1. The Obesity/Diabetes Epidemic: Adiposopathy & Obesity- The New Disease! Dx & (Rx) of Insulin Resistance & early DM Part 4 Stan Schwartz MD, FACP, FACE Private Practice, Ardmore Obesity Program Cardiometabolic Diabetes Center and Affiliate,

2. Obesity, IRS, Type 2 Diabetes and Atherosclerotic Disease Obesity carries with it increase CV Risk Factors Risk factors for macrovascular disease accrue before the diagnosis of diabetes as > 50% of patients with newly diagnosed Type 2 diabetes have pre- existing cardiovascular disease. 2-4 fold > risk of ASVD in diabetic vs. normal patients Cardiovascular disease causes 80% of all diabetic mortality- 75% coronary, 25% cerebral vascular l Type 2 diabetes is associated with an increased risk of morbidity and mortality from cerebrovascular disease versus the general population, and > HgA1c, >risk

3. Outline Epidemiology and Economics of obesity/diabetes Perspectives on Obesity Consequences of Obesity, Prediabetes, Obesity Obesity/ Diabetes Risk Factors, Obesity/ Diabetes Onset can be Prevented or Delayed – Early Risk Identification and Intervention. Medical Benefits to Weight Loss Treatment-CDC’s diabetes prevention program and other Evidence-Based Interventions- –Basics, –Next Lecture in Series

4. Obesity leads to Prediabetes and Diabetes Mellitus-Type 2

5. Each unit increase in BMI (about 2.7 - 3.6 kg) increases Type 2 diabetes risk by 12.1 percent 68 - 72 % of diabetes risk in the U.S. is attributable to or associated with excess weight For every kilogram increase in weight over 10 years, Type 2 diabetes risk increases 4.5 % Ford et al. Amer J Epidemiol 146:214,1997

6. Relationship Between BMI and Risk of Type 2 Diabetes Mellitus Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. Age-Adjusted Relative Risk Body Mass Index (kg/m 2 ) <23 24–24.9 25–26.927–28.933–34.9 0 25 50 75 100 1.0 2.9 4.3 5.0 8.1 15.8 27.6 40.3 54.0 93.2 <22 23–23.9 29–30.931–32.9 35+ 1.0 1.5 2.2 4.4 6.7 11.6 21.3 42.1 1.0 Men Women

7. Obesity, Insulin Resistance, Metabolic Syndrome and the Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia Microvascular Complications DEATH pp>7.8mM

8. Genes that Cause or are Associated with Diabetes Insulin action Insulin receptor PPARG Obesity FTO MCR4 Insulin Secretion Neonatal KCNJ11/Kir6.2 ABCC8/Sur1 Insulin MODYHNF-1α,1β, 4 α Glucokinase PDX1/IPF1 Neurod1/Beta2 KLF11 CEL Mitochondrial diabetes Type 2 CDKAL1 TCF7L2 HHEX/IDE SLC30A8/ZNT8 WFS1 NOTCH2-ADAM30 Unknown IGFBP2 CDKN2A/B KIF11 JAZF1 CDC123-CAMK1D TSPAN8-LGR5 THADA ADAMTS9 NOTCH-ADAM30 PHENOTYPE- eg: age of presentation, IFG/ IGT/Both/ severity depends on number of which kind of genes a person inherits – GENOTYPE Modified from McCarthy, NEJM 363:24,2339.

9. Obesity, Insulin Resistance, Metabolic Syndrome and the Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia Microvascular Complications DEATH pp>7.8

10. ‘Ominous Octet: Pathophysiological Contributions to Hyperglycemia in Type 2 Diabetes 5.Gut carbohydrate absorption Peripheral glucose uptake Hepatic glucose production -- - 1.Pancreatic insulin secretion 2.Pancreatic glucagon secretion HYPERGLYCEMIA 6.Fat- increased lipolysis, inc FFA 7.Brain- Inc. Appetite Insulin Resistance, Decrease, GLP-1 8.Kidney- 3.Muscle 4.Liver ? ‘Nonet’- Gut Biome

11. Type 2 Diabetes: Two Principal Defects; Overview Reaven GM. Physiol Rev. 1995;75:473-486 Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127. Insulin resistance- lipotoxicity  -cell dysfunction/ Failure; dec. mass ± Environment± IFGIGT Genes Type 2 diabetes Glucose Toxicity Glucose Toxicity hepatic peripheral Abn. first 1 st & 2nd Interactions will NOT occur if B-cells not genetically predisposed