Metabolic Syndrome: An overview. Kevin Niswender MD, PhD Vanderbilt University School of Medicine

Setting the scene GB, 43 yo AA man followed for hypothyroidism returns on LT4 125 mcg/d and has a TSH=1.1 mu/l. Weight has increased from 189-208 over the last 18 months. He is 5 10 (BMI=29); waist circumference is 42 ; BP=130/85 Fasting lipids: Tg = 178 mg/dl, HDL = 36 mg/dl, LDL =129 mg/dl, fasting glucose= 112 mg/dl

The response Physician: You need to lose weight Patient: You look overweight yourself. Why do I need to lose weight?

Cardiovascular risk: Framingham Sex Blood pressure Cholesterol Diabetes Smoking

Cardiovascular risk: Framingham Sex Blood pressure 1961 1961 Cholesterol Smoking 1960 1974 http://www.nhlbi.nih.gov/about/framingham/timeline.htm Diabetes 1991: Risk prediction model

Addressing Unaddressed classical risk: risk statins factors events (%) 30 25 20 15 10 LDL (mg/dl) 150 125 100 75 50 131 89 Statin 131 127 placebo 20-25% risk reduction Persistent risk 5 1 2 3 4 5 6 Years of follow-up Benefit/1000 (SE): 5(3) 20(4) 35(5) 46(5) 54(7) 60(18) Heart Protection Study, Lancet 2002

The evolving landscape

Cardiovascular disease: the landscape since Framingham 1985-2005 No Data <10% <10% 10% 14% 10% 14% 15% 19% 15% 19% 20% 24% 20% 24% 25-29% 30% 25% Mokdad et al., BRFSS CDC

Cardiovascular burden of obesity CVD deaths (thousands) 475 450 425 400 The new landscape 1990 1995 2000 2005 225 200 175 150 Diabetes Deaths (thousands) Source: NCHS and CDC

Why is obesity bad? Resistin Adiponectin The endocrine adipocyte. Bone Morphogenic Protein IGF-1 IGFBP TNF-α Interleukins TGF β FGF EGF Fatty Acids Lactate Adenosine Prostaglandins Glutamine Unknown Factors Estrogen Ang II Angiotensinogen Leptin PAI-1 Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S

Good fat bad fat?? Abdominal (Android) Lower Body (Gynoid)

Metabolic Syndrome Hypertension C-II C-III B-100 and Triglyceride VLDL HDL cholesterol Small dense LDL Glucose FFA Interleukin 6 Insulin Sympathetic nervous system C-reactive protein TNF Interleukin 6 Insulin Glycogen FFA FFA CO 2 Fibrinogen PAI-1 Adiponectin Eckel Lancet Prothrombic state Triglyceride (intramuscular droplet)

Metabolic syndrome Conceptualization An insulin resistance disorder An inflammatory disorder A prothrombotic disorder A controversial disorder Resulting in increased cardiometabolic risk

Metabolic Syndrome: ATP III 3 or more of the following: Central obesity as measured by waist circumference: Men Greater than or equal to 40 inches Women Greater than or equal to 35 inches Fasting blood triglycerides greater than or equal to 150 mg/dl Blood HDL cholesterol: Men Less than 40 mg/dl Women Less than 50 mg/dl Blood pressure greater than or equal to 130/85 mmhg Fasting glucose greater than or equal to 100 mg/dl

What is Cardiometabolic Risk? Beyond Framingham Type 2 Diabetes Elevated Blood Pressure Smoking Elevated LDL Elevated Blood Glucose Inflammatory Markers Abdominal Adiposity Elevated Triglycerides Low HDL Insulin Resistance CVD

Does metabolic syndrome increase morbidity or mortality? prevalence (%) 25 20 15 10 5 15 10 5 mortality (%)20 0 stroke MI CHD 0 all cause CHD without metabolic syndrome with metabolic syndrome WHO criteria, Botnia cohort, Isomaa, Diabetes Care 2001

Obesity correlates with (and we are learning, causes): Insulin resistance Hypertension Dyslipidemia Diabetes Inflammation Impaired fibrinolysis

Increased adiposity yields insulin resistance and risk of diabetes (dramatically) body weight (kg) 100 90 80 70 60 plasma insulin (µu/ml) 400 300 200 100 blood glucose (mg/dl) 400 300 200 100 50 0 0 20 40 60 80 100 time (min) 0 0 20 40 60 80 100 time (min) Genuth, Ann. Int. Med. 1977

Visceral adiposity is correlated with peripheral insulin resistance Insulin-mediated glucose disposal (mg/kg lean body mass/min) 15 10 5 0 p<0.005 0 2 4 6 Visceral adipose tissue volume (L) Banerji MA et al. J Clin Endocrinol Metab. 1999;84:137-44.

Inherent risk: diabetes dyslipidemia 7-Year Incidence of Fatal/Nonfatal MI Nondiabetic Diabetic 50 40 P<0.001 WOW! P<0.001 45.0 Incidence (%) 30 20 10 0 3.5 18.8 20.2 n = 1304 n = 69 n = 890 n = 169 No DM, No MI n = 1304 No DM, MI n = 69 DM, No MI n = 890 DM, MI n = 169 Haffner SM et al. N Engl J Med. 1998;339:229-234.

Obesity and cardiometabolic risk GB, 43 yo AA man followed for hypothyroidism returns on LT4 125 mcg/d and has a TSH=1.1 mu/l. Weight has increased from 189-208 over the last 18 months. He is 5 10 (BMI=29); waist circumference is 42 ; BP=130/85 Fasting lipids: Tg = 178 mg/dl, HDL = 36 mg/dl, LDL =129 mg/dl, fasting glucose= 112 mg/dl

Obesity dyslipidemia Hypertension C-II C-III B-100 and Triglyceride VLDL HDL cholesterol Small dense LDL Glucose FFA Interleukin 6 Insulin Sympathetic nervous system C-reactive protein TNF Interleukin 6 Insulin Glycogen FFA FFA CO 2 Fibrinogen PAI-1 Adiponectin Eckel Lancet Prothrombic state Triglyceride (intramuscular droplet)

Obesity dyslipidemia Hypercholesterolemia Hypertriglyceridemia Low and abnormal HDL cholesterol Abnormal LDL cholesterol

Insulin resistance and hypertriglyceridemia Plasma TG (mg/dl) 625 500 400 300 200 100 r = 0.73 P < 0.0001 100 200 300 400 500 600 Insulin Response to Oral Glucose* * Total area under 3-hour response curve (mean of 2 tests). Olefsky JM et al. Am J Med. 1974;57:551-560.

Obesity dyslipidemia Insulin FFA Liver TG

Plasma insulin, triglycerides and ischemic heart disease Quebec Cardiovascular Study Odds Ratio 8.0 6.0 4.0 2.0 0.0 1.0 1.5 p=0.005 4.6 5.4 P=0.002 <12 12-15 >15 F-Insulin (µu/ml) Despres JP et al. N Engl J Med 1996;334:952-957. 6.7 P<0.001 p=0.001 5.3 Triglycerides >150 mg/dl <150 mg/dl

Obesity dyslipidemia Fat Cells FFA Liver CE IR X Insulin TG ApoB VLDL CE VLDL (CETP) TG (CETP) TG LDL HDL SD LDL (hepatic lipase) Apo A-1 Kidney (lipoprotein or hepatic lipase) Lipids online (Ginsberg)

Is hepatic VLDL production a therapeutic target? Increasingly triglycerides are recognized as a cardiovascular risk factor VA-HIT, Helsinki Heart, Physicians Health study, EPIC-Norfolk Diabetics: WHO MSVDD Elderly, known CAD: CARE

Obesity, hypertension, and fibrinolysis Muniyappa, Endocr. Rev. 28(5): 463.

Insulin Blood flow (shear stress) Acetylcholine Endothelial function PI3K pathway Vasodilation PI3K Anti-atherogenic enos BH 4 Endothelial cell P enos CaM Ca 2+ PGIS Thrombolysis Other effects? Prostacyclin NO Vascular smooth muscle cell Rask-Madsen. Nat. Clin. Pract. Endocrinol. Metab. 2007; 3:46-56.

enos and hypertension Pharmacological inhibition of enos (n=7): 109(5)/65(3) 133(9)/79(5) Carotid wall stiffness 9.8(1.2) 12.6(2.0) Sugawara et al., Hypertension Res. 30(5) 2007

Hyperglycemia Free fatty acids Angiotensin II Insulin Endothelial dysfunction enos BH 2 NOX O 2 NO PKC ONOO PI3K pathway Selective insulin resistance N enos PGIS uncoupling Prostacyclin Endothelial cell synthase nitrosylation Thromboxane MAPK pathway ET-1 ET-1 Angiotensin II Vasoconstriction Smooth muscle proliferation Pro-atherotic Vascular smooth muscle cell Rask-Madsen. Nat. Clin. Pract. Endocrinol. Metab. 2007; 3:46-56.

Coagulation and Fibrinolysis Coagulation Factors Fibrinogen Fibrin t-pa, Urokinase Plasminogen PAI-1 Plasmin Lp(a) Fibrinolysis Homocysteine Cysteine Glutathione Lipids Online (Wilson)

PAI-1 increases with BMI Skurk, Int. J. of Obesity 2004

Insulin resistance as the defining lesion of metabolic syndrome Tissue Insulin effect Resistance Mechanism Brain Reduce food intake Increased food intake NPY/POMC Liver Suppress HGP Hyperglycemia Glycogenolysis/ GNG Fat Inhibit lipolysis/tg lipolysis/inc FFA HSL Endothelium Vasodilation dysfunction / hypertension PI3K-eNOS

Why insulin (and glucose)? Norhammer et al., (Lancet 2002) prospectively studied 181 acute MIs with no prior diagnosis of diabetes: -31% IGT -35% diabetes

Conclusions Obesity is associated with: Insulin resistance Inflammation Impaired fibrinolysis And: Hypertension Dyslipidemia Diabetes Cardiovascular disease Mechanisms involved are increasingly coming to light