THE METABOLIC SYNDROME A Reversible LifeThreatening Condition

1
THE METABOLICSYNDROMEA Reversible
Life-Threatening Condition

• The Main Threat
• To Human Health
• For The Next Decade?

2
Metabolic Syndrome

• A Multidimensional
• Risk Condition

3
The Emerging Threat of Cardiovascular Disease

• Cardiovascular disease will be the number one
  killer in the world in the 21st century
• Increase due to rising prevalence of risk factors
• Cigarette smoking
• Obesity
• Metabolic syndrome
• Type 2 diabetes

4
Cardiovascular Risk Factors An Evolving
Landscape
5
Increased Energy Density of Food
Standard food portions have increased over the
last 20 years
20 years ago 210 calories 500
calories 333 calories
Today 610 calories 850 calories 590
calories
6
Metabolic Syndrome Definition

• Clustering of Multiple
• Metabolic Risk Factors
• Atherogenic dyslipidaemia
• Elevated blood pressure
• Elevated plasma glucose
• Prothrombotic state
• Proinflammatory state

7
What Is The Metabolic Syndrome?
The concept has existed for more than 80 years
8
The Metabolic Syndrome An Evolving Concept
9
Obesity, Type 2 Diabetes, and Metabolic
Syndrome 3 Interrelated Epidemics
Overweight/Obesity a worldwide epidemic

• gt1 billion adults worldwide were
• - Overweight in 2002 1 - BMIgt25 kg/m2

• At least 300 million are clinically obese 2
• - BMIgt30 kg/m2

1- World Health Organization. Global strategy on
diet, physical activity and health,
2003. Available at http//www.who.int/hpr/NPH/doc
s/gs_obesity.pdf. Accessed November 11, 2003. 2-
International Obesity Task Force. Available at
http//www.iotf.org. Accessed November 13, 2003.

10
Latest Overweight and Obesity Rates
The Economist, December 13-19, 2003.
11
Latest Overweight and Obesity Rates
The Economist, December 13-19, 2003.
12
Global Projections for the Diabetes
Epidemic2003-2025
2003 2025
M million, AFR Africa, NA North America,
EUR Europe, SACA South and Central America,
EMME Eastern Mediterranean and Middle East,
SEA South-East Asia, WP Western
Pacific Diabetes Atlas Committee. Diabetes Atlas
2nd Edition IDF 2003.
13
Obesity and Type 2 Diabetes are Interrelated
Epidemics

• Global epidemic of overweight, obesity and
  diabetes

Mokdad, et al. Diabetes Care. 200023(9)1278-1283
. Mokdad, et al. JAMA. 2000286(10)1195-1200.
14
The Metabolic Syndrome Is A Metabolic Time Bomb

• With the elevated risk of diabetes
  andcardiovascular disease from the metabolic
  syndrome, there is an urgent need for strategies
  to defuse this metabolic time bomb

15
Metabolic Syndrome Dual Pathways Dual Outcomes
16
Insulin Resistance Multisystem Disorder

• Adipose tissue
• Increased NEFA and adipokine release
• Muscle
• Decreased glucose disposal
• Liver
• Increased gluconeogenesis and hepatic glucose
  output
• Endothelium
• Endothelial dysfunction

17
From Intra-abdominal Obesity To Insulin
Resistance

• Overabundance of circulating fatty acids a major
  contributor to the development of insulin
  resistance
• Increases in subcutaneous fat release fatty acids
  into the systemic circulation
• Intra-abdominal obesity increases the flux of
  adipose tissue-derived free fatty acids to the
  liver. In the liver, fatty acids exert direct
  effects on
• Glucose production
• Lipid synthesis
• Secretion of prothrombotic proteins

18
How Does Abdominal Obesity Cause Insulin
Resistance

Reduced Physical Activity
Excessive food intake
insulin receptor Substrate (IRS-1 IRS-2)
Inflammation
? IL-6
Genetic factors
? TNF-??
? various cytokines
adiponectin ?
ABDOMINAL OBESITY
Insulin resistance
? leptin
Hormones
? blood FFA
19
Candidate Genes for the Metabolic
SyndromeInsulin Receptor Substrate (IRS)
Kubota T, et al. Circulation 20031073073-3080.
20
Metabolic Concomitants of Insulin Resistance

• Atherogenic dyslipidaemia
• High TG/HDL-C ratio
• Higher blood pressure
• Hyperinsulinaemia and dysglycaemia
• Prothrombotic and proinflammatory states
• Endothelial dysfunction and microalbuminuria
• Fatty liver

21
Atherogenic Dyslipidaemia
22
Insulin Resistance of Abdominal Adipose Tissue
and Atherogenic Dyslipidaemia
Liver
?FFA
CE
(?HL)
? TG ? Apo B
?HD2
(CETP)
?VLDL
HDL3
Insulin Resistant Abdominal Adipocytes
TG
Apo A-1
(CETP)
TG
CE
Kidney
LDL

• small, Dense
• LDL

LDL
(? HL)
23
Underlying Risk Factors of the Metabolic Syndrome

• Overweight/obesity (esp. abdominal obesity)
• Insulin resistance
• Additional underlying factors
• Physical inactivity
• Aging
• Endocrine dysfunction
• Genetic factors

24
2005 Revised ATP III Clinical Screening Criteria
to Identify Metabolic Syndrome (AHA and NHLBI)
25
Diagnosis of The Metabolic SyndromeIDF CRITERIA
(2005)

• Central obesity (defined as waist circumference
  ?94 cm for Europid men and ?80 cm for Europid
  women, with ethnicity specific values for other
  groups)
• Plus any two of the following four factors
• TG ?150 mg/dl (1.7 mmol/l), or specific treatment
  for this lipid abnormality
• HDL lt40 mg/l (1.03 mmol/l) in males and lt50 mg/l
  (1.29 mmol/l) in females, or specific treatment
  for this lipid abnormality
• Systolic BP ?130 or diastolic BP ?85 mmHg, or
  treatment of previously diagnosed hypertension
• Fasting plasma glucose ?100 mg/dl (5.6 mmol/l),
  or previously diagnosed type 2 diabetes. If above
  5.6 mmol/l or 100 mg/dl, OGTT is strongly
  recommended but is not necessary to define
  presence of the syndrome

26
Diagnosis of The Metabolic SyndromeIDF CRITERIA
(2005)
Ethnic-specific cut-points for waist circumference
27
Diagnosis of The Metabolic SyndromeIDF CRITERIA
(2005)
Ethnic-specific cut-points for waist circumference
28
Prevalence of Central Obesity in Singapore
Tan CE, et al. Diabetes Care 2004.
29
C-Reactive Protein andMetabolic Syndrome
Ridker et al. Circulation. 2003107391.
30
Non-HDL Cholesterol andApolipoprotein B
31
Non-obese, Caucasian Off-spring of Parents with
Type 2 Diabetes

• Higher fasting NEFA
• Lower insulin sensitivity
• High NEFA ? low insulin sensitivity
• Defective insulin secretion
• Conclusions alterations in NEFA metabolism key
  to pathogenesis of type 2 diabetes
• Perseghin et al. Diabetes 1997461001-9.

Perseghin et al. Diabetes 1997461001-9.
32
NHANES II CVD Mortality Rates in US Adults with
Metabolic Syndrome and CVD
CVD Mortality
Adapted from Malik et al. Circulation 2004
1101245-1250.
33
Abdominal Obesity andInsulin Resistance

• Increased adipose tissue compartments
• Intra-abdominal fat (visceral fat)
• Abdominal subcutaneous fat
• Products of abdominal adipose tissue causing
  insulin resistance
• Excess free fatty acid release
• Adiponectin
• Inflammatory cytokines