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Part 5

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.

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Part 5

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  1. Part 5

  2. Insulin Resistance and -CellDysfunction: 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 Impaired Insulin Secretion Islet b-cell Increased HGP Decreased Glucose Uptake HGP=hepatic glucose production.

  5. Pathogenesis of Type 2 Diabetes Diabetes Normal glucose tolerance Diabetes Normal glucose tolerance Insulin Secretion Impaired Insulin Secretion 1st Phase 2nd Phase -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Time (minutes) i.v.Glucose Insulin Secretion 1st Phase 2nd Phase Islet b-cell Increased HGP -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Time (minutes) i.v.Glucose Decreased Glucose Uptake Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502. HGP=hepatic glucose production.

  6. Pathogenesis of Type 2 Diabetes Impaired Insulin Secretion Islet b-cell Increased HGP Decreased Glucose Uptake

  7. Pathogenesis of Type 2 Diabetes Control Control 4.0 4.0 T2DM T2DM 3.5 3.5 Impaired Insulin Secretion r=0.85P<0.001 r = 0.85P<0.001 Basal HGP(mg/kg • min) Basal HGP(mg/kg• min) 3.0 3.0 2.5 2.5 2.0 2.0 Islet b-cell Increased HGP 100 200 300 100 200 300 FPG (mg/dL) FPG (mg/dL) Decreased Glucose Uptake DeFronzo RA, et al. Metabolism. 1989;38:387-395.

  8. Pathogenesis of Type 2 Diabetes Impaired Insulin Secretion Islet b-cell Increased HGP Decreased Glucose Uptake

  9. The Disharmonious Quartet Impaired Insulin Secretion ↑ FFA Increased Lipolysis Islet b-cell Increased HGP Decreased Glucose Uptake FFA=free fatty acids.

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

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

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