Why all the controversy about the metabolic syndrome

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Why all the controversy about the metabolic
syndrome?
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Metabolic Syndrome
High LDL
Type 2 Diabetes
Coronary Heart Disease
U.S. NCEP ATP III
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What are unresolved questions about the MetS?
(Kahn et al. 2005)

• Metabolic syndrome name?
• Existence of metabolic syndrome?
• More than some of its parts?
• MetS vs. prediabetes type 2 diabetes
• Diagnostic utility?
• Pathogenesis?
• Clinical utility?

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Is the metabolic syndromea syndrome?

• A collection of things
• Clustering of signs and symptoms
• Three or more related entities

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What should the metabolic syndrome be called?

• Plurametabolic syndrome (Crepaldi)
• Syndrome X (Reaven)
• Deadly Quartet (Kaplan)
• Metabolic syndrome (WHO NCEP IDF)
• Insulin resistance syndrome (EGIR AACE)
• Dysmetabolic syndrome
• Cardiometabolic syndrome
• CHAOS (Australia)

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What is the metabolic syndrome?

• Clustering of
• Metabolic Risk Factors (3)
• Atherogenic dyslipidemia
• Elevated blood pressure
• Elevated plasma glucose
• Prothrombotic state
• Proinflammatory state

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Do metabolic risk factors really cluster?

• Girman et al. Hoorn sudy. Am J Epidemiol.
  2005162438-47
• Goodman et al. Princeton School District Study
  Circulation. 20051111970
• Yudkin et al. HIFMECH Study. Metab.
  200453852-7.
• Hodge et al. Mauritius Study. Int J Obes Relat
  Metab Disord. 200125126-31.
• Ang et al. Singapore National Health Survey.
  Diabetes Res Clin Pract. 20056753-62.
• Hanley et al. The Insulin Resistance
  Atherosclerosis Study. Diabetes. 2002512642-7.
  

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Cluster or Constellation
ATP III/IDF
Elevated Plasma Glucose
Atherogenic Dyslipidemia
Pro- inflammatory State
Elevated Blood Pressure
Pro- thrombotic State
ADA/EASD
Prediabetes
Atherogenic Dyslipidemia
Pro- inflammatory State
Elevated Blood Pressure
Pro- thrombotic State
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What are the clinical outcomes of the metabolic
syndrome?

• Cardiovascular disease
• Relative risk 2x
• Type 2 diabetes
• Relative risk 5x
• Fatty liver
• Obstructive sleep apnea
• Cholesterol gallstone
• Polycystic ovarian disease

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What is the relation of metabolic syndrome to
hyperglycemia?
Metabolic Overlap 78 of prediabetes
patients have MetS 86 of T2DM patients have
MetS
Metabolic Syndrome
Prediabetes
Type 2 Diabetes
Microvascular Disease
Macrovascular Disease
Should metabolic syndrome, prediabetes and type
2 diabetes be merged into a single condition?
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How do metabolic risk factors increase risk?
Type 2 Diabetes
Cardio- vascular Disease
Atherogenic Dyslipidemia Elevated Blood
Pressure Elevated Plasma Glucose Prothrombotic
State Proinflammatory State
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Two Views of the Metabolic Syndrome
Metabolic Syndrome (MetS)
Insulin Resistance
Pre- Diabetes (75 MetS)
Type2 Diabetes (86 MetS)
Cardiovascular Disease
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The Big Debate

• What are the
• causes
• of the
• metabolic syndrome?

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What are the contributing causes of the
metabolic syndrome?

• Obesity
• - Esp. abdominal obesity
• Insulin resistance
• Physical inactivity
• Advancing age
• Endocrine dysfunction
• Genetic factors

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(No Transcript)
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How does obesity contribute to MetS?
Adipose Tissue
?NEFA
? Angioten- sinogen
? Cytokines (TNF? IL-6)
? Resistin
? Leptin
?Adiponectin
? PAI-1
Metabolic Risk Factors
Pro- inflammatory State
Atherogenic Dyslipidemia
Pro- thrombotic State
Elevated Blood Pressure
Elevated Glucose
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What is the contribution of insulin resistance?

• Insulin resistance of adipose tissue increased
  release of NEFA and other adipokines adipose
  tissue inflammation lower adiponectin
• Insulin resistance of muscle decreased hepatic
  uptake of glucose diversion of NEFA to the liver
• Insulin resistance of liver increased hepatic
  glucose output increased production of VLDL-TG
  increased synthesis of hepatic lipase
• Insulin resistance of other tissues vascular
  endothelium, kidney, brain, and heart
• Insulin resistance vs. hyperinsulinemia

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What is the relation of insulin resistance to
metabolic syndrome?
Insulin Resistance
Cortico- steroids
Obesity
Aging
Physical Inactivity
Multiple Metabolic Risk Factors
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Physical Inactivity
Adipose Tissue Disorders
Obesity
Generalized Metabolic Derangement (Insulin
Resistance)
Genetic Insulin Resistance
Race and Ethnicity
Genetics Ethnicity
Endocrine Dysfunction
Drugs
Multiple Metabolic Risk Factors
Risk Factor Specific Metabolic Derangement
Ethnic and Individual Variation
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What is Cardiometabolic Risk?
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Cardiometabolic Risk (J.P Despres)
? Insulin
Visceral obesity
Insulin resistance
? ApoB Dense LDL
? TG ? HDL
Dyslipidemic states not related to MS
Age Male sex
Hypertension
Inflam- mation
Smoking
Diabetes
METABOLIC SYNDROME
IFG
LDL
HDL
Thromb- osis
? BP

GLOBAL CARDIOMETABOLIC RISK
Diabetes
Cardiovascular disease
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Cardiometabolic Risk (ADA MCR Initiative)
? Insulin
Visceral obesity
Insulin resistance
? ApoB Dense LDL
? TG ? HDL
?LDL
Age Male sex
Insulin Resistance Syndrome
Hyper tension
Smoking
Diabetes
Inflam- mation
?HDL
IFG
Thromb- osis
? BP

GLOBAL CARDIOMETABOLIC RISK
Diabetes
Cardiovascular disease
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Cardiometabolic Risk Risk for Cardiovascular and
Metabolic Diseases

• Cardiovascular Diseases
• Coronary heart disease
• Stroke
• Peripheral arterial disease
• Congestive heart failure
• Chronic renal disease
• Atrial fibrillation

• Metabolic Diseases
• Diabetes
• Prediabetes
• Non-alcoholic fatty liver
• Cholesterol gallstone
• Polycystic ovarian syndrome
• Obstructive sleep apnea

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Other Causes
Metabolic Derangement
Obesity
Metabolic Disease Diabetes Prediabetes Fatty
liver disease Cholesterol gallstones Polycystic
ovarian syndrome Obstructive sleep apnea
Cardiovascular Disease Coronary heart
disease Stroke Peripheral arterial
disease Congestive heart failure Chronic renal
disease Arrhythmia
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Metabolic SyndromeInterested Disciplines

• Cardiovascular
• Lipids, hypertension, thrombosis
• Diabetes
• Epidemiology
• Gastroenterology
• Neurology/sleep disorders
• Endocrinology
• Pediatrics
• Immunology/inflammation