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Diabetes Mellitus 101 for Medical Professionals

Diabetes Mellitus 101 for Medical Professionals. An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes :. Part 3. Stanley Schwartz MD, FACE, FACP Emeritus, Clinical Associate Professor of Medicine University of Pennsylvania

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Diabetes Mellitus 101 for Medical Professionals

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  1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Part 3 Stanley Schwartz MD, FACE, FACP Emeritus, Clinical Associate Professor of Medicine University of Pennsylvania Affiliate, Main Line Health System Wynnewood, Pa.

  2. Treatment of Type 2 Diabetes:Pathophysiology

  3. Natural History of Type 2 Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunctionPCO,ED Disability Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type II DM  Beta Cell Secretion BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

  4. Prevention Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Disability Obesity(visceral) Poor Diet Inactivity IR PhenotypeAtherosclerosisObesityHypertensionHDL,TG, HYPERINSULINEMIA Endothelial DysfunctionPCO,ED Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type 2 DM  -Cell Secretion BlindnessAmputationCRF EyeNerveKidney ETOHBPSmoking Risk of Complications Disability Microvascular Complications

  5. 70 62% Finnish 58% 58% 60 55% Da Qing – Diet + Exercise 50 42% 41% DPP-Lifestyle 40 Diabetes Mellitus Reduction (%) 31% DPP-Metformin 30 25% STOP-NIDDM 20 TRIPOD XENDOS 10 DREAM 0 Diabetes Prevention Clinical Trials Is it Possible to Delay the Onset of Type 2 DM? 55% PIOPOD FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50 DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44 DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403 STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77 TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803 XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61 DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:1096-1105

  6. Alter the Natural History of Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Disability Obesity(visceral) Poor Diet Inactivity IR PhenotypeAtherosclerosisObesityHypertensionHDL,TG, HYPERINSULINEMIA Endothelial DysfunctionPCO,ED Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type 2 DM  -Cell Secretion BlindnessAmputationCRF EyeNerveKidney ETOHBPSmoking Risk of Complications Disability Microvascular Complications

  7. ADOPT: Treatment effect on primary outcome N = 4351 Hazard ratio (95% CI) Rosiglitazone vs metformin, 0.68 (0.55–0.85), P < 0.001 Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P < 0.001 40 Glyburide 30 Cumulative incidence of mono-therapy failure*(%) Metformin 20 Rosiglitazone 10 0 0 1 2 3 4 5 Years *Time to FPG >180mg/dL Kahn SE et al. N Engl J Med. 2006;355:2427-43.

  8. Exenatide: Sustained A1cReductions Mean  A1c (%) Time (wk) 0 10 20 30 40 50 60 70 80 90 0.5 Baseline A1C 8.3% Placebo BID (N = 128) Exenatide 5 mcg BID (N = 128) Exenatide 10 mcg BID (N = 137) 0.0 8.3% 8.3% -0.5 -1.0 -1.5 -2.0 Open-Label Extension Placebo-Controlled Trials Kendall D, et al. American Diabetes Association Scientific Sessions. June 2005

  9. Natural History of Type 2 Diabetes-Insulin Resistance Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL, TG Endothelial dysfunctionPCO Disability Insulin Resistance MICVAAmp DEATH IGT Type II DM  Beta Cell Secretion d.ec 1st phase Inc 2nd phase BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

  10. Metformin Advantages Improves insulin resistance in liver High initial response rate Effective, 2% HbA1c (1% with extended-release metformin) No initial weight gain or modest weight loss (UKPDS) Advantageous lipid profile No hypoglycemia when used alone or with TZD, incretins Potential to delay or prevent DM and progression, but secondary failure is = SU Decreases MIs (39% UKPDS obese subgroup,retrospective analysis) Decreases AGEs, improved endothelial dysfunction Cheap

  11. Metformin Disadvantages GI side effects on initiation Hold after radiologic studies using intravascular iodinated contrast media until Cr stable Risk of lactic acidosis: Don’t use if… Cr >1.4 female, >1.5 male Cr Clearance <70 (age >70), blood levels increase Cr Clearance <40, lactic acidosis cases seen Impaired hepatic function (CHF not a contr-indication any more) Don’t order metformin as admit to hospital

  12. The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß-Cell Dysfunction Atherothrombosis Liver Artery CRP, PAI-1 FFA, TNFa, IL-6 Angiotensinogen, PAI-1 FFA, TNFa Obesity IR Diabetes ASVD Adiponectin Adiponectin FFA Resistin, TNFa Visceral fat cells Leptin Sns FFA, TNFa, Leptin Muscle Brain Pancreas

  13. Pleotrophic Effects of PIOGLITAZONE: Modifying The Adipocytokine Syndrome: A Model Relating Obesity, Insulin Resistance and ß-Cell Dysfunction and ASCVD Reduce Atherosclerotic Risk Factors Liver: ↓Insulin resistance ↓Atherothrombosis ↓CRP, PAI-1 ↓ FFA, TNFa, IL-6 Angiotensinogen, PAI-1 et al ↓FFA, TNFa ↑Adiponectin Improves peripheral Insulin Resistance in ↑Adiponectin PIOGLITAZONE ↓ FFA resistin, TNFa Muscle ↓Size, Insulin Resistance in Visceral Fat cells ↓FFA, TNFa, Leptin Brain: Improve Satiety PANCREAS:Improve beta cell function

  14. TZD MECHANISM OF ACTION Effect of Meds on Fat Topography Direct PPAR effect on vascular cells to decrease endothelial dysfunction and inflammation IR, TG, FFA Insulin, BP, Inflam. En Dys. IR, TG, FFA Insulin, BP Inflam. En Dys. TZD Intra-muscular fat Subcutaneousfat Intra-abdominalfat Intra-hepatic fat

  15. HIGH LOW Coronary Heart Disease Risk Weight Gain: Subcutaneous Adipose Tissue: Reduced Visceral Fat Subcutaneous adipose tissue Visceral Adipose Tissue PPAR- Agonists -Pio- ViscerallyObese Obese HDL = high-density lipoprotein; LDL = low-density lipoprotein.

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