1. Part 5

2. Insulin Resistance and  -Cell Dysfunction: Summary Individuals with impaired glucose tolerance –Are maximally or near-maximally insulin resistant –Have lost ~80% of their  -cell function –Have an incidence of diabetic retinopathy of ~10%

3. Pathogenesis of Diabetes Evolving Concepts

4. Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

5. Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Time (minutes) 1st Phase2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5-5 -10-10 051010 1515 2020 2525 3030 3535 4040 4545 50505 6060 6565 7070 7575 8080 8585 9090 100100 9595 Insulin Secretion Time (minutes) 1st Phase2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5-1005101520253035404550556065707580859010095 Insulin Secretion Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.

6. Pathogenesis of Type 2 Diabetes Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

7. DeFronzo RA, et al. Metabolism. 1989;38:387-395. Pathogenesis of Type 2 Diabetes Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Basal HGP (mg/kg min) FPG (mg/dL) 2.0 2.5 3.0 3.5 4.0 100200300 r = 0.85 P<0.001 Control T2DM

8. Pathogenesis of Type 2 Diabetes Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

9. The Disharmonious Quartet Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake ↑ FFA IncreasedLipolysis FFA=free fatty acids.

10.  FACoA  Gluconeogenesis  Glucose Utilization  Lipolysis  Plasma FFA  HGP Role of Free Fatty Acids Hyperglycemia  HGP Muscle Liver FACoA=FFA-derived long-chain acyl-CoA esters. Boden G. Proc Assoc Am Physicians. 1999;111:241-248. IncreasedLipolysis

11. Free Fatty Acids Impair  -Cell Function *Percent difference between lipid infusion and saline infusion in subjects with family history of T2DM. Kashyap S, et al. Diabetes. 2003;52:2461-2474. Δ C-peptide Concentration (%)* First PhaseSecond Phase Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM P<0.001 P<0.04