The Metabolic Syndrome

Miriam Cnop, MD PhD

Division of Endocrinology and

Laboratory of Experimental Medicine

Université Libre de Bruxelles

Metabolic Syndrome

Clustering of cardiovascular risk factors

Central obesity

Diabetes

Hypertension

Dyslipidemia

Also known as

The Dysmetabolic Syndrome

The Insulin Resistance Syndrome

Deadly quartet

First report

The degree of masculine differentiation to obesity:

a factor determining predisposition to diabetes,

atherosclerosis, gout and uric calculus disease.

(Vague Am J Clin Nutr 4:20, 1956)

Prevalence of the Metabolic Syndrome

National Health and Nutrition Examination Survey III

(US 1988-1994)

Adults > 20 yrs: 24%

> 60 yrs: 44%

(Ford et al. JAMA 287:356, 2002)

Global Epidemic

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Body Mass Index = weight (kg)/[height (m)]2

Obesity Trends* Among U.S. Adults1985

No Data <10% 10%–14%

(*BMI ≥30)

(Behavioral Risk Factor Surveillance System, Centers for Disease Control)

Obesity Trends* Among U.S. Adults1986

No Data <10% 10%–14%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1987

No Data <10% 10%–14%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1988

No Data <10% 10%–14%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1989

No Data <10% 10%–14%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1990

No Data <10% 10%–14%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1991

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1992

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1993

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1994

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1995

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1996

No Data <10% 10%–14% 15%–19%

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1997

No Data <10% 10%–14% 15%–19% ≥20

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1998

No Data <10% 10%–14% 15%–19% ≥20

(*BMI ≥30)

Obesity Trends* Among U.S. Adults1999

No Data <10% 10%–14% 15%–19% ≥20

(*BMI ≥30)

Obesity Trends* Among U.S. Adults2000

No Data <10% 10%–14% 15%–19% ≥20

(*BMI ≥30)

Obesity Trends* Among U.S. Adults2001

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

(*BMI ≥30)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults2002(*BMI ≥30)

Source: Behavioral Risk Factor Surveillance System, CDC

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults2003(*BMI ≥30)

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Predicted evolution of BMI distribution

(AM Prentice Br Med Bull 53:229, 1997)

20th century

21st century

Many people enjoy the opportunity of eating more than they

need with little requirement for physical exertion.

(Pinkney et al. Lancet 357:1357, 2001)

Pathogenesis of obesity

Obesity = chronic imbalance between

caloric intake and expenditure

Obesity = chronic imbalance between

caloric intake and expenditure

Obesity = chronic imbalance between

caloric intake and expenditure

Body fat mass is the result of energy balance

The US food industry produces 3800 kcal/person/day

whereas the average requirement is 2000 kcal/day.3 to 5-y-old UK children spend only 2% of their time in moderate

to vigorous physical activity. Their total energy expenditure was

200 kcal/day lower than the estimated requirement.

(Reilly et al. Lancet 363:211, 2004)

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(Photograph Howard Berman 1990)

Environmental and genetic factors determine insulin sensitivity

Variability in insulin sensitivity is accounted for by:

Adiposity 25-30%

Physical fitness 25-30%

Genetic factors 40-50%

Insulin resistance = decreased ability of peripheral

tissues to respond properly to normal circulating

concentrations of insulin

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(Zimmet et al. J Intern Med 254:114, 2003)

Definition: World Health Organization (1999)

Type 2 diabetes

Impaired Glucose Tolerance

(2h glucose 140-199 mg/dl)

Insulin Resistance

Obesity BMI>30 kg/m2

Waist/hip >0.90 (M)

>0.85 (F)

Hypertension (>140/90 mm Hg)

Dyslipidemia (high TG, low HDL)

Microalbuminuria

At least 1 of At least 2 of+

Definition:National Cholesterol Education Program (2001)

At least 3 of

Abdominal obesity: waist circumference > 102 cm (M)

> 88 cm (F)

Hypertriglyceridemia > 150 mg/dl

Low HDL cholesterol < 40 mg/dl (M)

< 50 mg/dl (F)

Hypertension (> 130/85 mm Hg)

Impaired Fasting Glucose or Type 2 diabetes (> 100 mg/dl)

(ATP III. JAMA 285:2486, 2001)

Pathogenesis of the Metabolic Syndrome

Type 2 Diabetes

Hypertension

Dyslipidemia

Central obesityInsulin

Resistance

Assessment of Insulin Sensitivity

Gold Standard: Hyperinsulinemic clamp

0

2

4

6

8

15 30 45 60 75 90 105 120

20

40

60

80

100

120

0 30 60 90 120

40

80

120Glycemia

Insulinemia

Glucose Infusion Rate

(Cnop and Fery; Unpublished data)

Assessment of Insulin Sensitivity

Fasting insulin

Homeostasis Model Assessment HOMA IR

Insulin (U/ml) x Glucose (mmol/l) / 22.5

Quantitative Insulin Sensitivity Check Index QUICKY

1/[log Insulin (U/ml) + log Glucose (mg/dl)]

Oral Glucose Tolerance Test

Intravenous Glucose Tolerance Test IVGTT

Relationship between BMI and insulin sensitivity

174 healthy, normoglycemic subjects

73 M and 101 F

age 52.5±0.7 yrs

Determine BMI and quantify the insulin sensitivity

index (SI) using Bergman’s minimal model

Insulin sensitivity in healthylean and obese subjects

0

10

20

30

15 20 25 30 35 40 45

BMI (kg/m2)

SI (

x10-5

min

-1/p

M)

(Cnop et al. Diabetes 51:1005, 2002)

Role of body fat distribution

Normal Type 2 diabetes

Question

Do lean insulin sensitive, lean insulin resistant, and

obese insulin resistant subjects have similar

abdominal fat distribution?

Body Mass Index and Insulin Sensitivity

0

10

20

30

LIS LIR OIR

BM

I (kg

/m2 )

**,ˆ

0

2.5

5

7.5

10

LIS LIR OIR

SI (

x10-5

min

-1/p

M)

**,ˆ**

(Cnop et al. Diabetes 51:1005, 2002)

Intra-Abdominal and Subcutaneous Fat Areas

0

50

100

150

LIS LIR OIR

IAF

are

a (c

m2 )

**,ˆ

**

0

100

200

300

LIS LIR OIR

SC

F a

rea

(cm

2 )

**,ˆ

**

(Cnop et al. Diabetes 51:1005, 2002)

Summary

Compared to lean insulin sensitive subjects, lean insulin resistant and obese insulin resistant subjects have:

• increased intra-abdominal fat area

• increased subcutaneous fat area

Whereas the BMI of the 2 lean groups did not differ, LIR subjects had 50% more abdominal fat.

Question

Is insulin resistance associated with a particular fat depot?

Intra-abdominal fat is highly predictive ofinsulin sensitivity

SI (

x10-5

min

-1/p

M)

0

10

20

30

0 100 200 300 400

Intra-abdominal fat area (cm2)

-1

0

1

2

3

2.0 3.0 4.0 5.0 6.0

Loge Intra-abdominal fat area

Log e

SI

r = -0.688

(Cnop et al. Diabetes 51:1005, 2002)

SI (

x10-5

min

-1/p

M)

0

10

20

30

0 100 200 300 400

Intra-abdominal fat area (cm2)

Intra-abdominal fat is highly predictive ofinsulin sensitivity

Summary

InsulinResistance

Adipose tissue: an endocrine organ

Fat

Adiponectin

FFA

InsulinResistance

TNFIL-6, Leptin, Resistin

Relationship between leptin andsubcutaneous fat

0

10

20

30

40

50

60

0 200 400 600 800

Subcutaneous fat area (cm2)

Lept

in (

ng/m

l)

0

10

20

30

40

50

60

70

0 200 400 600 800

Subcutaneous fat area (cm2)

r = 0.754

r = 0.783

(Cnop et al. Diabetes 51:1005, 2002)

Relationship between adiponectin andintra-abdominal fat

0

5

10

15

20

0 100 200 300 400

Intra-abdominal fat area (cm2)

Adi

pone

ctin

(g

/ml)

0

5

10

15

20

0 100 200 300 400

Intra-abdominal fat area (cm2)

(Cnop et al. Diabetologia 46:459, 2003)

r=-0.362r=-0.218

The Metabolic Syndrome

Type 2 Diabetes

Hypertension

Dyslipidemia

Central obesityInsulin

Resistance

Worldwide prevalence of type 2 diabetes

mill

ion

0

100

200

300

1980 1990 2000 2010 2020 2030

Year

(Adapted from Zimmet Nature 414:782, 2001)

Background

Type 2 diabetes is characterized by variable degrees of insulin resistance and pancreatic -cell dysfunction.

First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia.

1994 2001 p

n 35 34BMI (kg/m2) 28.9 ± 0.8 31.3 ± 1.1 <0.01

Waist circumference (cm) 101 ± 2 105 ± 3 <0.05

Hip circumference (cm) 111 ± 2 110 ± 2Glucose (mg/dl) 93 ± 1 95 ± 3HDL cholesterol (mg/dl) 44 ± 2 43 ± 2LDL cholesterol (mg/dl) 118 ± 5 125 ± 4 <0.05

Triglycerides (mg/dl) 85 ± 9 96 ± 7 <0.05

Systolic BP (mm Hg) 116 ± 2 123 ± 3 <0.01

Diastolic BP (mm Hg) 73 ± 2 75 ± 2

(Cnop and Kahn; Unpublished data)

Evolution of glucose tolerance categories over 7 years

0

25

50

75

100

1994 2001

Diabetes

IGT

NGT

% o

f su

bje

cts

(Cnop and Kahn; Unpublished data)

Evolution of cell function over 7 years

(Cnop and Kahn; Unpublished data)

DI (%)

0

10

20

30

1994 2001

p<0.05

Summary

While insulin sensitivity did not change, -cell

function declined over time in first-degree relatives

of individuals with type 2 diabetes.

Pathogenesis of type 2 diabetes

Insulin Deficiency

Type 2 Diabetes

Hypertension

Dyslipidemia

Central obesityInsulin

Resistance

Hypothesis

Pancreatic cell Dysfunction

Fat

Adiponectin

FFA, TNFLeptin, Resistin

InsulinResistance

Pancreatic cell Dysfunction

(Cnop et al. Diabetes 50:1771, 2001)(Cnop et al. Endocrinology 143:3449, 2002)

(Kharroubi et al. BBRC 312:1118, 2003)

In vitro studies

The Metabolic Syndrome

Type 2 Diabetes

Hypertension

Dyslipidemia

Central obesityInsulin

Resistance

DyslipidemiaDensity Gradient Ultracentrifugation

(Nieves et al. Diabetes 52:172, 2003)

0

10

20

30

38 34 30 26 22 18 14 10 6 2

Lipoprotein fractions

Cholesterol (mg/dl) HDL

VLDLIDL LDL

buoyant dense

Dyslipidemia and the Metabolic Syndrome

VLDL

IDL

LDL

buoyant

dense

HDL-10

-5

0

5

10

C

ho

lest

ero

l (m

g/d

l)

(Nieves et al. Diabetes 52:172, 2003)

InsulinResistant

InsulinSensitive

Adiponectin

(Cnop et al. Diabetologia 46:459, 2003)

The Metabolic Syndrome and Hypertension

(Steinberger et al. Circulation 107:1448, 2003)

Intra-abdominal adiposity and insulin resistance are

associated with increased:

• Sodium retention and sensitivity

• Angiotensinogen and angiotensin II levels

• Sympathetic activity

• PAI-1 levels

• Cortisol production in visceral fat compartment

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.NAFLD

Oxidativestress

CoagulopathyInflammation

Endothelialdysfunction

Sleep apneasyndrome

Polycystic ovarysyndrome

Heartfailure

Breastcancer

Treatment: Lifestyle

(NIH Guidelines, 1998)(Hill et al. Science 299:853, 2003)

Diet: Estimate the patients current daily caloric needs

- 500 kcal/d

Initial goal is 10% weight loss over 6 months

(- 25-30% in visceral fat and insulin resistance)

Exercise: 30 min/day

100/100 plan: reduce intake by 100 kcal/day

increase activity by 100 kcal/day

(“Slimming Down” Photographer unidentified. From the Everett Collection)

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(“Only in the US”, from the Only in … series)

Treatment: Lifestyle

Its effectiveness recalls Voltaire’s dictum that the

art of medicine is “ to keep the patient occupied

while the disease runs its inevitable course ”

(Pinkney et al. Lancet 357:1357, 2001)

Treatment: Lifestyle

(Tuomilehto et al. N Engl J Med 344:1343, 2002)(Chiasson et al. Lancet 359:2072, 2002)

(Diabetes Prevention Program Research Group. N Engl J Med 346:393, 2003)

Finnish Diabetes Prevention Study

STOP-NIDDM Trial

US Diabetes Prevention Program

7% weight loss

150 min/week exercise

Reduction of diabetes incidence by 60%

Compared to 25-30% reduction for pharmacological intervention

Treatment: Drugs

(Haffner et al. Circulation 108:1541, 2003)

Underlying conditions (hypertension, diabetes, lipid disorders)

should be treated.

An aggressive and early treatment strategy has been proposed.

Therapeutic agents might include fibrates, statins, metformin,

thiazolidinediones, and, possibly, dual PPAR- and agonists.

No consensus optimal treatment targets have been determined

and pharmacotherapy remains at present unproven.

Preop 4 m 2.5 yrs

Weight (kg) 116 92 76

relative loss 21% 34% (12-53)

success rate (>20%) 94%

failure rate (<5%) 0%

BMI (kg/m2) 42 33 28

Surgical treatment of obesity Follow up data (n=32)

For both: p<0.001 by ANOVA for repeated measures

Preop 2.5 yrs

Body fat mass (%) 41±1 32±1

Leptin (ng/ml) 57±3 16±2

Subcutaneous fat area (cm2) 664±21 331±26

Intra-abdominal fat area (cm2) 160±12 69±8

HOMA IR (%) 39±3 88±5

Surgical treatment of obesity Follow up data

For all: p<0.001 by ANOVA for repeated measures

Preop 4 m 2.5 yrs

Glucose (mg/dl) 92±2 85±2 82±1 p<0.01

Normal 81% 92% 97%

Impaired 16% 8% 3%

Diabetic 3% 0% 0%

Surgical treatment of obesity Follow up data

NGT 65%IGT 26%DGT 9%

Preop 4 m 2.5 yrs

Blood pressure

Systolic 125 117 115 p<0.01

Diastolic 73 71 70 NS

Hypertension

Systolic 48% 14% 5%

Diastolic 39% 25% 29%

Surgical treatment of obesity Follow up data

Preop 4 m 2.5 yrs

Lipids

Triglycerides 163±15 123±10 91±8 p<0.001

HDL cholesterol 51±3 47±2 61±2 p<0.001

Dyslipidemia

Triglycerides 47% 28% 3%

HDL cholesterol 50% 60% 23%

Surgical treatment of obesity Follow up data

Conclusions

We are facing a global epidemic of the Metabolic Syndrome, and of its associated cardiovascular and other diseases.

Intra-abdominal adiposity is strongly related to insulin resistance, probably via the secretion of adipocyte-derived free fatty acids and adipokines. These compounds can also contribute to the development of the disorders associated with the Metabolic Syndrome.

Implementing lifestyle modifications for the prevention and treatment of this disease will prove to be a challenge.

Acknowledgments

Steven KahnBob KnoppWil FujimotoJohn BrunzellPeter Havel

Françoise FéryJean Mockel

Division of Metabolism, University of Washington, Seattle

Division of Endocrinology, ULB

Décio EizirikIlham Kharroubi

Laboratory of Experimental Medicine, ULB

Thank you