ESPEN - LLL 10-05-2014

Het metabool syndroom

en zijn gevolgen

Dr. Ann VerhaegenIsm . Prof. Dr. L. Van Gaal

Dept Endocrinology, Diabetology and Metabolism University of Antwerp

Historiek

1920Associatie

hypertensie, Hyperglycemie

jicht

1947 Viscerale obesitas

CVDType 2 DM

1965AHT

Hyperglycemieobesitas

1988 ReavenCluster van

risicofactorenSyndroom X

1989Abd overgewicht

AHTHyperglycemie

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 Geen

Extra criteria 2 2 3 1

BMI of buikomtrek BMI > 30 kg/m² ofWHR man > 0.9; vrouw > 0.85

WC ≥ 94 cm man; ≥ 80 cm vrouw

WC ≥ 102 cm man; ≥ 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 vrouwOf 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)

Familiaal T2DM, PCO, sedentariteit, leeftijd, ethniciteit

* Na herziening in 2004 om te harmonieren met ADA criteria voor IFG

WC = waistcircumference; IGT impaired glucose tolerance; IFG: impaired fasting glucose, IR: insulin resistance

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 metabolicsyndrome under both definitions.

E. Ford, Diabetes Care, 2003

Age-specific prevalence of the MS

8814 US adults from NHANES III

Data are presented as

percentage (SE)

Reference: Ford E et al.

JAMA 2002; 287: 356-59 Age, Y

Perc

enta

ge,

%

0

5

10

15

20

25

30

35

40

45

50

20-29 30-39 40-49 50-59 60-69 >70

Men

Women

E. Ford, Diabetes Care, 2003

The prevalence of MetS in Europe isroughly comparable to the US

14

23

41

4

13

26

0

5

10

15

20

25

30

35

40

45

< 40 40 - 55 > 55

Men

Women

Overall frequency (%) of MetS (WHO criteria) in different European cohort studies

EGIR, Diabetes Metab 2002;28:364-376

Age (yrs)

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

Vissers et al, Acta Paedriatica, 2007

Over-all prevalence 4.1 % to 39 % among obese children

Life expectancy at age 40:Impact of excess body weight

35

40

45

50

Female non-smoker Male non-smoker

Lif

e e

xp

ecta

ncy (

years

)

Peeters et al. Ann Intern Med, 2003

Normal 18.5–24.9 kg/m2

Overweight 25–29.9 kg/m2

Obese 30 kg/m2

46.3

43.0

39.2

43.4

40.3

37.5

7.1 y

5.8 y3.1 y

3.3 y

Framingham Heart Study

<8484-<92 92-<99

99-<107107

<25

25-<30

300

5

10

15

20

Pre

vale

nce (

%)

WC quintile (cm)

BMI category (kg/m2)

Prevalence of diabetes across quintiles of waistand BMI subgroups in the IDEA study (men)

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

Age-adjusted prevalence of metabolic syndrome in the US

population over 50 years of age categorized by glucose intolerance

86,0%

71,3%

33,1%

25,8%

0%

25%

50%

75%

100%

NFG IGT IFG DM

Meta

bo

lic S

yn

dro

me

Pre

vale

nce

% of total population

56.9 % 13.7 % 12.3% 17.1%

Alexander CM et al, Diabetes 2003;52:1210-1214

MetS is frequently found in diabetic andpre-diabetic subjects

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

Abdominal Adiposity Increases CHD Risk Independently of BMI

0

20

40

60

80

100

120

140

Low (73.6)

Medium (73.7-81.7)

High (81.8)

WaistCircumference

Tertiles (cm)

High(25.2)

Medium(22.2-25.1)

Low(22.1)

BMI Tertiles (kg/m2)

Age

-Ad

just

ed

CH

D

Inci

de

nce

/10

0,0

00

Pe

rso

n-Y

ear

s

Rexrode et al. JAMA 1998; 280: 1843-8

77

4655

106

8997

128

110

83

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

Esposito K et al. Diab Care 2012;35:2402-2411

Metabolic Syndrome and Risk of Cancer

Omgevingsfactoren• Sedentariteit• Roken• Energie dense voeding• Slaapstoornissen• Maladaptatie aan stress

Congenitale factoren• Thrifty geno - fenotype• Maternele/nutritionele factoren tijdens zwangerschap…

Vetcelhyperplasie en hypertrofieCentrale vetstapeling (VAT)Δ vrij vetzuur metabolisme Δ Vrijstelling van adipokines

Portale VVZ

↑Lipoproteine synthese↑ gluconeogenese

Dyslipidemie

Insuline resistentiehyperinsulinemie

Δ β-cell functie

hyperglycemie

Activatie RAAS en SNS

Natrium reabsorptievasoconstrictie

hypertensie

Oxidatieve stress en endotheeldysfunctie

Proinflammatoire statusProthrombotische status

hypercoagulatie

Metabool syndroom

Positieve energiebalans

Δ vetstapelingEctopische vetstapeling

Steatose/steatohepatitisVetstapeling cardiaal, skeletspier

Adapted from Kaur. Cardiology research practice 2014

37

Buikomtrek ( cm)

Vrouwen Mannen

Normaal <80 <94

Verhoogd 80-88 94-102

Sterk verhoogd > 88 > 102

0

20

40

60

80

100

Pre

vale

nce o

f

insu

lin

resis

tan

ce (

%)

Prevalence of insulin resistance in metabolic abnormalities

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

30

20

10

0Low

HDL-Ca

High

TGb

High

FPGc

High

BPd

>2 risk

factorse

Pre

vale

nce o

f h

igh

wais

t

cir

cu

mfe

ren

ce

asso

cia

ted

wit

h (

%)

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

US population age >20 years

NHANES 1999–2000 cohort

Diabetes and the metabolic syndrome -a highly atherogenic lipid triad

American Diabetes Association. Diabetes Care 2003;26 (Suppl. 1):S83-86

High triglycerides

Low HDL-C

Near normal LDL-C

More small, dense LDL-C

particles

Small,

dense

LDL-C

TG

HDL-C

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

Kotronen A, Yki-Järvinen H, ATVB 2008;28:27-38

Liver fat and metabolic syndrome components

C-Reactive Protein and Adiponectin Levels According to the Degree of Obesity and the Insulin-Resistance Category.

Weiss R et al. N Engl J Med 2004;350:2362-2374.

CRP and adiponectin in obesity and insulin resistance

Other factors linking the metabolic syndrome to cardiovascular disease and type 2 diabetes

TNF-α

Leptin

PAI-1

Unknown adipocytokines

HB-EGF

IL - 6Resistin

Insulin Resistance

AtherosclerosisAdiponectin

PAI-1, obesity and visceral fat

Mertens I. et al, Obesity Reviews, 2002

12.0±0.8

18.1±9.9

12.1±8.3

0

10

20

30

40

non obese obese obese

PAI-

1 (

AU

/ml)

<VAT median >VAT

*

*p=0.001

Incidence of type 2 diabetes by quartiles of fibrinogen, CRP and PAI-1

Festa et al, Diabetes 2002

p=0.001p=0.001p=0.06

PAI-1 predicts the development of type 2 diabetes independent of insulin resistance and other risk factors

C-Reactive Protein (CRP) as Predictor of Cardiovascular Mortality

Jager A et al. Arterioscler Thromb Vasc Biol 1999

1.00

0.98

0.96

0.94

0.92

0.90

0 1 2 3 4 5

Follow-up (years)

Fra

cti

on

of

su

bje

cts

ali

ve

NGT IGT NIDDM

Su

bje

cts

wit

h C

RP

>2

.84

mg/l (

%)

60

50

40

30

20

10

0

CRP < 2.84mg/l

p<0.006

CRP>2.84mg/l

CRP and the metabolic syndrome

N. Sattar et al, Circulation 2003

Maternal nutrition and fetal programming in the metabolicsyndrome

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

Prothrombosis

Fibrinogen

PAI-1

Liver steatosis

And NAFLD

Renal

hyperfiltration,

MicroalbuminuriaInflammatory

response

Left ventricular hypertrophy

Congestive heart failure

HypertensionTriglycerides

Apolipoprotein-B

HDL-C

Small, dense particles

Visceral

adiposity

Insulin resistance

Glucose intolerance

Hyperglycaemia

Type 2 diabetes

Endothelial

dysfunction

DyslipidaemiaHypertensionType 2 DM

Weight Loss and Cardiovascular Risk

Obesity

Glycaemia HbA1c

Systolic BP Diastolic BP

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)

0

10

20

30

40

50

0 1 2 3 4 5 6

YEAR

Intervention group Control Group

Leefstijl

Metformin

DPS - Finland DPP - VS SLIM - Nederland

IDPP - India

Risico - 58% ↓

Risico - 58% ↓

Risico - 58% ↓

Risico - 28,5% ↓

ControlEDIPS Newcastle - UK

Risico - 55% ↓

Da Qing - China

Risico 43% ↓

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 doesnot improve metabolic risk

Klein S et al., NEJM, 2004

Klein et al., NEJM, 2004

Reduction of subcutaneous fat mass doesnot improve inflammatory status

Stanhope et al., J Clin Invest 2009

Effect of glucose and fructose-sweetened beverages

on visceral fat in obese subjects

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 metabolicsyndrome

Strasser. Ann NY Acad Sci. 2013;1281:141-159

Aerobic endurance training

Resistance training

Exercise and VAT reduction

Vissers, Van Gaal. PLoS One. 2013;8(2):e56415. doi: 10.1371/journal.pone.0056415. Epub 2013 Feb 8.