2. Natural History of Type 2 Diabetes Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota. ObesityIFG*DiabetesUncontrolled Hyperglycemia 50 100 150 200 250 300 350 50 100 150 200 250 Glucose (mg/dL) Relative Function (%) -10-5051015202530 Years of Diabetes Post-meal Glucose Fasting Glucose Insulin Resistance Insulin Level  -cell Failure *IFG = impaired fasting glucose

4. Natural History of T2DM OB-DIAB Lo INS LEANNGTOB-DIAB Hi INS OB-IGT OBNGT Insulin- Mediated Glucose Uptake (mg/m 2 min) 300250 200 150 100 DeFronzo & Felber Diabetes 37:667-687, 1988 Metabolism 39:1068-75, 1990 Mean Plasma Insulin During OGTT (µU/ml) Mean Plasma Glucose During OGTT (mg/dl) 140 100 60 20 400 300 200 100

5. Abnormal Insulin Secretion in T2DM Early responses during meals/OGTT First and second phase insulin responses Pulsatile insulin release Responses to non-glucose stimuli Proinsulin:insulin ratios

6. NATURAL HISTORY OF BETA CELL FAILURE IN T2DM Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated

7. DX DM 2% /yr decline 18%/yr decline Belfast Diet Study-Bi-phasic Loss of B-Cell FUNCTION Deteriorating beta-cell function in type 2 diabetes: a long-term model. Bagust A, Beale S. QJM. 2003 Apr;96(4):281-8

8. A model of long-term metabolic progression of type 2 diabetes mellitus for evaluating treatment strategies. Bagust A, Evans M, Beale S, Home PD, Perry AS, Stewart M. Pharmacoeconomics. 2006;24 Suppl 1:5-19.

12. Potential Causes of Beta Cell Dysfunction Unknown Genetic Factors Intrauterine Nutrition Glucose Toxicity Lipotoxicity Amyloid Cytokines Insulin Resistance

13. IGT <160 <180 <200 <160 <180 <200 IGT PLASMA GLUCOSE AND INSULIN AUC 0 4 8 12 Glucose AUC (mmol/L  120 min) 0 4 8 12 Insulin AUC (pmol/L  120 min) CON CON T2DM Q1 Q2 Q3Q4Q1Q2Q3Q4 T2DM

14. IGT <200 <160 <180 INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT 30 20 10 0 40 ∆ INS/ ∆ GLU ÷  IR Lean NGT <100 <120 <140 Obese 2-Hour PG (mg/dl)

15. 6 -4 0 -2 2 4 6. 5 4. 0 4. 5 5. 0 5. 5 6. 0 Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index Ln ∆I/ ∆G ÷  IR (ml/min kg FFM ) Ln 2h-PG (mg/dl) r = 0.91 p < 0.00001 T2DM IGT NGT

16. 6 -4 0 -2 2 4 6. 5 4. 0 4. 5 5. 0 5. 5 6. 0 Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index Ln ∆I/ ∆G ÷  IR (ml/min kg FFM ) Ln 2h-PG (mg/dl) r = 0.91 p < 0.00001 T2DM IGT NGT

17. FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH NGT, IFG, & T2DM Butler et al, Diabetes 52:102-110,2003 FPG (mg/dl) ß-cell Volume (%) 4 3 2 1 0 250 200 150 100 50 NGT IFG p<0.01 T2DM p<0.001

18. SUMMARY ● Are maximally/near-maximally insulin resistant ● Have lost ~80% of their beta cell function (DeFronzo) ● Have lost significant beta cell mass (Butler) ● Have an incidence of diabetic retinopathy of ~10% Individuals with IGT: