metabool syndroom

ESPEN - LLL
10-05-2014
Het metabool syndroom
en zijn gevolgen
Dr. Ann Verhaegen
Ism . Prof. Dr. L. Van Gaal
Dept Endocrinology, Diabetology and Metabolism
University of Antwerp
Historiek
1920
Associatie
hypertensie,
Hyperglycemie
jicht
1965
AHT
Hyperglycemie
obesitas
1947
Viscerale obesitas
CVD
Type 2 DM
1988 Reaven
Cluster van
risicofactoren
Syndroom X
1989
Abd overgewicht
AHT
Hyperglycemie
HyperTG
From insulin resistance to the metabolic syndrome
Initial syndrome X
Insulin resistance
Hyperinsulinemia
Glucose intolerance
Hypertriglyceridemia
Low HDL-cholesterol
Hypertension
Coronary heart disease
Reaven G et at, Diabetes 1988
WHO
(1998)
EGIR
(1999)
ATPIII
(2001)
AACE
(2003)
IDF
(2005)
Insulin resistance
IGT, IFG, T2DM or ↑
IR
Plasma insuline > 75
%
geen
IGT of IFG
Extra criteria
2
2
3
1
BMI of buikomtrek
BMI > 30 kg/m² of
WHR man > 0.9;
vrouw > 0.85
WC ≥ 94 cm man; ≥ 80 WC ≥ 102 cm man; ≥
cm vrouw
88 cm vrouw
BMI ≥ 25 kg/m²
≥ WC
( ras specifiek)
+ 2 van onderstaande
Lipiden
TG ≥ 150 mg/dl en/of
HDL ≤ 35 mg/dl man;
≤ 39 mg/dl vrouw
TG ≥ 150 mg/dl en/of
HDL ≤ 39 mg/dl
TG ≥ 150 mg/dl en/of
HDL ≤ 40 mg/dl man;
≤ 50 mg/dl vrouw
TG ≥ 150 mg/dl en/of
HDL ≤ 35 mg/dl man;
≤ 39 mg/dl vrouw
TG ≥ 150 mg/dl en/of
HDL ≤ 40 mg/dl man;
≤ 50 mg/dl vrouw
Of R/
Bloeddruk
≥ 140/90 mmHg
≥ 140/90 mmHg of R/
≥ 130/85 mmHg
≥ 130/85 mmHg
≥ 130/85 mmHg of R/
Glucose
IGT, IFG, T2DM
IGT of IFG
> 100 mg/dl ( *)
IGT of IFG
≥100 mg/dl
Other
µAlb ( > 20 mg/min of
albumin/creat > 30
mg/g)
WC = waistcircumference; IGT impaired glucose tolerance; IFG: impaired fasting glucose, IR: insulin resistance
* Na herziening in 2004 om te harmonieren met ADA criteria voor IFG
Familiaal T2DM, PCO,
sedentariteit, leeftijd,
ethniciteit
Geen
Geslacht en ras specifieke criteria voor
tailleomtrek
Ethnische groep
Tailleomtrek ( cm)
Mannen
Vrouwen
Europeanen
≥ 94
≥ 80
USA
≥ 102
≥ 88
Zuid Azië
(gebaseerd op Chinese, Malaysische en
Indiase populatie)
≥ 90
≥ 80
Chinese
≥ 90
≥ 80
Japanese
≥ 90
≥ 80
Ethnische Zuid en Centraal –Amerikaanse
populaties
Zuid Aziatische criteria tot meer gegevens
Sub Sahara Afrika
Europese criteria tot meer gegevens
Oost Mediteraans en Arabische populatie
Europese criteria tot meer gegevens
Kaur. Cardiology res and pract 2014
Prevalence of metabolic syndrome
Participants (n=8608)
ATP III
WHO
all
23.9 %
25.1 %
African-American men
16.5 %
24.9 %
86.2 % were classified as either having or not having the metabolic
syndrome under both definitions.
E. Ford, Diabetes Care, 2003
Age-specific prevalence of the MS
50
8814 US adults from NHANES III
Men
Women
Percentage, %
45
40
35
30
25
20
15
10
Data are presented as
percentage (SE)
Reference: Ford E et al.
JAMA 2002; 287: 356-59
5
0
20-29
30-39
40-49
50-59
60-69
>70
Age, Y
E. Ford, Diabetes Care, 2003
The prevalence of MetS in Europe is
roughly comparable to the US
45
40
35
41
Men
Women
30
26
23
25
20
15
14
13
10
4
5
0
Age (yrs)
< 40
40 - 55
> 55
Overall frequency (%) of MetS (WHO criteria) in different European cohort studies
EGIR, Diabetes Metab 2002;28:364-376
Prevalence of metabolic syndrome in youngsters
• In the pediatric population, the overall prevalence is estimated at 4%,
but it is 20% to 50% in overweight children.
• Cook et al., Arch Pediatr Adolesc Med, 2003
• Weiss et al., NEJM, 2004
• Invitti et al., Int J Obes, 2006
Metabolic syndrome in Antwerp schoolchildren
Over-all prevalence 4.1 % to 39 % among obese children
Vissers et al, Acta Paedriatica, 2007
Life expectancy at age 40:
Impact of excess body weight
Normal 18.5–24.9 kg/m2
Framingham Heart Study
Overweight 25–29.9 kg/m2
Life expectancy (years)
50
Obese 30 kg/m2
3.3 y
45
7.1 y
3.1 y
46.3
5.8 y
43.4
43.0
40
40.3
39.2
37.5
35
Female non-smoker
Male non-smoker
Peeters et al. Ann Intern Med, 2003
Prevalence of diabetes across quintiles of waist
and BMI subgroups in the IDEA study (men)
Prevalence (%)
20
15
10
5
30
0
<84
25-<30
84-<92 92-<99
99-<107
<25
BMI category (kg/m2)
107
WC quintile (cm)
Balkau B, Després J-P, Van Gaal et al. Circulation 2007
Metabolic syndrome as a predictor of type 2 diabetes
(NCEP-ATP III)
Ford et al. Diabetes Care, 2005
MetS is frequently found in diabetic and
pre-diabetic subjects
Age-adjusted prevalence of metabolic syndrome in the US
population over 50 years of age categorized by glucose intolerance
100%
Metabolic Syndrome
Prevalence
86,0%
71,3%
75%
50%
33,1%
25,8%
25%
0%
NFG
% of total
population
56.9 %
IGT
13.7 %
IFG
12.3%
DM
17.1%
Alexander CM et al, Diabetes 2003;52:1210-1214
Metabolic syndrome and cardiovascular disease
(NCEP-ATP III)
Ford et al. Diabetes Care, 2005
Which risk with metabolic syndrome in children?
Berenson et al., NEJM, 1998
Age-Adjusted CHD
Incidence/100,000 Person-Years
Abdominal Adiposity Increases CHD Risk Independently of BMI
Waist
Circumference
Tertiles (cm)
128
140
120
100
80
60
40
20
0
110
106
97 83
89
77
55
46
High
(25.2)
Medium
(22.2-25.1)
High (81.8)
Medium (73.7-81.7)
Low (73.6)
Low
(22.1)
BMI Tertiles (kg/m2)
Rexrode et al. JAMA 1998; 280: 1843-8
The metabolic syndrome and its association with CHD, CVD and
total mortality
Unadjusted Kaplan-Meier hazard curves for men with and without the Metabolic Syndrome
based on factor analysis. Median follow-up was 11.6 (9.1-13.7) years. Relative risks were
determined by age-adjusted Cox proportional hazards regression analysis.
Lakka HM et al, J Am Med Assoc 2002; 288:2709--16
Metabolic Syndrome and Risk of Cancer
Esposito K et al. Diab Care 2012;35:2402-2411
Omgevingsfactoren
• Sedentariteit
• Roken
• Energie dense voeding
• Slaapstoornissen
• Maladaptatie aan stress
Δ vrij vetzuur metabolisme
Congenitale factoren
• Thrifty geno - fenotype
• Maternele/nutritionele factoren
tijdens zwangerschap
…
Positieve energiebalans
Vetcelhyperplasie en hypertrofie
Centrale vetstapeling (VAT)
Insuline resistentie
hyperinsulinemie
Portale VVZ
Δ β-cell functie
↑Lipoproteine synthese
↑ gluconeogenese
hyperglycemie
Dyslipidemie
Δ vetstapeling
Ectopische
vetstapeling
Steatose/steatohepatitis
Vetstapeling cardiaal,
skeletspier
Δ Vrijstelling van adipokines
Activatie RAAS en SNS
Oxidatieve stress
en endotheeldysfunctie
Natrium reabsorptie
vasoconstrictie
Proinflammatoire status
Prothrombotische status
hypertensie
hypercoagulatie
Metabool syndroom
Adapted from Kaur. Cardiology research practice 2014
Buikomtrek ( cm)
Vrouwen
Mannen
Normaal
<80
<94
Verhoogd
80-88
94-102
> 88
> 102
Sterk verhoogd
37
Prevalence of
insulin resistance (%)
Prevalence of insulin resistance in metabolic
abnormalities
100
80
60
40
20
0
Adapted from Bonora E, et al. Diabetes 1998; 47:1643–1649.
Effect of Insulin Resistance on the Prevalence of the Metabolic
Syndrome According to the Degree of Obesity.
Weiss R et al. N Engl J Med 2004;350:2362-2374.
High waist circumference is associated with multiple cardio
vascular risk factors
Prevalence of high waist
circumference
associated with (%)
US population age >20 years
30
20
10
0
Low
HDL-Ca
High
TGb
High
FPGc
High
BPd
>2 risk
factorse
a<40
mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL;
d>130/85 mmHg; eNCEP/ATP III metabolic syndrome
NHANES 1999–2000 cohort
Diabetes and the metabolic syndrome a highly atherogenic lipid triad
Small,
dense
LDL-C
 TG
 High triglycerides
 Low HDL-C
 Near normal LDL-C
 More small, dense LDL-C
particles
 HDL-C
American Diabetes Association. Diabetes Care 2003;26 (Suppl. 1):S83-86
Free fatty acids contribute to insulin resistance & ectopic fat
Adapted from L. Van Gaal et al, Nature, 2006
Després JP et al Nature 2006
Effect of short-term carbohydrate overfeeding and long-term weight
loss on liver fat in overweight humans
Sevastianova K et al. Am J Clin Nutr 2012;96:727-734
Liver fat and metabolic syndrome components
Kotronen A, Yki-Järvinen H, ATVB 2008;28:27-38
C-Reactive Protein and Adiponectin Levels According to the Degree of Obesity and the
Insulin-Resistance Category.
CRP and adiponectin in obesity and insulin resistance
Weiss R et al. N Engl J Med 2004;350:2362-2374.
Other factors linking the metabolic syndrome to
cardiovascular disease and type 2 diabetes
TNF-α
PAI-1
Leptin
HB-EGF
IL - 6
Resistin
Adiponectin
Atherosclerosis
Insulin Resistance
Unknown adipocytokines
PAI-1, obesity and visceral fat
PAI-1 (AU/ml)
40
*
18.1±9.9
30
12.1±8.3
20
12.0±0.8
10
0
non obese
*p=0.001
obese
<VAT median
obese
>VAT
Mertens I. et al, Obesity Reviews, 2002
Incidence of type 2 diabetes by quartiles of fibrinogen, CRP
and PAI-1
p=0.06
p=0.001
p=0.001
PAI-1 predicts the development of type 2 diabetes
independent of insulin resistance and other risk factors
Festa et al, Diabetes 2002
C-Reactive Protein (CRP) as Predictor of
Cardiovascular Mortality
CRP < 2.84mg/l
0.98
p<0.006
Subjects with CRP>2.84mg/l (%)
Fraction of subjects alive
1.00
0.96
0.94
0.92
0.90
0
60
CRP>2.84mg/l
50
40
30
20
10
0
NGT
1
IGT NIDDM
2
3
Follow-up (years)
4
5
Jager A et al. Arterioscler Thromb Vasc Biol 1999
CRP and the metabolic syndrome
N. Sattar et al, Circulation 2003
Maternal nutrition and fetal programming in the metabolic
syndrome
Brenseke. J Pregnancy. 2013;2013:368461. doi: 10.1155/2013/368461. Epub 2013 Feb 14.
Sleep apnoea and metabolic syndrome
Eur Respir Rev 2013;22:353-364
Klinische uiting van het metabool syndroom
Triglycerides 
Apolipoprotein-B 
HDL-C 
Small, dense particles
Endothelial
dysfunction
Liver steatosis
And NAFLD
Prothrombosis
Fibrinogen 
PAI-1 
Hypertension
Visceral
adiposity
Inflammatory
response 
Left ventricular hypertrophy
Congestive heart failure
Insulin resistance
Glucose intolerance
Hyperglycaemia
Type 2 diabetes
Renal
hyperfiltration,
Microalbuminuria
Weight Loss and Cardiovascular Risk
Obesity
Type 2 DM
Hypertension
 Glycaemia
 HbA1c
 Systolic BP
 Diastolic BP
Dyslipidaemia
 Total Cholesterol
 LDL Cholesterol
 HDL Cholesterol
Moderate
Weight Loss
(5-10%)
Van Gaal L. et al Int J Obesity, 1998
How do We Define Response at 1 Year?
<5% loss
•
Improved CV risk profile (Wilson 1999)
>5%
•
•
•
Diabetes prevention (Tuomilehto 2001, Knowler 2002)
Improved Quality of Life (Kolotkin 1995)
Symptomatic improvements- OA of knee (Felson DT, 1992)
>10% loss
•
•
•
Improvements in sleep apnoea (Largerstrand 1993)
Improved lung function in asthma (Stenius-Aarniala 2000)
Decreased mortality (Singh 1992, Williamson 1995)
DPP - VS
DPS - Finland
Intervention group
SLIM - Nederland
Control Group
Risico - 58% ↓
50
40
Risico - 58% ↓
Risico - 58% ↓
30
20
10
0
0
1
2
3
4
5
6
YEAR
EDIPS Newcastle - UK
Da Qing - China
Risico 43% ↓
Risico - 55% ↓
IDPP - India
Control
Risico - 28,5% ↓
Metformin
Leefstijl
Targeting the consequences of the metabolic syndrome in the
Diabetes Prevention Program
Goldberg, Mather. Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2077-90
Swedish Obese Subjects (SOS) trial – a prospective controlled intervention
study of bariatric surgery
Journal of Internal Medicine Volume 273, Issue 3, pages 219-234, 8 FEB 2013 DOI: 10.1111/joim.12012
Differentiated long-term effects of intentional weight
losson diabetes and hypertension
346 patients gastric surgery vs. control (8-year follow-up)
Sjostrom CD et al. Hypertension 2000;36:20
Intra-abdominal obesity or fat mass?
Reduction of subcutaneous fat mass does
not improve metabolic risk
Klein S et al., NEJM, 2004
Reduction of subcutaneous fat mass does
not improve inflammatory status
Klein et al., NEJM, 2004
Effect of glucose and fructose-sweetened beverages
on visceral fat in obese subjects
Stanhope et al., J Clin Invest 2009
Dietary strategies to reduce metabolic syndrome
Reviews in Endocrine and Metabolic Disorders 2013;14 (3):241-254
Physical exercise and mortality
Strasser. Ann NY Acad Sci. 2013;1281:141-159
Physical exercise and effects on the components of the metabolic
syndrome
Aerobic endurance training
Resistance training
Strasser. Ann NY Acad Sci. 2013;1281:141-159
Exercise and VAT reduction
Vissers, Van Gaal. PLoS One. 2013;8(2):e56415. doi: 10.1371/journal.pone.0056415. Epub 2013 Feb 8.

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