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The Metabolic Syndrome

The Metabolic Syndrome. Miriam Cnop, MD PhD Division of Endocrinology and Laboratory of Experimental Medicine Université Libre de Bruxelles. Metabolic Syndrome. Clustering of cardiovascular risk factors Central obesity Diabetes Hypertension Dyslipidemia.

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The Metabolic Syndrome

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  1. The Metabolic Syndrome Miriam Cnop, MD PhD Division of Endocrinology and Laboratory of Experimental Medicine Université Libre de Bruxelles

  2. Metabolic Syndrome • Clustering of cardiovascular risk factors • Central obesity • Diabetes • Hypertension • Dyslipidemia

  3. AlsoknownasThe Dysmetabolic SyndromeThe Insulin Resistance SyndromeDeadly quartet

  4. Firstreport • The degree of masculine differentiation to obesity: a factor determining predisposition to diabetes, atherosclerosis, gout and uric calculus disease. (Vague Am J Clin Nutr 4:20, 1956)

  5. Prevalence of the Metabolic Syndrome • National Health and Nutrition Examination Survey III • (US 1988-1994) • Adults > 20 yrs: 24% • > 60 yrs: 44% (Ford et al. JAMA 287:356, 2002)

  6. Global Epidemic • Body Mass Index = weight (kg)/[height (m)]2

  7. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1985 (*BMI ≥30) (Behavioral Risk Factor Surveillance System, Centers for Disease Control)

  8. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1986 (*BMI ≥30)

  9. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1987 (*BMI ≥30)

  10. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1988 (*BMI ≥30)

  11. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1989 (*BMI ≥30)

  12. No Data <10% 10%–14% Obesity Trends* Among U.S. Adults1990 (*BMI ≥30)

  13. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1991 (*BMI ≥30)

  14. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1992 (*BMI ≥30)

  15. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1993 (*BMI ≥30)

  16. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1994 (*BMI ≥30)

  17. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1995 (*BMI ≥30)

  18. No Data <10% 10%–14% 15%–19% Obesity Trends* Among U.S. Adults1996 (*BMI ≥30)

  19. No Data <10% 10%–14% 15%–19% ≥20 Obesity Trends* Among U.S. Adults1997 (*BMI ≥30)

  20. No Data <10% 10%–14% 15%–19% ≥20 Obesity Trends* Among U.S. Adults1998 (*BMI ≥30)

  21. No Data <10% 10%–14% 15%–19% ≥20 Obesity Trends* Among U.S. Adults1999 (*BMI ≥30)

  22. No Data <10% 10%–14% 15%–19% ≥20 Obesity Trends* Among U.S. Adults2000 (*BMI ≥30)

  23. Obesity Trends* Among U.S. Adults2001 (*BMI ≥30) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

  24. Obesity Trends* Among U.S. Adults2002 (*BMI ≥30) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

  25. Obesity Trends* Among U.S. Adults2003 (*BMI ≥30) No Data <10% 10%–14% 15%–19% 20%–24% ≥25% Source: Behavioral Risk Factor Surveillance System, CDC

  26. Predicted evolution of BMI distribution 20th century 21st century (AM Prentice Br Med Bull 53:229, 1997)

  27. Pathogenesis of obesity • Many people enjoy the opportunity of eating more than they need with little requirement for physical exertion. (Pinkney et al. Lancet 357:1357, 2001)

  28. Body fat mass is the result of energy balance • Obesity = chronic imbalance between • caloric intake and expenditure • Obesity = chronic imbalance between • caloric intake and expenditure • Obesity = chronic imbalance between • caloricintake and expenditure • The US food industry produces 3800 kcal/person/day whereas the average requirement is 2000 kcal/day. • 3 to 5-y-old UK children spend only 2% of their time in moderate to vigorous physical activity. Their total energy expenditure was 200 kcal/day lower than the estimated requirement. (Reilly et al. Lancet 363:211, 2004)

  29. (Photograph Howard Berman 1990)

  30. Environmental and genetic factors determine insulin sensitivity • Insulin resistance = decreased ability of peripheral tissues to respond properly to normal circulating concentrations of insulin • Variability in insulin sensitivity is accounted for by: • Adiposity 25-30% • Physical fitness 25-30% • Genetic factors 40-50%

  31. (Zimmet et al. J Intern Med 254:114, 2003)

  32. Definition: World Health Organization (1999) • Type 2 diabetes • Impaired Glucose Tolerance • (2h glucose 140-199 mg/dl) • Insulin Resistance • At least 1 of • + • At least 2 of • Obesity BMI>30 kg/m2 • Waist/hip >0.90 (M) • >0.85 (F) • Hypertension (>140/90 mm Hg) • Dyslipidemia (high TG, low HDL) • Microalbuminuria

  33. Definition:National Cholesterol Education Program (2001) • At least 3 of • Abdominal obesity: waist circumference > 102 cm (M) • > 88 cm (F) • Hypertriglyceridemia > 150 mg/dl • Low HDL cholesterol < 40 mg/dl (M) • < 50 mg/dl (F) • Hypertension (> 130/85 mm Hg) • Impaired Fasting Glucose or Type 2 diabetes (> 100 mg/dl) (ATP III. JAMA 285:2486, 2001)

  34. Pathogenesis of the Metabolic Syndrome Type 2 Diabetes Insulin Resistance Central obesity Dyslipidemia Hypertension

  35. Assessment of Insulin Sensitivity • Gold Standard: Hyperinsulinemic clamp Glucose Infusion Rate 8 120 120 Glycemia 100 6 80 80 60 4 Insulinemia 40 40 2 20 0 0 30 60 90 120 15 30 45 60 75 90 105 120 (Cnop and Fery; Unpublished data)

  36. Assessment of Insulin Sensitivity • Fasting insulin • Homeostasis Model Assessment HOMA IR • Insulin (mU/ml) x Glucose (mmol/l) / 22.5 • Quantitative Insulin Sensitivity Check Index QUICKY • 1/[log Insulin (mU/ml) + log Glucose (mg/dl)] • Oral Glucose Tolerance Test • Intravenous Glucose Tolerance Test IVGTT

  37. Relationship between BMI and insulin sensitivity • 174 healthy, normoglycemic subjects • 73 M and 101 F • age 52.5±0.7 yrs • Determine BMI and quantify the insulin sensitivity index (SI) using Bergman’s minimal model

  38. Insulin sensitivity in healthylean and obese subjects 30 20 SI (x10-5 min -1/pM) 10 0 15 20 25 30 35 40 45 BMI (kg/m2) (Cnop et al. Diabetes 51:1005, 2002)

  39. Role of body fat distribution • Normal • Type 2 diabetes

  40. Question • Do lean insulin sensitive, lean insulin resistant, and obese insulin resistant subjects have similar abdominal fat distribution?

  41. Body Mass Index and Insulin Sensitivity **,ˆ 30 10 7.5 20 SI (x10-5 min-1/pM) ** BMI (kg/m2) 5 **,ˆ 10 2.5 0 0 LIS LIR OIR LIS LIR OIR (Cnop et al. Diabetes 51:1005, 2002)

  42. Intra-Abdominal and Subcutaneous Fat Areas **,ˆ **,ˆ 300 150 ** IAF area (cm2) 200 100 ** SCF area (cm2) 100 50 0 0 LIS LIR OIR LIS LIR OIR (Cnop et al. Diabetes 51:1005, 2002)

  43. Summary • Compared to lean insulin sensitive subjects, lean insulin resistant and obese insulin resistant subjects have: • increased intra-abdominal fat area • increased subcutaneous fat area • Whereas the BMI of the 2 lean groups did not differ, LIR subjects had 50% more abdominal fat.

  44. Question • Is insulin resistance associated with a particular fat depot?

  45. Intra-abdominal fat is highly predictive ofinsulin sensitivity 30 20 10 0 0 100 200 300 400 Intra-abdominal fat area (cm2) 3 r = -0.688 2 SI (x10-5 min -1/pM) Loge SI 1 0 -1 2.0 3.0 4.0 5.0 6.0 Loge Intra-abdominal fat area (Cnop et al. Diabetes 51:1005, 2002)

  46. 30 20 10 0 0 100 200 300 400 Intra-abdominal fat area (cm2) Intra-abdominal fat is highly predictive ofinsulin sensitivity SI (x10-5 min -1/pM)

  47. Summary • Insulin • Resistance

  48. Insulin • Resistance Adipose tissue: an endocrine organ •  FFA •  Fat •  TNFaIL-6, Leptin, Resistin • Adiponectin

  49. Relationship between leptin andsubcutaneous fat 60 50 40 30 20 10 0 0 200 400 600 800 70 60 50 Leptin (ng/ml) r = 0.783 40 30 20 r = 0.754 10 0 0 200 400 600 800 Subcutaneous fat area (cm2) Subcutaneous fat area (cm2) (Cnop et al. Diabetes 51:1005, 2002)

  50. Relationship between adiponectin andintra-abdominal fat 20 20 15 15 Adiponectin (mg/ml) r=-0.218 10 10 r=-0.362 5 5 0 0 0 100 200 300 400 0 100 200 300 400 Intra-abdominal fat area (cm2) Intra-abdominal fat area (cm2) (Cnop et al. Diabetologia 46:459, 2003)

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