METABOLIC METABOLIC SYNDROME SYNDROME Lajos Lajos Szollár Szollár Professor of Pathophysiology Professor of Pathophysiology Semmelweis University, Semmelweis University, Faculty of Medicine Faculty of Medicine Institute of Pathophysiology Institute of Pathophysiology 2007 2007
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METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of Medicine Institute of Pathophysiology 2007 METABOLIC SYNDROME.
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METABOLICMETABOLIC SYNDROMESYNDROME
Lajos Lajos SzollárSzollárProfessor of PathophysiologyProfessor of Pathophysiology
Semmelweis University, Semmelweis University, Faculty of MedicineFaculty of Medicine
Institute of PathophysiologyInstitute of Pathophysiology20072007
Recommends a diagnosis when 3 of these risk factors are present
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.
Updated ATPIII Criteria for Diagnosis of Metabolic Syndrome
Measure (any 3 of the following)Categorical cutpoints
Elevated waist circumference ≥102 cm men≥88 cm women
Elevated triglycerides ≥150 mg/dL (1.7 mmol/L) or on Rx for elevated TG
Reduced HDL-C <40 mg/dL (1.03 mmol/L) men<50 mg/dL (1.3mmol/L) women
or on Rx for reduced HDL-C
Elevated blood pressure ≥130 mm Hg systolic or ≥85 mm Hg diastolic or on
antihypertensive Rx with history of hypertension
Elevated fasting glucose ≥100 mg/dL or on Rx for elevated glucose
Grundy et al. Diagnosis and management of the metabolic syndrome. An AHA/NHLBI Scientific Statement Circulation 2005 112:2735-2752
International Diabetes Federation definition of the metabolic syndrome
Central obesity (defined as waist circumference > 94cm for Europid men; > 80cm for Europid women; ethnicity specific values for other groups)
Plus any two of the following four factors:• Raised triglyceride level: > 150 mg/dL (1.7 mmol/L), or specific treatment
for this lipid abnormality• Reduced HDL cholesterol : < 40 mg/dL (1.03 mmol/L) in males and < 50
mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality
• Raised blood pressure: systolic BP > 130 or diastolic BP > 85 mm Hg, or treatment of previously diagnosed hypertension
• Raised fasting plasma glucose > 100 mg/dL (5.6 mmol/L or previously diagnosed type 2 diabetes (if above 5.6 mmol/L, OGTT strongly recommended but not necessary to define presence of the syndrome)
International Diabetes Federation. Worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf.
Kalff KG, et al. Aviat Space Environ Med. 1999 Dec;70(12):1223-1226.Hansen BC. Ann N Y Acad Sci. 1999 Nov 18;892:1-24.
The Metabolic SyndromeThe Metabolic Syndrome
Approximately 20% to 30% of the middle-aged population in highly industrialized countries has the metabolic syndrome
By the year 2010, the number of people with the metabolic syndrome in the US could rise to between 50 and 75 million
PrevalencePrevalence
NHANES III: Age-Specific Prevalence of the Metabolic Syndrome (ATP III)
Data are presented as percentage (SE).Age, y
50
45
40
35
30
25
20
15
10
5
0
Pre
va
len
ce
, %
Men
Women
Ford ES, et al. JAMA. 2002;287:356-359.
20-29 30-39 40-49 50-59 60-69 > 70
NHANES III: Age-Adjusted Prevalence of NHANES III: Age-Adjusted Prevalence of 3 Risk Factors for the Metabolic Syndrome*3 Risk Factors for the Metabolic Syndrome*
*Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%.
Pre
vale
nce,
%
24.8
16.4
28.3
22.825.7
35.6
0
5
10
15
20
25
30
35
40
White
25.7% difference
African American Mexican American
Men
Women
56.7%difference
Ford ES, et al. JAMA. 2002;287:356-359.
Epidemiology of the Metabolic Syndrome
0%
5%
10%
15%
20%
25%
30%
35%
40%
Obesity Low HDL HTN HypTrig IR
Age-Adjusted Prevalence of component risk factors
23.7% Overall23.7% Overall 47,000,000 US 47,000,000 US
residents have the residents have the syndromesyndrome
Ford et al: JAMA 2002:287
Association of Multiple Risk Factor Clusteringwith Coronary Artery Disease (CAD)
Jpn Circ J 2001
0
10
20
30
40
0 1 2 3 4Number of Risk Factors
Mul
tiva
riat
e-a d
j ust
edO
dd
s R
atio
fo r
CA
D
1.05.1
9.7
31.3
Metabolic Syndrome
Cardiovascular Disease Mortality Increased in the Metabolic Syndrome
Lakka HM, et al. JAMA. 2002;288:2709-2716.
15
10
5
0
0 2 4 6 8 10 12
Cardiovascular Disease Mortality
RR (95% Cl), 3.55 (1.98-6.43)
Metabolic SyndromeYesNo
Cumulative Hazard, %
Follow-up, y
Prevalence of CHD risk factors: an evolving landscape
• SedentarinessSedentariness• Energy densityEnergy density of foodof food
Metabolic Syndrome is an independent Metabolic Syndrome is an independent predictor of Coronary Heart Disease (CHD)predictor of Coronary Heart Disease (CHD)
Variable
Hazard Ratio
95% CI
Metabolic syndrome
1.7 1.4-2.1
Age (10 year) 1.8 1.5-2.1
LDL-C 1.3 1.1-1.5
Current smoking
1.6 1.3-1.8
WOSCOPS trial (n=6,447 males, aged 45-64)
0% 5% 10% 15%
+METS
-METS
P<.0001
5 yr CHD rate
• Prevalence of METS: 23.8%
*L’Italien et al: American College of Cardiology 2003
Risk of ischemic heart disease (IHD) according to the cumulativenumber of “traditional” and “non-traditional” risk factors
The Québec Cardiovascular Study
Traditional: Traditional: LDL-cholesterol, triglycerides and HDL-cholesterolLDL-cholesterol, triglycerides and HDL-cholesterolNon-traditional: Non-traditional: Insulin, apolipoprotein B and small, dense LDL particlesInsulin, apolipoprotein B and small, dense LDL particles
* Odds ratios are adjusted for systolic blood pressure, family history of IHD* Odds ratios are adjusted for systolic blood pressure, family history of IHD and medication useand medication use
1.0 1.0 1.84.7
2.8
9.1(0.01)
4.4(0.01)
20.8(<0.001)
Od
ds
ra
tio
*
0 1 2 3
Traditional risk factorsNon-traditional risk factors
15
10
5
0
20
25
30
From Lamarche B et al. JAMA (1998) 279:1955-1961
InsulinResistance
Dysregulationof Risk Factor
Parameters
ElevatedBlood Pressure
AtherogenicDyslipidemia
ElevatedGlucose
Pro-thrombotic
State
Pro-inflammatory
State
Obesity
MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
Assessment of accumulation of abdominal fatby measurement of waist at mid-distance between bottom of rib cage and iliac crest. Amount of visceral adipose tissue that can be assessed by CT canbe estimated by waist measurementDespres et al. BMJ 322:716,2001
High visceral fat increases cardiovascular risk
From Pouliot MC et al.Diabetes (1992) 41:826-834
1
1
11
11,2
11
1 (mm
ol/l)
0.0
3.0
6.0
9.0
12.0
15.0
-30 0 30 60 90 120 150 180
Time (min)
1,2
Time (min)
0
200
400
800
1000
1200
6001,2
1,2
1,2 1,2
1,21,2
1,2
1,2
1
Are
a
1,2
Are
a
-30 0 30 60 90 120 150 180 (p
mol
/l)
InsulinGlucose
1 significantly different from Nonobese2 significantly different from Obese with low visceral AT levels
Relationship between waist circumferenceRelationship between waist circumferenceand visceral adipose tissue accumulationand visceral adipose tissue accumulation
20
60
100
140
180
220
Waist girth (cm)Waist girth (cm)
Insu
lin
Insu
lin
(p
mo
l/L
)(p
mo
l/L
)
0,8
0,9
1
1,1
1,2
1,3
Waist girth (cmWaist girth (cm))
Ap
o B
(g
/L)
Ap
o B
(g
/L)
Average apo B (A) and fasting insulin (B) levels among deciles of waist circumference.C LDL particle diameter among deciles of TGconcentration. Dotted lines mean apo B,fasting inslin and LDL peak particle diameter of overall cohort.Lemieux et al. Ciculation 102:179,2000
MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
Risk of Major CHD Event Associated with High Risk of Major CHD Event Associated with High Insulin Levels in Non-diabetic MenInsulin Levels in Non-diabetic Men
Q1 to Q5 = quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile).
Years
Proportion with a major CHD
event
00
5
0.05
0.10
0.15
0.20
0.25
1.00
10 15 20 25
Log rank:Overall P = .001Q5 vs Q1 P < .001
Q1
Q2
Q3Q4Q5
Pyörälä M et al. Circulation 1998;98:398–404.
Central Obesity: The Metabolic Syndrome
(CETP)
VLDL-apoB Intra-abdominal fat
Insulin resistance
Free fatty acids Hepatic Lipase
TG
Small, dense LDL
HDL/HDL2
Brunzell 2001
Ser/Thr phosphorylation of the IRS molecules induces insulin resistanceLe Roith et al., Diabetes Care 24:588 (2001)
Mechanism of fatty acid-induced insulin resistance in skeletal muscle
as proposed by Randle et al.Shulman, J Clin Invest
106:171, 2000
FFA
FA
VLDL
DNL
Adipose tissue
Muscle
Liver
Intestine
TG mobilizationby tissue lipases
TG, CEApoB
Cytosolic TGstores
Oxidation
Lipases
LPL
Mechanisms of VLDL-apoB overproduction Mechanisms of VLDL-apoB overproduction in Insulin Resistancein Insulin Resistance
Hepatic Insulin Resistance
Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425.Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.
Insulin resistance related to dyslipidemia Insulin resistance related to dyslipidemia and cardiovascular diseaseand cardiovascular diseaseGinsberg, J Clin Invest 106:453, 2000Ginsberg, J Clin Invest 106:453, 2000
IRS and StressIRS and Stress
Fatty acid-level elevating psychosocial stressors: Type A personality, anxiety, Fatty acid-level elevating psychosocial stressors: Type A personality, anxiety, depression, hostility, job demand, vital exhaustion, differences in income depression, hostility, job demand, vital exhaustion, differences in income
HemHemingway et al.,BMJ 318:1460 (1999)ingway et al.,BMJ 318:1460 (1999)
Hopelessness in a healthy population (Kuopio)
Everson SA & al Psychosom Med 1996;58:113
Degree of depression and CHD mortality
Lespérance F & al.Circulation 2002;105:1049
BDI=Beck Depression Inventory
P=0.01
P<0.001
P<0.001
AdiposeAdiposeTissueTissue LiverLiver
CytokinesCytokinesUnstableUnstable PlaquesPlaques
CRPCRP
Proinflammatory State
Apo BHDL Prothrombotic
State
Diabetes
The Metabolic Syndrome
Dysregulation of adipocytokinesPortal FFA↑ Adiponectin↓
Insulin resistanceLipoprotein synthesis ↑
PAI-1 ↑Adiponectin↓
HypertensionImpaired glucose tolerance
Hyperlipidemia
?
Environmental Factors Genetic Factors
Atherosclerosis
Visceral Fat Accumulation
TNF- ↑
Atherogenic dyslipidemia Triglycerides
HDL-cholesterol Cholesterol/HDL-cholesterol ratio
«Normal» LDL-cholesterol but apo BSmall, dense LDL and HDLPostprandial hyperlipidemia