“... good health is more than just exercise and diet. It’s really a point of view and a mental attitude you have about yourself.” ....Albert Schweitzer

1. The Metabolic Syndrome
The Lifestyle Disease
Dr Dharmendra Kumar
Dept of Physiology
AFMC, Pune
“... good health is more than just exercise and diet. It’s really a point of
view and a mental attitude you have about yourself.”
....Albert Schweitzer

2. Scope
• Introduction
• History
• Pathophysiology
• Recent advances
• Summary & conclusion
• Take home message
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3. Metabolic syndrome is also known as:
• Metabolic syndrome X
• Insulin resistance syndrome
• Visceral fat syndrome
• Multiple risk factor clustering syndrome
• Cardiometabolic syndrome
• Obesity dyslipidemia syndrome
• Reaven's syndrome (named for Dr. Gerald Reaven)
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4. Introduction
• Metabolic syndrome is a cluster of metabolic risk factors
• Strongly responsible for excess of CVD morbidity among overweight
and Obese patients and those with Type-2 DM.
• Simple concept :
• Most dangerous risk factors for CVD & Type-2 DM
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5. Introduction
Globally:
• The NHANES 1999-2002 database shows Overall prevalence 34.5%
• Risk
- 2 times mortality
- 3 times- CVD or stroke
- 5-7 times- diabetes type 2
• Prevalence increases with weight.
• 5% of normal weight, 22% of overweight, and 60% of obese
• Gained significant importance recently
• NCEP-ATP III
• An independent risk factor for CVD
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6. History
• 250 ys ago , Morgagni : visceral fat and HTN, Atherosclerosis
• First World War- metabolic abnormalities, relation b/w DM &HTN
• 1920- word clustering, risk factors associated with diabetes
• 1930-1950- non-communicable disease era
• 1947: French Jean Vague-. Central obesity, excess fat--metabolic complications
• Various term:
• 1950 : Term Metabolic syndrome
• 1960 : Plurimetabolic Syndrome
• 1980 : Syndrome X : glucose & insulin metab + obesity
• 1988: Dr Gerald Reaven’s - Insulin sensitivity - risk CHD - insulin resistance
• Various definition
• 1998, 2001, 2005/6, 2009
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7. Definitions of the Metabolic Syndrome
• According to clinical outcomes
• According to underlying causes
• Insulin resistance-WHO definition
• Lifestyle: especially obesity- NCEP ATP III
• According to metabolic components
• According to clinical criteria
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8. Timeline of Metabolic Syndrome Criteria
• World Health Organization (1998)#*
• European Group for the Study of Insulin Resistance (1999)#
• National Cholesterol Education Program (2001)#
• American Association of Clinical Endocrinologists (2003)
• International Diabetes Federation (2005)#*
• American Heart Association & NHLBI (2005)#
• “Harmonized” definition (2009)#
#Measure of obesity included *BMI included (nonexclusively)
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9. Definitions of the Metabolic Syndrome
WHO Definition : 1998
• Based on insulin resistance, BMI, Microalbuminuria
NCEP ATP III : 2001
• Abdominal obesity is not an essential component
• No cut-off points for WC
IDF definition : 2005
• abdominal obesity an essential component
• cut-off points for WC
“Harmonized” definition : 2009
• Abdominal obesity is not an essential component
• Most accepted
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10. Metabolic syndrome: “Harmonized” definition
(2009)
Abdominal obesity is not an essential component
Parameter: (Any three)
•Waist Circumference
•Triglycerides (mg/dL)
•HDL (mg/dL)
•Blood pressure (mmHg)
•Fasting glucose (mg/dL)
Limit Values:
•Population specific
•> 150
•Men: < 40; Women: <50
•>130/>85
•> 100
Note: Waist Circumference is the only observable parameter
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11. Causative Factors in the Metabolic Syndrome
The Two significant factors :
“Central Obesity” and “Insulin Resistance
Other possible Factors :
• Genetics
• Physical inactivity
• Aging
• High carbohydrate diets (>60% of energy intake)
• Pro inflammatory state
• Hormonal state
(These may play variable roles in different ethnic groups)
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12. Normal Obesity
Visceral Fat Distribution: Normal vs Obesity
Diagnosis of metabolic syndrome- visceral fat areas as determined by CT scan > 100 cm2
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13. Pathophysiology
1. Insulin Resistance
2. Visceral adiposity
3. Dyslipidemia
4. Glucose Intolerance
5. Hypertension
6. Proinflammatory Cytokines
7. Adiponectin
Metabolic
Syndrome
Visceral
adiposity
Insulin
Resistance
Cardiovascular disease
Dyslipidemia Type 2 Diabetes Hypertension
Stress
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14. TNF, Adipokines
NO production
Pathophysiology: The role of abdominal obesity
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15. Inhibit
Protein kinase in Ms
• Insulin inhibitory lipolys
Action
• Protein kinase in Liver
expression of ß3 – adrenergic receptors
Randle’s Cycle
Inhibit glycolysis,
increase lipolysis
& Insulin resistance
Pathophysiology: The role of abdominal obesity
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• Lipotoxic to B-cell
• Compensatory
hyperinsulinemic state fail

16. Pathophysiology- Neurohormonal activation
expression of ß3 – adrenergic receptors
Inhibit glycolysis
& Insulin resistance
anti-inflammatory
antiatherogenic,
lipogenesis
And HTN
Hypothalamus,
Leptin resistance
NADP
oxidase
ACE
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17. Pathophysiology- Inflammation
expression of ß3 – adrenergic receptors
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 CRP
 Prothrombin
 Adhesion to
endothelium
 Local RAS

18. Pathophysiology- Insulin Resistance
Fasting hyperinsulinemia
Insulin resistance
Lipolysis by LPL
Toxic injury to
pancreatic islets
Insulin
resistance
Type 2 DM
Impaired insulin
mediated glucose uptake
Hyperglycemia
Abundance of FFA’s
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19. Pathophysiology- Insulin Resistance
expression of ß3 – adrenergic receptors
Inhibit glycolysis
& Insulin resistance
anti-inflammatory
antiatherogenic
And HTN
hypothalamus
NADP
oxidase
ACE
• postprandial
hyperinsulinemia
• fasting hyperinsulinemia
• fasting hyperglycemia
• IR…. FFA…IR
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20. Pathophysiology- Insulin Resistance
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Hyperlipidemia
Inflamation
Oxidative stress
Insulin Receptor

21. The inflammatory component of the metabolic
syndrome
• Vascular dysfunction
• Endothelial dysfunction
• Microalbuminuria
• Proinflammatory state
• Elevated hsCRP
• Elevated inflammatory cytokines (TNF-α, IL-6)
• Decreased adiponectin levels
• Prothrombotic state
• Increased antifibrinolytic factors (PAI-1)
• Increased fibrinogen
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22. CLINICAL FEATURES
1. Symptoms and Signs:
• The metabolic syndrome
typically is not associated
with symptoms.
• On physical examination,
waist circumference-
expanded and BP
elevated.
2. Associated
Diseases/increases risk
of:
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23. Acanthosis Nigricans
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24. DIAGNOSIS
• Purpose:
• Reduce the multiple risk factors
• Lifestyle modification
• History/examination
• Bedside and laboratory test
• fasting lipids and glucose
• biomarkers associated with insulin resistance
• ApoB, hsCRP, fibrinogen, urinary microalbumin, and liver function.
• sleep study
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25. Therapeutic Goals for Management
LIFESTYLE
Diet
Physical Activity
Behavior Modification
Obesity
Drugs:
• LDL cholesterol
• Triglycerides
• HDL cholesterol
• Blood pressure
• Impaired fasting glucose
• Insulin resistance
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26. Applied aspects
• Insulin resistance
• Thiazolidinediones (rosiglitazone, insulin sensitizing drug)
• Leptin resistance
• Congenital leptin deficiency
• Lifestyle disorders
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27. Thiazolidinediones Adipose tissue
Muscle Liver
Decreased FFA and TNFa release
Decreased tissue triglycerides
Increased adiponectin
Decreased
glucose
output
Increased
glucose
utilization
b-cell
Increased
insulin
secretion
Vascular
Increased
endothelial
function
PPARg
Adapted from Goldstein BJ. Am J Cardiol. Suppl 2002.
Applied aspects
Effects of Thiazolidinediones Mediated via Adipose Tissue
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28. Recent advances
• New generation of PPAR agonists,
• Interact with both PPARα and γ-receptors, thereby combining lipid and
glycaemic effects.
• Protein tyrosine phosphatase 1B inhibitors (PTP1B)
• Act as a negative regulator of insulin and leptin receptor signalling pathways.
• Leptin receptor antagonists and offer potential as future therapies
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29. Summary & Conclusions
• Global epidemic
• Variations exist in the diagnostic criteria and definition
• The concept of metabolic syndrome
• Based on visceral fat accumulation & Insulin resistance
• Major target for the prevention of cardiovascular disease
• Lifestyle modification
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30. 30

31. 31

32. Takeaway message
• Hidden volcano
• Screening >3 yrs
• Evaluation ≥25 yrs
• We should not wait till
these killers develop
Thank
You
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33. "The doctor of the future will give no medicine,
but will interest his patients in the care of the
human body, in diet, and in the cause and
prevention of disease." .... Thomas Edison
So, what can you do?
The Lifestyle Disease
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