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Part 6

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  1. Part 6

  2. The Quintessential Quintet Impaired Insulin Secretion Islet b-cell Increased HGP Decreased Glucose Uptake DecreasedIncretin Effect Increased Lipolysis

  3. GLP-1 and GIP Responses in Type 2 Diabetes NGT IGT T2DM Postprandial GLP-1 Levels Are Decreased in Patients withIGT and T2DM GIP Levels AreIncreased in T2DM * * 20 100 P<0.01 * * * Meal * * * * 80 * 15 60 GIP (pmol/L) 10 GLP-1 (pmol/L) 40 * 5 20 0 0 240 0 60 120 180 -30 0 60 120 180 210 Time (min) Time (min) *P<0.05.GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Jones IR, et al. Diabetologia. 1989;32:668-677; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

  4. GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance P<0.00005 P<0.05 16 4 P<0.005 12 14 3 10 12 8 10 2 AUC1 GLP-1 (nmol/L · min) 8 6 AUC1 GIP (nmol/L · min) AUC1 Insulin (mU/mL · min) 1 6 4 4 2 0 2 0 -1 0 -2 Controls NGT IGT T2DM Controls NGT IGT T2DM Controls NGT IGT T2DM Vaag AA, et al. Eur J Endocrinol. 1996;135:425-432.

  5. The Setaceous Sextet Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Increased HGP Decreased Glucose Uptake DecreasedIncretin Effect Increased Lipolysis

  6. Pancreatic -Cells and -Cells inNormal Individuals Cabrera O, et al. PNAS. 2006;103:2334-2339; Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.

  7. Area of -Cells Is Increased inType 2 Diabetes P<0.05 -CellIslet Area(%) (n=10) (n=15) Clark A, et al. Diabetes Res. 1988;9:151-159.

  8. Basal Glucagon Levels and Basal HepaticGlucose Production in Type 2 Diabetes P<0.001 P<0.001 58% T2DM+ SRIF T2DM + SRIF 250 160 200 120 150 Plasma Glucagon (pg/mL) Basal HGP (mg/m2 • min) 80 100 40 50 44% 0 0 NGT T2DM NGT T2DM SRIF=somatostatin infusion. Baron A, et al. Diabetes. 1987;36:274-283.

  9. Hyperglucagonemia and Insulin-Mediated Glucose Metabolism Plasma Glucose (mmol/L) Plasma Insulin (mU/L) Plasma Glucagon (mU/L) Plasma FFA (mol/l) 0 24 48 hr 0 24 48 hr Del Prato S, et al. J Clin Invest. 1987;79:547-556.

  10. Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGT 100 r=0.72 P<0.0001 r=-0.62 P<0.001 90 80 70 Glucose Appearance (mmol/5 hr) 60 50 40 12 15 6 8 10 14 0 5 10 20 Peak Postprandial Plasma Glucose Level (mmol/L) Plasma Insulin:Glucagon Ratio Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese. Mitrakou A, et al. N Engl J Med. 1992;326:22-29.

  11. Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 Diabetes Type 2 diabetes (n=12) Normal subjects (n-=11) Meal 360 330 300 Glucose (mg %) 270 240 110 80 120 90 Insulin (µU/mL) 60 Delayed/depressed insulin response 30 0 140 130 Nonsuppressed glucagon 120 Glucagon (pg/mL) 110 100 90 -60 0 60 120 180 240 Time (min) Müller WA, et al. N Engl J Med. 1970;283:109-115.

  12. The Septicidal Septet Impaired Insulin Secretion Islet a-cell Increased Glucose Reabsorption Islet b-cell Increased HGP DecreasedIncretin Effect Increased Lipolysis Increased Glucagon Secretion Decreased Glucose Uptake

  13. Renal Glucose Reabsorption in Type 2 Diabetes • Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule • Renal glucose reabsorption is increased in type 2 diabetes • Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43.

  14. Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% 10% No Glucose