The Metabolic Syndrome

1
The Metabolic Syndrome

• Miriam Cnop, MD PhD
• Division of Endocrinology and
• Laboratory of Experimental Medicine
• Université Libre de Bruxelles

2
Metabolic Syndrome

• Clustering of cardiovascular risk factors
• Central obesity
• Diabetes
• Hypertension
• Dyslipidemia

3
Also known as The Dysmetabolic Syndrome The
Insulin Resistance SyndromeDeadly quartet
4
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 420, 1956)
5
Prevalence of the Metabolic Syndrome

• National Health and Nutrition Examination Survey
  III
• (US 1988-1994)

Adults gt 20 yrs 24 gt 60 yrs 44
(Ford et al. JAMA 287356, 2002)
6
Global Epidemic
Body Mass Index weight (kg)/height (m)2
7
Obesity Trends Among U.S. Adults1985
(BMI 30)
(Behavioral Risk Factor Surveillance System,
Centers for Disease Control)
8
Obesity Trends Among U.S. Adults1986
(BMI 30)
9
Obesity Trends Among U.S. Adults1987
(BMI 30)
10
Obesity Trends Among U.S. Adults1988
(BMI 30)
11
Obesity Trends Among U.S. Adults1989
(BMI 30)
12
Obesity Trends Among U.S. Adults1990
(BMI 30)
13
Obesity Trends Among U.S. Adults1991
(BMI 30)
14
Obesity Trends Among U.S. Adults1992
(BMI 30)
15
Obesity Trends Among U.S. Adults1993
(BMI 30)
16
Obesity Trends Among U.S. Adults1994
(BMI 30)
17
Obesity Trends Among U.S. Adults1995
(BMI 30)
18
Obesity Trends Among U.S. Adults1996
(BMI 30)
19
Obesity Trends Among U.S. Adults1997
(BMI 30)
20
Obesity Trends Among U.S. Adults1998
(BMI 30)
21
Obesity Trends Among U.S. Adults1999
(BMI 30)
22
Obesity Trends Among U.S. Adults2000
(BMI 30)
23
Obesity Trends Among U.S. Adults2001
(BMI 30)
No Data lt10 1014
1519 2024 25
24
Obesity Trends Among U.S. Adults2002
(BMI 30)
No Data lt10 1014
1519 2024 25
25
Obesity Trends Among U.S. Adults2003
(BMI 30)
No Data lt10 1014
1519 2024 25
Source Behavioral Risk Factor Surveillance
System, CDC
26
Predicted evolution of BMI distribution
20th century
21st century
(AM Prentice Br Med Bull 53229, 1997)
27
Pathogenesis of obesity
Many people enjoy the opportunity of eating more
than they need with little requirement for
physical exertion.
(Pinkney et al. Lancet 3571357, 2001)
28
Body fat mass is the result of energy balance
Obesity chronic imbalance between caloric
intake and expenditure
Obesity chronic imbalance between caloric
intake and expenditure
Obesity chronic imbalance between caloric
intake and expenditure
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 363211, 2004)
29
(Photograph Howard Berman 1990)
30
Environmental and genetic factors determine
insulin sensitivity
Insulin resistance decreased ability of
peripheral tissues to respond properly to normal
circulating concentrations of insulin
Variability in insulin sensitivity is accounted
for by Adiposity 25-30 Physical
fitness 25-30 Genetic factors 40-50
31
(Zimmet et al. J Intern Med 254114, 2003)
32
Definition World Health Organization (1999)
At least 1 of
At least 2 of

• Type 2 diabetes
• Impaired Glucose Tolerance
• (2h glucose 140-199 mg/dl)
• Insulin Resistance

Obesity BMIgt30 kg/m2 Waist/hip gt0.90
(M) gt0.85 (F) Hypertension (gt140/90 mm
Hg) Dyslipidemia (high TG, low HDL) Microalbuminur
ia
33
DefinitionNational Cholesterol Education
Program (2001)
At least 3 of Abdominal obesity waist
circumference gt 102 cm (M) gt 88 cm
(F) Hypertriglyceridemia gt 150 mg/dl Low HDL
cholesterol lt 40 mg/dl (M) lt 50 mg/dl
(F) Hypertension (gt 130/85 mm Hg) Impaired
Fasting Glucose or Type 2 diabetes (gt 100 mg/dl)
(ATP III. JAMA 2852486, 2001)
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Pathogenesis of the Metabolic Syndrome
Type 2 Diabetes
Insulin Resistance
Central obesity
Dyslipidemia
Hypertension
35
Assessment of Insulin Sensitivity
Gold Standard Hyperinsulinemic clamp
Glucose Infusion Rate
8
120
120
Glycemia
100
6
80
80
60
4
Insulinemia
40
40
2
20
0
0
30
60
90
120
15
30
45
60
75
90
105
120
(Cnop and Fery Unpublished data)
36
Assessment of Insulin Sensitivity
Fasting insulin Homeostasis Model Assessment HOMA
IR Insulin (mU/ml) x Glucose (mmol/l) /
22.5 Quantitative Insulin Sensitivity Check Index
QUICKY 1/log Insulin (mU/ml) log Glucose
(mg/dl) Oral Glucose Tolerance Test Intravenous
Glucose Tolerance Test IVGTT
37
Relationship between BMI and insulin sensitivity

• 174 healthy, normoglycemic subjects
• 73 M and 101 F
• age 52.50.7 yrs
• Determine BMI and quantify the insulin
  sensitivity index (SI) using Bergmans minimal
  model

38
Insulin sensitivity in healthylean and obese
subjects
(Cnop et al. Diabetes 511005, 2002)
39
Role of body fat distribution

• Normal

Type 2 diabetes
40
Question

• Do lean insulin sensitive, lean insulin
  resistant, and obese insulin resistant subjects
  have similar abdominal fat distribution?

41
Body Mass Index and Insulin Sensitivity
,ˆ
30
10
7.5
20
SI (x10-5 min-1/pM)
BMI (kg/m2)

5
,ˆ
10
2.5
0
0
LIS
LIR
OIR
LIS
LIR
OIR
(Cnop et al. Diabetes 511005, 2002)
42
Intra-Abdominal and Subcutaneous Fat Areas
(Cnop et al. Diabetes 511005, 2002)
43
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.

44
Question

• Is insulin resistance associated with a
  particular fat depot?

45
Intra-abdominal fat is highly predictive
ofinsulin sensitivity
3
r -0.688
2
SI (x10-5 min -1/pM)
Loge SI
1
0
-1
2.0
3.0
4.0
5.0
6.0
Loge Intra-abdominal fat area
(Cnop et al. Diabetes 511005, 2002)
46
Intra-abdominal fat is highly predictive
ofinsulin sensitivity
SI (x10-5 min -1/pM)
47
Summary
Insulin Resistance
48
Adipose tissue an endocrine organ
? FFA
? Fat
? TNFa??IL-6, Leptin, Resistin
? Adiponectin
49
Relationship between leptin andsubcutaneous fat
70
60
50
Leptin (ng/ml)
r 0.783
40
30
20
r 0.754
10
0
0
200
400
600
800
Subcutaneous fat area (cm2)
Subcutaneous fat area (cm2)
(Cnop et al. Diabetes 511005, 2002)
50
Relationship between adiponectin
andintra-abdominal fat
20
20
15
15
Adiponectin (mg/ml)
r-0.218
10
10
r-0.362
5
5
0
0
0
100
200
300
400
0
100
200
300
400
Intra-abdominal fat area (cm2)
Intra-abdominal fat area (cm2)
(Cnop et al. Diabetologia 46459, 2003)
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The Metabolic Syndrome
Type 2 Diabetes
Insulin Resistance
Central obesity
Dyslipidemia
Hypertension
52
Worldwide prevalence of type 2 diabetes
300
200
million
100
0
1980
1990
2000
2010
2020
2030
Year
(Adapted from Zimmet Nature 414782, 2001)
53
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.

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(Cnop and Kahn Unpublished data)
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Evolution of glucose tolerance categories over 7
years
100
75
Diabetes
50
IGT
of subjects
NGT
25
0
1994
2001
(Cnop and Kahn Unpublished data)
56
Evolution of b cell function over 7 years
(Cnop and Kahn Unpublished data)
57
Summary

• While insulin sensitivity did not change, ?-cell
  function declined over time in first-degree
  relatives of individuals with type 2 diabetes.

58
Pathogenesis of type 2 diabetes
Central obesity
Insulin Resistance
Insulin Deficiency
Dyslipidemia
Hypertension
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Hypothesis
In vitro studies
Pancreatic b cell Dysfunction
Fat
(Cnop et al. Diabetes 501771, 2001) (Cnop et al.
Endocrinology 1433449, 2002) (Kharroubi et al.
BBRC 3121118, 2003)
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The Metabolic Syndrome
Type 2 Diabetes
Insulin Resistance
Central obesity
Dyslipidemia
Hypertension
61
DyslipidemiaDensity Gradient Ultracentrifugation
VLDL
IDL
LDL
HDL
buoyant
dense
(Nieves et al. Diabetes 52172, 2003)
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Dyslipidemia and the Metabolic Syndrome
Insulin Resistant
VLDL
dense
LDL
Adiponectin
IDL
HDL
buoyant
Insulin Sensitive
(Nieves et al. Diabetes 52172, 2003)
(Cnop et al. Diabetologia 46459, 2003)
63
The Metabolic Syndrome and Hypertension

• 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

(Steinberger et al. Circulation 1071448, 2003)
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(No Transcript)
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Treatment Lifestyle
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
(NIH Guidelines, 1998) (Hill et al. Science
299853, 2003)
66
(Slimming Down Photographer unidentified. From
the Everett Collection)
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(Only in the US, from the Only in series)
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Treatment Lifestyle
Its effectiveness recalls Voltaires dictum that
the art of medicine is to keep the patient
occupied while the disease runs its inevitable
course
(Pinkney et al. Lancet 3571357, 2001)
69
Treatment Lifestyle
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
(Tuomilehto et al. N Engl J Med 3441343,
2002) (Chiasson et al. Lancet 3592072,
2002) (Diabetes Prevention Program Research
Group. N Engl J Med 346393, 2003)
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Treatment Drugs
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-a and g agonists. No
consensus optimal treatment targets have been
determined and pharmacotherapy remains at present
unproven.
(Haffner et al. Circulation 1081541, 2003)
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Surgical treatment of obesity Follow up data
(n32)
Preop 4 m 2.5 yrs Weight (kg) 116 92 76
relative loss 21 34 (12-53) success
rate (gt20) 94 failure rate (lt5)
0 BMI (kg/m2) 42 33 28
For both plt0.001 by ANOVA for repeated measures
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Surgical treatment of obesity Follow up data
Preop 2.5 yrs Body fat mass ()
41 1 321 Leptin (ng/ml) 573 162 Subcutan
eous fat area (cm2) 66421 33126 Intra-abdominal
fat area (cm2) 16012 698 HOMA IR ()
393 885
For all plt0.001 by ANOVA for repeated measures
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Surgical treatment of obesity Follow up data
Preop 4 m 2.5 yrs Glucose (mg/dl) 922 852
821 plt0.01 Normal 81 92
97 Impaired 16 8 3 Diabetic 3 0
0
NGT 65 IGT 26 DGT 9
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Surgical treatment of obesity Follow up data
Preop 4 m 2.5 yrs Blood pressure
Systolic 125 117 115 plt0.01 Diastolic
73 71 70 NS Hypertension
Systolic 48 14 5 Diastolic 39 25
29
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Surgical treatment of obesity Follow up data
Preop 4 m 2.5 yrs Lipids Triglycerides 16315
12310 918 plt0.001 HDL cholesterol
513 472 612 plt0.001 Dyslipidemia
Triglycerides 47 28 3 HDL cholesterol
50 60 23
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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.

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Acknowledgments
Division of Endocrinology, ULB
Françoise Féry Jean Mockel
Laboratory of Experimental Medicine, ULB
Décio Eizirik Ilham Kharroubi
Division of Metabolism, University of Washington,
Seattle

• Steven Kahn
• Bob Knopp
• Wil Fujimoto
• John Brunzell
• Peter Havel

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Thank you