Metabolic Syndrome:
Pathophysiology

International Diabetes Center


What to call the syndrome?
•
•
•
•
•
•

Reaven’s Syndrome
Deadly Quartet
Insulin Resistance Syndrome
Syndrome X
Dysmetabolic Syndrome X
Multiple Metabolic Syndrome

• Metabolic Syndrome
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Clinical Identification
Metabolic Syndrome
Any Three of the Following:
Risk Factor
Defining Level
1. Abdominal obesity

Men
Women

Waist circumference
>40 in. (>102 cm)
>36 in. (90 cm)
>32 in. (80 cm)
>35 in. (>88 cm)

2. Triglycerides

≥150 mg/dL (1.7 mmol/L)

3. HDL-C
Men
Women

<40 mg/dL (1.0 mmol/L)
<50 mg/dL (1.3 mmol/L)

4. Blood pressure

≥130/85 mmHg
≥110 mg/dL (6.1 mmol/L)

5. Fasting glucoseCholesterol Education Program, Adult
National
Treatment Panel III. JAMA. 2001;285:2486.

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Prevalence(%)

50
45
40
35
30
25
20
15
10
5
0

Prevalence of the Metabolic
Syndrome Among US Adults

Men
Women

20-29

30-39

40-49

50-59


60-69

>70

Age (Years)
n=8814 men and women from the 3rd National Health
and Nutrition Examination Survey defined using NCEP ATP III Criteria
Ford et al. JAMA 2002; 287:356-359.
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Components of the Metabolic Syndrome
Hyperglycemia
Dyslipidemia

Hypertension

Insulin
Resistance
Abnormal

Thrombotic Risk

vascular behavior

Fat Mass
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Components of the Metabolic Syndrome

Hyperglycemia
Hyperglycemia
Dyslipidemia
Dyslipidemia

Hypertension
Hypertension

Insulin
Resistance

Abnormal
Abnormal

Thrombotic Risk
Thrombotic Risk

vascular behavior
vascular behavior

Fat Mass
Fat Mass
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Insulin Receptor
Insulin
α-subunit
Plasma Membrane
β-subunit


IRS-1
P

Tyr P
Tyr P
Tyr P
IRS-2
P

IRS-3
P

IRS = Insulin Receptor
Substrate
P = Phosphate group
Tyr = Tyrosine Kinase

Insulin Signaling Pathways Activated Affecting:
• Glucose, lipid and protein metabolism
• Cell division (mitosis)
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Potential Causes of Insulin Resistance
•Insulin Receptor Level
–Reduced tyrosine kinase activity
–Elevated phosphotyrosine phosphatase

•Post- Receptor Defects

–Reduced tyrosine phosphorylation of IRS1,
IRS2, IRS3
–Causes-likely many factors involved
•Free Fatty Acids
•Tumor Necrosis Factor-α
•Resistin???
White Mol Cell Biochem 1998; 182:3
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Role of FFA in Insulin Resistance
Adipose
Tissue
Free Fatty
Acids (FFA)

• Increase in adipocyte
number and size causes a
rise in FFA output
• High FFA concentration
decreases glucose uptake
and utilization in muscle and
liver
• Potential mechanisms:
– Increased accumulation of
triglyceride in liver and muscle
– Decreased glucose
transporter (Glut4) expression
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Obesity Induced Insulin Resistance: Role
of Tumor Necrosis Factor Alpha (TNF-α)
TNF-α Cytokine released from adipose tissue,
expressed at high levels in obese individuals
TNF-α

X
X

TNF-α
Adipose Tissue

Nucleus

TNF-α Receptor
Insulin Receptor
Glucose Transporter (GLUT 4)
Similar process may occur in fat and liver cells

GGG
GG
Muscle Cell
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Components of the Metabolic Syndrome
Hyperglycemia
Hyperglycemia
Dyslipidemia

Dyslipidemia

Hypertension
Hypertension

Insulin
Resistance
Abnormal
Abnormal
vascular behavior

Thrombotic Risk
Thrombotic Risk

Fat Mass

International Diabetes Center


Role of Obesity In Metabolic
Syndrome
• Central obesity is critical factor
– Waist to hip ratio >1
– Waist >40 inches in men
– Waist >35 inches in women
• Abdominal adipose tissue is more
metabolically active than
subcutaneous fat
• Increased release of FFA, TNFα leading to insulin resistance
FFA


TNF-α

Others
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It is not how much fat
you have, but where
you store it!!!

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Components of the Metabolic Syndrome

Hyperglycemia
Hypertension
Hypertension

Dyslipidemia
Dyslipidemia

Resistance
Abnormal
Abnormal

Thrombotic Risk
Thrombotic Risk


vascular behavior
vascular behavior

Fat Mass
International Diabetes Center


Prevalence of Metabolic Syndrome
(Percent Adults)
78-84%
(7 mmol/L)
(7 mmol/L)

(IFG)

(6.5 mmol/L)
(6.5 mmol/L)

Based on Fasting BG

(11.1 mmol/L)
(11.1 mmol/L)

42-64%

(IGT)

10-15%

(7.8 mmol/L)

(7.8 mmol/L)

Based on 2 hr. OGTT

Adapted from ADA and Isomaa et al. Diabetes Care 2001:24:683
10 to 15% of those with normal glycemia by fasting or OGTT have metabolic syndrome

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The Natural History of Glucose
Intolerance
Insulin Resistance and Insulin Deficiency

Insulin
Insulin
Resistance
Resistance

Relative
Relative
Insulin
Insulin
Deficiency
Deficiency

Pre-diabetes and
Pre-diabetes and
Type 2 Diabetes
Type 2 Diabetes

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Components of the Metabolic Syndrome
Hyperglycemia

Dyslipidemia

Hypertension
Hypertension

Resistance
Abnormal
Abnormal

Thrombotic Risk
Thrombotic Risk

vascular behavior
vascular behavior

Fat Mass
International Diabetes Center


Types of Lipoproteins
•Very Low Density Lipoprotein (VLDL)
–Produced in the liver
–Primary carriers of triglyceride


• Low Density Lipoprotein (LDL)
– Major carrier of cholesterol
– Diet high in saturated fat increases level

• High Density Lipoprotein (HDL)
– Function by returning cholesterol to liver
– Modest increase with exercise
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Dyslipidemia Associated with
Metabolic Syndrome
• Elevated Triglycerides
–

>150 mg/dL (1.7 mmol/L)

• Low Level of HDL
– <40 mg/dL (1.0 mmol/L) men
– <50 mg/dL (1.3 mmol/L) women

• Small dense LDL particles

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Increase in Triglycerides
Adipose Tissue
1. Increased fat stores result in breakdown
of triglyceride, released as FFA


FFA

2. Insulin resistance impedes
FFA uptake in adipose tissue

3. FFA taken up
by the liver
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Effect of FFA on Liver

High FFA leads to high VLDL,
a fatty liver, and high blood
triglycerides
Increased VLDL release

VLDL ParticlesCarrier of
Triglycerides

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Why low HDL in Metabolic Syndrome?
Hepatic
Lipase

P
CET

Large LDL

VLDL
(Triglyceride Rich)

Cholesterol
Triglyceride
Apo A1
Apo B100

Small Dense
LDL
Hepatic
Lipase

CET
P

HDL2

HDL3

CEPT = Cholesterol Ester
Transfer Protein
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Are all LDL particles the same?
LDL = 130 mg/dL in both examples


vs

Large “Fluffy” LDL
Less atherogenic

Small “Dense” LDL
More atherogenic
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Atherosclerosis

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Cellular Events Leading to
Atherosclerosis
BLOOD

Monocyte
adherence

HDL

LDL

ENDOTHELIUM

Foam cell
CE


LDL
Oxidation

CE

Macrophage
CE

Ox-LDL

CE

Activation

N

N
MATRIX

Smooth muscle cells

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