Metabolic Syndrome Dr. Hasan AYDIN

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

Definition

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)

Syndrome X Reaven 1988 –Insulin resistance –Glucose intolerance –Raised triglycerides –Low HDL cholesterol –Hypertension

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)

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

Metabolic Syndrome increases with age Inter99 (n=6.784)

Prevalence in Turkey METSAR Study

Waist Measurements (cm) METSAR Study

Waist Measurements Age Groups METSAR Study

Abdominal Obesity METSAR Study

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

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

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

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

Assessment of Insulin Sensitivity Gold Standard: Hyperinsulinemic clamp Glycemia Insulinemia Glucose Infusion Rate

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)

Insulin sensitivity in healthy lean and obese subjects

Role of body fat distribution Normal Type 2 diabetes

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

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

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

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

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

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

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

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

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

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

Dyslipidemia and the Metabolic Syndrome VLDL IDL LDL buoyant dense HDL  Cholesterol (mg/dl) Insulin Resistant Insulin Sensitive Adiponectin

NFollow upMenWomen Busselton years√ns Helsinki Policemen years√-- Helsinki Policemen97022 years√-- SAHS25698 years√√ DECODE6156 men years√√ Does Hyperinsulinemia predict CVD?

Does MS predict CVD? ATP III metabolic syndrome Percent %

HRCHDCVDStrokeCHD - death CVD- death All-cause mortality Botnia Study, n=4, Kuopio, (men) n=1, DECODE, n=6, (m) 2.78(w) 1.44(m) 1.38(w) Trevisan,Italy n= 41, (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?

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

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

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

Treatment

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

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

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

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

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

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

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

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.

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

Diabetes Prevention Program: Change of BMI – 1 year

Diabetes Prevention Program: Goal Achievement

Diabetes Prevented

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

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