Obesity, Metabolic Syndrome, and Diabetes: Making the Connections

Transcription

1 Obesity, Metabolic Syndrome, and Diabetes: Making the Connections Alka M. Kanaya, M.D. Associate Professor of Medicine & Epi/Biostats University of California, San Francisco February 26, 21 Roadmap 1. Prevalence & Pathogenesis 2. Metabolically normal Obesity 3. Fat Distribution 4. Metabolic Syndrome Adult Overweight Prevalence Diabetes Prevalence, Oxford Health Alliance 7 2 Percent with Diabetes Percent with Diabetes Number with Diabetes Numer with Diabetes (Millions) Year CDC, 28 1

2 U.S. Adults with Obesity or Diabetes Pathogenesis of DM Obesity (BMI 3 kg/m 2 ) Complex disorder: Insulin resistance Β-cell dysfunction No Data <14.% % % % >26.% Diabetes GWAS studies: (mostly European populations) Found mostly genes for β-cell or insulin secretory defects few genetic clues for insulin resistance No Data <4.5% % % % >9.% Insulin Resistance Etiology of T2DM Definition: Change in physiologic regulation, when a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. Recognized since 193 s Still don t know the exact mechanism Bergman,

3 Adipose Tissue Distribution Normal Glucose Tolerance Pre-diabetes Impaired Glucose Tolerance (IGT) Impaired Fasting Glucose (IFG) Type 2 Diabetes Fat Depots: Subcutaneous: 6-7% Intra-abdominal: 15-25% Visceral (or intraperitoneal) Retroperitoneal (5%) Intramuscular: 5-1% Linked with diabetes and atherosclerosis since 194 s Visceral Fat Visceral Fat distribution Déspres, Quebec 3

4 Metabolically Normal Obesity Weight, kg Waist, cm Body fat, % Fatty liver, % Fast. Glucose HOMA-IR HDL, mg/dl Triglycerides Normal weight Overweight Obese Ins Sens Obese Ins Res Stefan, Arch Int Med, 28 Intramyocellular Fat Subcutaneous Fat, kg Liver Fat, kg Visceral Fat, kg Normal OW Ob-IS Ob-IR Normal OW Ob-IS Ob-IR Stefan, 28 Metabolically Normal Obesity Adipose Tissue Overflow Hypothesis Insulin Sensitivity Carotid IMT, mm Subcutaneous depot can only store a set amount Excess fat is deposited in visceral depot and inside organs (liver, muscle, pancreas, heart, endothelium) Metabolically benign obesity exists (2-25% of obese individuals) High liver fat distinguished metabolically benign from abnormal obesity.better than visceral fat Recruitment of lipids in nonadipocytes to store fat cause lipotoxicity & lipoapoptosis lean body mass destruction 4

5 Ethnic differences in fat dist. Coexistence of Obesity, Diabetes, and MS Latinos and Asians are more prone to visceral obesity African Americans and Whites develop less visceral obesity A.A. have more subcutaneous fat stores than Whites Obesity T2 DM Metabolic Syndrome The Metabolic Syndrome Six Definitions Also known as: WHO 1998 EGIR 1999 NCEP 21 AACE 23 IDF 25 AHA 25 Syndrome X Glucose Insulin Resistance Syndrome The Deadly Quartet The Dysmetabolic syndrome Glucose Intolerance, Diabetes Visceral Obesity Dyslipidemia Hypertension HDL TG BP Waist Other: Ins. Ualb Ins. Many more 5

6 Harmonization of Guidelines Fulfill 3 criteria: Waist: population-specific criteria HDL: <4 for men,<5 for women (or niacin or fibrate use) Triglycerides: 15 mg/dl (or niacin or fibrate use) BP: 13/ 85 (or BP med use) Fasting glucose: 1 mg/dl (or use of diabetes med) Alberti, Circ, 29 Waist criterion MEN WOMEN White, European 12 (94) 88 (8) Asian 9 (85) 8 (9) Middle East, Mediter Sub-Saharan Africa 94 8 Central & South Amer. 9 8 Alberti, Circ, 29 Prevalence of Met Syn MS Prevalence Men 6 5 Women Total Men Women 4 % AHA/NHBLI IDF-revised Ford, CDC, 29 Black White Mex. Am Park, Arch Int Med, 23 6

7 Prevalence by BMI Pathophysiology 6 6 % Normal Weight Overweight Obese Insulin Resistance Third Factor? Visceral/Ectopic Fat Men Women Park, Arch Int Med, 23 Why is visceral fat so bad? What adipose secretes FFA Fat Cells Kopelmen, 2 Hormones Leptin Cortisol Estradiol Lipoproteins LPL CETP Apo E PLTP Peptides Adiponectin PAI-1 Angiotensinogen Agouti Resistin Complement Factors Adipsin C3 Adipose Tissue Cytokines TNFα IL-6 Growth Factors TGF-ß IGF-1 VEGF 7

8 Proposed Mechanism Summary Reduced Thrombolysis PAI-1 Vascular Inflammation IL-6 & TNF-α Visceral Adipose tissue FFA Resistin & Adiponectin Insulin Resistance Dyslipidemia Hypertension CVD Twin pandemics-obesity and diabetes Metabolically normal obesity exists Ectopic fat deposition and adipocytokines may explain this risk Metabolic syndrome useful clinical way of determining those at high risk Rosenson, 25 8