 0 – 50 – l -12 l -10 l -6 l -2 l0l0 l2l2 l6l6 l 10 l 14 Impaired Glucose Tolerance Postprandial Hyperglycemia UKPDS:  -cell Loss Over Time 8

9. Müller WA, et al. N Engl J Med. 1970;283:109-115. Normal Glucose Homeostasis and Pre- and Postmeal Insulin and Glucagon Dynamics 9 PremealPostmeal  Insulin  Insulin  Glucagon  HGP  Glucagon  HGP Just enough glucose to meet metabolic needs between meals Modest postprandial increase with prompt return to fasting levels Glucose (mg %) Glucagon (pg/mL) Time (min) -60 060120180240 Meal 120 90 60 30 0 140 130 120 110 100 90 Insulin (µU/mL) 360 330 300 270 240 110 80 Normal (n=11)

10. PremealPostmeal  Insulin  Glucagon  HGP  Glucagon  HGP  FPG  PPG Hyperglycemia in Type 2 Diabetes Results from Abnormal Insulin and Glucagon Dynamics Glucose (mg %) Insulin (µU/mL) Glucagon (pg/mL) Time (min) -60 060120180240 Meal 120 90 60 30 0 140 130 120 110 100 90 360 330 300 270 T2DM (n=12) Normal (n=11) 240 110 80 10 Müller WA, et al. N Engl J Med. 1970;283:109-115.

11. Acute Insulin Response Is Reduced in Type 2 Diabetes IRI=immunoreactive insulin. Pfeifer MA, et al. Am J Med. 1981;70:579-588. Plasma IRI (µU/ml) Time (minutes) 20 g glucose infusion 2nd phase1st -30 0 20 40 60 80 100 0306090120 Normal (n=85) Type 2 diabetes (n=160) 11

12. Defective Insulin Action in T2DM Leg Glucose Uptake (mg/kg leg wt per min) Time (minutes) 0 P<0.01 12 180140100602020 8 4 0 Total Body Glucose Uptake (mg/kg min) T2DMNormal 0 7 6 5 4 3 2 1 DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155. 12

13. DeFronzo RA, et al. Metabolism. 1989;38:387-395. Elevated Fasting Glucose in Type 2 Diabetes Results From Increased HGP 13

14. Normal IFG/IGT Type 2 Diabetes Complications Disability Death Secondary prevention Secondary prevention 79,000,00025,800,000 Tertiary prevention Tertiary prevention Primary prevention Primary prevention Garber AJ, et al. Endocr Pract. 2008;14:933-46. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Type 2 Diabetes: A Progressive Disease 14

15. Summary: Hyperglycemia in Type 2 Diabetes Hyperglycemia results from the combination of –Pancreatic  -cell dysfunction, resulting in impaired insulin secretion –Increased hepatic glucose production due to excessive glucagon –Decreased peripheral glucose uptake due to insulin resistance 15 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.