Part 5. Insulin Resistance and  -Cell Dysfunction: Summary Individuals with impaired glucose tolerance –Are maximally or near-maximally insulin resistant.

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Part 5

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%

Pathogenesis of Diabetes Evolving Concepts

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

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 Insulin Secretion Time (minutes) 1st Phase2nd Phase i.v. Glucose Diabetes Normal glucose tolerance Insulin Secretion Adapted from Weyer C, et al. J Clin Invest. 1999;104: ; Ward WK, et al. Diabetes Care. 1984;7:

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

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

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

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

 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: IncreasedLipolysis

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: 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