1. Metabolic Syndrome Dr. Hasan AYDIN

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

3. Definition

4. First report 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. Syndrome X Reaven 1988 –Insulin resistance –Glucose intolerance –Raised triglycerides –Low HDL cholesterol –Hypertension

6. The Metabolic Syndrome Proposed Definitions WHO Main criteria Insulin resistance OR DM / IGT / IFG Other components 1)Blood pressure ≥140/90 2)Dyslipidemia 3)Central obesity 4)Microalbuminura (two or more) ATPIII 1)Abdominal obesity 2)High triglycerides 3)Low HDL cholesterol 4)Blood pressure ≥130/85 5)High fasting glucose (three or more) EGIR Main criteria Insulin resistance Other components 1)Hyperglycemia 2) Blood pressure ≥140/90 3)Dyslipidemia 4)Central obesity (two or more)

7. NCEP ATP III Working Definition of the Metabolic Syndrome Risk factorsDefining Level Abdominal obesity (Waist circumference) Men>102 cm Women>88 cm Triglycerides≥150 mg/dl HDL cholesterol Men<40 mg/dl Women<50 mg/dl Blood pressure≥130/≥85 mmHg Fasting glucose≥110 mg/dl ≥3 of the following

8. Metabolic Syndrome increases with age Inter99 (n=6.784)

9. Prevalence in Turkey METSAR Study

10. Waist Measurements (cm) METSAR Study

11. Waist Measurements Age Groups METSAR Study

12. Abdominal Obesity METSAR Study

13. What causes metabolic syndrome? Genetic predisposition Ethnicity Lifestyle and culture of inactivity and obesity Aging

14. The Metabolic Syndrome Abdominal obesity Lipolysis FFA oxidation Insulin resistance VLDL Triglyceride HDL Hyperglycemia Hypertension Endothelial dysfunction Microalbuminuria Physical inactivity

15. Pathogenesis of MS Type 2 Diabetes Hypertension Dyslipidemia Central obesity Insulin Resistance

16. Environmental and genetic factors determine insulin sensitivity Variability in insulin sensitivity is accounted for by: Adiposity25-30% Physical fitness25-30% Genetic factors40-50% Insulin resistance = decreased ability of peripheral tissues to respond properly to normal circulating concentrations of insulin

17. Assessment of Insulin Sensitivity Gold Standard: Hyperinsulinemic clamp 0 2 4 6 8 153045607590105120 20 40 60 80 100 120 0306090120 40 80 120 Glycemia Insulinemia Glucose Infusion Rate

18. 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 (OGTT) Intravenous Glucose Tolerance Test (IVGTT)

19. Insulin sensitivity in healthy lean and obese subjects

20. Role of body fat distribution Normal Type 2 diabetes

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

22. Body Mass Index and Insulin Sensitivity 0 10 20 30 LISLIROIR BMI (kg/m 2 ) **,ˆ 0 2.5 5 7.5 10 LISLIROIR SI (x10 -5 min -1 /pM) **,ˆ ** (Cnop et al. Diabetes 51:1005, 2002)

23. S I (x10 -5 min -1 /pM) Intra-abdominal fat is highly predictive of insulin sensitivity

24. Adipose tissue: an endocrine organ  Fat  Adiponectin  FFA Insulin Resistance  TNF  IL-6, Leptin, Resistin

25. The Metabolic Syndrome Type 2 Diabetes Hypertension Dyslipidemia Central obesity Insulin Resistance

26. Type 2 Diabetes GeneticReactive Hypoglycemia Glucose Intolerance Preclinical Diabetes Early Clinical Diabetes Overt Diabetes Late Clinical Period Insulin Resistance Insulin Secretion Asymptomatic Period Symptomatic period

27. NFollow upDefinitionDevelopment of diabetes SAHS1,7347-8 yearsNCEPOR=3.3 Strong Heart study2,2837.8 yearsNCEP√ Kuopio (men only)1,0054 yearsWHO NCEP OR=8.0 OR=5.0 Mauritius2,6055 yearsOther√ Does the metabolic syndrome predict incident diabetes?

28. Resnick H et al. Diabetes Care 2003 Tertile of HOMA-IR Does hyperinsulinemia predict diabetes? Percent (%)

29. The Metabolic Syndrome Type 2 Diabetes Hypertension Dyslipidemia Central obesity Insulin Resistance

30. The Metabolic Syndrome and Hypertension Intra-abdominal adiposity and insulin resistance are associated with increased: – Sodium retention and sensitivity – Angiotensinogen and angiotensin II levels – Sympathetic activity – PAI-1 levels – Cortisol production in visceral fat compartment

31. Dyslipidemia and the Metabolic Syndrome VLDL IDL LDL buoyant dense HDL -10 -5 0 5 10  Cholesterol (mg/dl) Insulin Resistant Insulin Sensitive Adiponectin

32. NFollow upMenWomen Busselton339012 years√ns Helsinki Policemen9709.5 years√-- Helsinki Policemen97022 years√-- SAHS25698 years√√ DECODE6156 men125078.8 years√√ Does Hyperinsulinemia predict CVD?

33. Does MS predict CVD? ATP III metabolic syndrome Percent %

34. HRCHDCVDStrokeCHD - death CVD- death All-cause mortality Botnia Study, n=4,483 -- 2.962.632.27 Kuopio, (men) n=1,209 -- 3.322.81.8 DECODE, n=6,156 -- 2.26(m) 2.78(w) 1.44(m) 1.38(w) Trevisan,Italy n= 41,056 -- 3.01(m) 17.8(w) 2.49(m) 15.9(w) 1.95(m) 2.54(w) Strong Heart, n=2,283 --n.s.-- Does the metabolic syndrome predict CVD?

35. How Insulin Resistance leads to coronary disease Insulin resistance Environmental influences Genetic influences Hyperinsulinemia Glucose intolerance Increased triglycerides Decreased HDL Increased BP Small, dense LDL Increased uric acid Increased PAI-1 Coronary Artery Disease

36. NAFLD Oxidative stress Coagulopathy Inflammation Endothelial dysfunction Sleep apnea syndrome Polycystic ovary syndrome Heart failure Breast cancer Insulin Resistance Macrovascular Disease Obesity Hypertension Hyperglycemia Dyslipidemia Macrovascular Disease

37. Medical Evaluation of Metabolic Syndrome Physical Exam –Blood Pressure –BMI –Waist Circumference –Atheromas –Skin Tags Lab Evaluation –Fasting Glucose –Lipid –Homocysteine –hsCRP –Uric Acid –TSH –A1c –ALT –Creatinine

38. Treatment

39. Therapy for Insulin Resistance Nonpharmacologic / Pharmacologic Exercise Weight control Diet Smoking cessation

40. Modest Weight Loss Can Drastically Reduce Visseral Fat Before Weight Loss After 10 kg Weight Loss (95 kg, BMI 32) (85 kg, BMI 29)

41. NCEP/ATP III Guidelines Clinical Management of the Metabolic Syndrome Management of underlying cause –Weight control enhances LDL lowering and reduces all risk factors –Physical activity reduces VLDL, increases HDL, and may lower LDL Management of lipid and nonlipid risk factors –Treat hypertension –Use of aspirin in CHD patients –Treat elevated triglycerides and low HDL

42. Dietary Interventions Reduce calories Reduce saturated fat Increase whole grains Increase fruits and vegetables Eat fish 1-2 times per week Use monounsaturated or polyunsaturated oils –Olive, Canola, and Peanuts –Safflower, Sunflower or Sesame seed, Corn, or Soy

43. Exercise Interventions Goal for Patients: 240 minutes of purposeful activity per week Write exercise prescription 10,000 steps per day

44. Treatment: Lifestyle Finnish Diabetes Prevention Study STOP-NIDDM Trial US Diabetes Prevention Program 7% weight loss 150 min/week exercise Reduction of diabetes incidence by 60% Compared to 25-30% reduction for pharmacological intervention

45. Pharmacologic Management Aggressive Treatment of Hypertension –ACE Inhibitor is the drug of choice –Beta Blockers promote weight gain –Thiazide diuretics increase insulin resistance Metformin 500mg BID—diabetes prevention Lipid—Statin medication or combination Aspirin for Everyone!!! Excellent Candidates for Aggressive Weight loss intervention –Healthy Ways –Weight Loss Meds: Sibutramine, Orlistat –Aggressive Dietary Intervention: VLCD if BMI>27

46. Treatment: Drugs Underlying conditions (hypertension, diabetes, lipid disorders) should be treated. An aggressive and early treatment strategy has been proposed. Therapeutic agents might include fibrates, statins, metformin, thiazolidinediones, and, possibly, dual PPAR-  and  agonists. No consensus optimal treatment targets have been determined and pharmacotherapy remains at present unproven.

47. Does Treating the Metabolic Syndrome Make a Difference? Finnish Diabetes Prevention Study

49. Diabetes Prevention Program: Change of BMI – 1 year

50. Diabetes Prevention Program: Goal Achievement

51. Diabetes Prevented

52. In Summary—Be Aggressive! Identify patients with Metabolic Syndrome Aggressive Lifestyle Intervention Aggressive Pharmacologic Intervention –BP –Lipid –Metformin –Aspirin –Weight Loss Therapies

53. Thank youThank you