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Part 4

Part 4. Etiology of Type 2 Diabetes. Insulin Resistance and -Cell Dysfunction. Etiology of Type 2 Diabetes. Primary Predisposing Factors Genes Adverse intrauterine environment Tertiary Accelerating Factors Glucose and lipid toxicity. Secondary Precipitating Factors Obesity

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Part 4

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  1. Part 4

  2. Etiology of Type 2 Diabetes Insulin Resistance and -Cell Dysfunction

  3. Etiology of Type 2 Diabetes Primary Predisposing Factors Genes Adverse intrauterine environment Tertiary Accelerating Factors Glucose and lipid toxicity Secondary Precipitating Factors Obesity Low physical activity Age Smoking Sleep disturbance Other

  4. Type 2 Diabetes: A HeterogeneousDisorder Failing -cell Functional -cell Insulin resistance Insulin resistance Metabolic syndrome Hyperglycemia Heine RJ, Spijkerman AM. 2006.

  5. Type 2 Diabetes: Insulin Resistance Plus Impaired -Cell Function Normal-cell function Abnormal-cell function Relative insulin deficiency Compensatory hyperinsulinemia Hyperglycemia Normoglycemia (Metabolic syndrome) Type 2 diabetes Both insulin resistance and b-cell dysfunction are present at the time of diagnosis of type 2 diabetes Insulinresistance

  6. Natural History of Type 2 Diabetes 300 140 Insulin-MediatedGlucoseUptake(mg/m2 • min) 250 MeanPlasma InsulinDuring OGTT (µU/mL) 100 200 60 150 20 100 400 MeanPlasma GlucoseDuring OGTT (mg/dL) 300 200 100 OB NGT Lean NGT OB- IGT OB- DM Hi INS OB- DM Lo INS DM=diabetes mellitus; IGT=impaired glucose tolerance; INS=insulin; NGT=normal glucose tolerance; OB=obesity. DeFronzo RA.Diabetes. 1988;37:667-687; Jallut D, et al. Metabolism. 1990;39:1068-1075.

  7. Etiology of -Cell Dysfunction in Type 2 Diabetes Age Genetics (TCF 7L2) ↓ Incretin Effect Amyloid (Islet Amyloid Polypeptide) Deposition Insulin Resistance Lipotoxicity↑ Free Fatty Acids GlucoseToxicity -CellDysfunction

  8. Natural History of -Cell Dysfunction in Type 2 Diabetes β-Cell failure occurs muchearlier in the natural history of type 2 diabetes and is more severe than previously appreciated

  9. San Antonio Metabolism andVAGES Studies Normal glucose tolerance 318 Impaired glucose tolerance 259 Type 2 diabetes 201 Subjects Number Subjects were classified as Nonobese if BMI <30 kg/m2 Obese if BMI ≥30 kg/m2 Methods: OGTT and insulin clamp VAGES=Veterans Administration Genetic Epidemiology Study. Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435; Ferrannini E, et al. J Endocrinol Metab. 2005;90:493-500; Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

  10. Plasma Glucose and Insulin AUC Q2 Q3 Q4 Q3 Q4 Q2 Q1 Q1 <160 <180 <200 <200 <160 <180 IGT T2DM IGT T2DM NGT NGT 12 12 8 8 Glucose AUC (mmol/L  120 min) Insulin AUC (pmol/L  120 min) 4 4 0 0 Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

  11. Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT Lean Obese <140 <120 <160 <180 <100 <240 <200 <280 <320 <360 <400 >400 NGT IGT T2DM 40 30 ∆ I / ∆ G÷IR 20 10 0 2-Hour Plasma Glucose (mg/dL) G=glucose; I=insulin; IR=insulin resistance. Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

  12. Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index 6 NGT IGT 4 T2DM 2 Ln ∆I / ∆G÷ IR (mL/min • kgFFM) 0 -2 r=0.91 P<0.00001 -4 4.0 4.5 5.0 5.5 6.0 6.5 Ln 2-Hour Plasma Glucose (mg/dL) Ln=log normalization. Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

  13. GENFIEV: Insulin Secretion as a Function of Insulin Sensitivity Trend test P<0.001 Δ AUC C-peptide / Δ AUCGlucose ÷ HOMA-R 2-Hour Plasma Glucose(mg/dL) HOMA-R=homeostasis model assessment index ratio. Diabetes. 2006;55(suppl 2):A322.

  14. GeNFIEV: Stimulus-response Curve (Proportional Control) of Insulin Secretion GENFIEV: Stimulus-Response Curve(Proportional Control) of Insulin Secretion * Insulin Secretion Rate (pmol . min-1 . m-2) § # Plasma Glucose (mmol/L) *P<0.01 vs NFG/NGT; §P<0.05 vs NFG/IGT and IFG/NGT; #P<0.05 vs IFG/IGT and NFG/DGT. Diabetes. 2006;55(suppl 2):A2472.

  15. Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT Decrease in AIR Necessary to Convert From NGT to IGT Pima Indian Latino/Hispanic White Δ AIR (%) AIR=acute insulin response to glucose. Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139.

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