Metabolic syndrome

The Metabolic Syndrome: Complex Exposures

Blind Men Study the Elephant; artist: Liu Zhangde; granite; Wuhan; 1985

It was six men of It was six men of Indostan To learning Indostan To learning much inclined,much inclined,

Who went to see the Who went to see the Elephant (Though all Elephant (Though all of them were blind),of them were blind),

That each by That each by observation Might observation Might satisfy his mindsatisfy his mind

John Godfrey Saxe(1816-1887)

Origins of Obesity• Fetal origins of metabolic syndrome• Thrifty genotype hypothesis• Maladaptation to modern, post-industrial

life– High dietary energy availability– Sedentary life style

• Precursor to Metabolic syndrome

Environmental factorsEnvironmental factorsDietary factorsDietary factors

Obesity and Obesity and Chronic diseaseChronic disease

Secular trends in obesity

Adipokines or adipocytokines are cytokines secreted by adipose tissue (fat cells).

• Energy balance:– leptin (Ob ligand) – adiponectin

• Pro-coagulant– plasminogen activator inhibitor-1 (PAI-1)

• Inflammation– tumor necrosis factor-alpha (TNFα)

Metabolic Syndrome: A constellation of metabolic risk factors associated with risk of type 2 diabetes and risk of atherosclerotic cardiovascular disease.

– Abdominal obesity – Atherogenic dyslipidemia

• high triglycerides• low HDL cholesterol • high LDL cholesterol

– Hypertension – Insulin resistance– Prothrombotic state

• High fibrinogen or • High plasminogen activator inhibitor–1 (PAI-1)

– Proinflammatory state (elevated C-reactive protein)

History• 1988—Reaven, GM proposed Syndrome X

• 1998—World Health Organization proposed a formal definition of the Metabolic Syndrome

• 2001--National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) definition proposed

• 2005—Definitional debates, national and international consensus meetings

– American Heart Association/ National Heart Lung and Blood Institute (AHA/NHLBI)

– International Diabetes Federation (IDF)– European Association for the Study of Diabetes/ American Diabetes

Association (EASD/ADA)

Operational Definition

Reference: Kahn, R et al. Diabetes Care, 2005;28(9):2289-2304.

Criteria NCEP/ATP III World Health Organization (WHO)

Three or more of the following five criteria:

Presence of Diabetes, IFG, IGT, or insulin resistance (assessed by clamp studies) and at least two of the following criteria:

Central Obesity Waist Circumference >102 cm in men and >88 cm in women

Waist to hip ratio >0.9 in men or >0.85 in women

Dyslipidemia Serum Triglycerides >=1.7 mmol/l Serum Triglycerides >=1.7 mmol/l or HDL cholesterol <0.9 mmol/l in men and <1.0 mmol/l in women

HDL cholesterol <1.0 mmol/l in men and <1.3 mmol/l in women

Hypertension Blood pressure >=130/85 mmHg Blood pressure >=140/90 mmHg

Hyperglycemia Serum glucose >= 6.1 mmol/l (revised to >=5.6)

Other Urinary albumin excretion rate >20 micrograms/min or albumin to creatinine ratio >=30 mg/g

Reference: Ford ES et al. Diabetes Care, 2003:26;575-581.

Reference: Duncan GE et al. Diabetes Care, 2004: 27;2438-2443

Clustering• Epidemiologic research:

– Outcome / Dependent Variable

– Predictor / Independent Variables

• Two scenarios in chronic disease– Multiple risk factors for a

given disease– Multiple diseases due to a

given risk factor

Statistical Analysis– Multivariate Regression

Initial ModelInitial Model Final ModelFinal Model

Statistical Analysis– Factor Analysis

The objective of this study was to investigate, using factor analysis, the clustering of physiologic variables using data from 1,087

nondiabetic participants in the insulin Resistance Atherosclerosis

Study (IRAS).

From Hanley AJG, et al. Factor Analysis of Metabolic Syndrome Using Directly Measured Insulin Sensitivity. Diabetes 2002, 51: 2642-2647

Metabolic Syndrome

From Hanley AJG, et al. Factor Analysis of Metabolic Syndrome Using Directly Measured Insulin Sensitivity. Diabetes 2002, 51: 2642-2647

Table 4. Loadings of 13 Age-Adjusted Variables on the 4 Factors Rotated and Extracted With Factor Analysis*

Lakka, H.-M. et al. JAMA 2002;288:2709-2716.

Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based, prospective cohort study of 1209 Finnish men aged 42 to 60 years at baseline (1984-1989) who were initially without CVD, cancer, or diabetes.

Copyright restrictions may apply.

Lakka, H.-M. et al. JAMA 2002;288:2709-2716.

Unadjusted Kaplan-Meier Hazard Curves

Physiol Genomics. 2008; 35:55-64.Physiol Genomics. 2008; 35:55-64.