COMPLICANZE

CAUSE DI MORTE NEGLI U.S.A.

0

100

200

300

400

Uso didroghe

Incidentistradali

Armida fuoco

Alcool Infezioni Obesità Fumo

Mo

rti

/ an

no

(mig

liai

a)

McGinnis et al, JAMA, 1993

0 20 25 30 35 400,0

0,5

1,0

1,5

2,0

2,5

Mo

rtal

ità

Ris

chio

rel

ativ

o

BMI

Moltobasso Basso Moderato Alto

Moltoalto

RELAZIONE TRA MORTALITÀ E BMI

Bray, Clin Endocrinol Metab, 1999

20 21 22 23 24 25 26 27 28 29 300

1

2

3

4

5

6

BMI

Type 2 Diabetes

Hypertension

Cholelithiasis

Coronary heart disease

RELATIONSHIP BETWEEN BMI AND THE RELATIVE RISK OF:

Willet et al, N Engl J Med, 1999

Rea

lati

ve r

isk

Body Mass Index - B M I (Kg/m2)

International Obesity Task Force

< 18.5 = Sottopeso

18.5 - 24.9 = Normopeso

25.0 - 29.9 = Sovrappeso

30.0 - 34.9 = Obesità classe I

35.0 - 39.9 = Obesità classe II

> 40 = Obesità classe III

0

3

6

9

12

15

18

21

1 2 3 4 5 6 7 8 9 10

RR

Dia

bet

e ti

po

2

Decili

Circonferenza vita

BMI

Wang et al, Am J Clin Nutr, 81: 555-63, 2005

RELAZIONE TRA DECILI DI CIRONFERENZA VITA E BMI E RISCHIO RELATIVO DI DIABETE TIPO 2

Calle et al, N Engl J Med, 1999

RELATIONSHIP BETWEEN BMI AND CAUSES OF DEATH

20 22 24 26 28 30 32 34 36 38 400.6

1.0

1.4

1.8

2.0

2.4

2.8

BMI

Cardiovascular disease

Cancer

All other causes

Rea

lati

veri

sko

f d

eath

20 22 24 26 28 30 32 34 36 38 400.6

1.0

1.4

1.8

2.0

2.4

2.8

BMI

Cardiovascular disease

Cancer

All othercauses

Rea

lati

veri

sko

f d

eath

20 24 28 30 >32

1.0

2.0

3.0

BMIStevens et al, N Engl J Med, 1998

> 85 aa

75-84 aa65-74 aa55-64 aa

45-54 aa

30-44 aaR

ea

lati

veri

sk

of

de

ath

RELATIONSHIP BETWEENCARDIOVASCULAR MORTALITY AND BMI

• Sindrome Metabolica:Insulino-resistenza, diabete, dislipidemia,ipertensione;

• Malattie cardiovascolari• Neoplasie • Colelitiasi• Artrosi• Disordini psico-sociali• Apparato respiratorio:

Insufficienza restrittiva (grandi obesi);Apnee notturne (potenziale grave ipossia).

MORBILITÀ NELL’OBESITÀ

OBESITÀ E RISCHIO CARDIOVASCOLARE

Cause diretteIpertrofia ventricolo sn.Morte improvvisaIpertensione

Cause indiretteSindrome Metabolica:Insulino-resistenza, diabete, dislipidemia, ipertensione;

CAUSE DIRETTE

Ipertrofia del ventricolo sinistro

- Volemia (sodio-ritenzione, attivaz. simpatica, PRA)

- Gittata sistolica- Postcarico

Morte improvvisa - Aritmie (Ipertrofia ventr sin; dilataz. atrio sin;

infiltrazione grassa del sistema di conduzione)

- Q-T- Apnee notturne

CAUSE INDIRETTE Sn. Metabolica

(oppure Sn. da insulino-resistenza o Sn. X)

• Insulino-resistenza• Iperinsulinemia• Diabete tipo 2 o IGT o IFG• Ipertensione• HDL• Trigliceridi• Apo B• LDL piccole e dense• Fibrinogeno• PAI-1• IL-6 e PCR• Disfunzione endoteliale

G.B. Morgagni

Around 1750, Joannes Baptista Morgagni clearly described increased intraabdominal and mediastinal fat accumulation in android obesity. Remarkably, he also recognized the association between visceral obesity, hypertension, hyperuricemia, atherosclerosis, and obstructive sleep apnea syndrome. 

In 1947, Jean Vague “rediscovered” the importance of the “android” obesity phenotype and its association with diabetes, atherosclerosis, gout, and uric-acid calculous disease.

Vague J. La différenciacion sexuelle, facteur déterminant des formes de l'obésité. Presse Med;30:339-40, 1947

Vague J. The degree of masculine differentiation of obesities: a factordetermining predisposition to diabetes, atherosclerosis, gout, and uriccalculous disease. Am J Clin Nutr.;4:20–34, 1956

Overweight, Obesity, and Mortality in a Large ProspectiveCohort of Persons 50 to 71 Years Old

Adams et al, NEJM, 2006530.000, 50-71 aa, 10 yrs

ASSOCIATION OF GENERAL AND ABDOMINAL OBESITY WITH MULTIPLE HEALTH OUTCOMES IN

OLDER WOMANThe IOWA Woman’s Health Study

Folsom AF et al, Arch Internal Med, 2000

Uterine Cancer31.700 55-69 aa

0

3

6

9

12

15

18

21

1 2 3 4 5 6 7 8 9 10

RR

Dia

bet

e ti

po

2

Decili

Circonferenza vita

BMI

Wang et al, Am J Clin Nutr, 81: 555-63, 2005

RELAZIONE TRA DECILI DI CIRONFERENZA VITA E BMI E RISCHIO RELATIVO DI DIABETE TIPO 2

INTERNATIONAL DAY FOR THE EVALUATION OFABDOMINAL OBESITY (IDEA)

A Study of Waist Circumference, Cardiovascular Disease, and DiabetesMellitus in 168 000 Primary Care Patients in 63 Countries

Balkau B et al, Circulation, 2007

Fre

qu

ency

(%

)

Waist Circunference (cm)

Fre

qu

ency

(%

)

CVD

DIABETES

020406080

100120140160180

Lower Higher

Lower

Higher

LOWER-BODY ADIPOSITY AND METABOLIC PROTECTION IN POSTMENOPAUSAL WOMEN

Leg Fat Visce

ral F

at

Tri

gly

ceri

des

(mg

/dl)

Van Pelt et al, J Clin Endocrinol Metab, 90:4573–4578, 2005

4,8

5

5,2

5,4

5,6

5,8

6

3 2 1

3

2

1

Low sc thigh fat is a risk factor for unfavourable glucose and lipid levels

The Health ABC StudyF

asti

ng

glu

cose

(mm

ol/l

)

Snijder et al, Diabetologia, 2005

Visceral Fattertiles

3.000, 70-79 aa

SC thig

h Fat

terti

les

0102030405060708090

100

<23 23- 25- 27,5- 30-

<0,85

0,9

1,0-

BMI

Rapporto

Vita/F

ianch

i

Pre

vale

nza

CH

D %

PREVALENZA DI RISCHIO 10-y-CHD > 15% PER CLASSI DI BMI E WHR:

HEALTH SURVEY FOR ENGLAND

Nanchahal et al, Int J Obes 29:317, 20053.000

Obesity and the risk of MI in 27000 participants from 52 countries: a case-control study

INTERHEART study

Yusuf S et al, Lancet, 366:1640-1649, 2005

AMI

BMI quintiles Waist-to-hip quintiles

Obesity and the risk of MI in 27000 participants from 52 countries: a case-control study

INTERHEART study

Yusuf S et al, Lancet, 366:1640-1649, 2005

AMI

Waist quintiles Hip quintiles

Bellia et al, Diabetes (ADA) 2004

“STUDIO LINOSA”:(364, > 18 aa)

Ford ES, Diabetes Care 2005

PREVALENZA DI OBESITÀ ADDOMINALENELLA S. METABOLICA (NCEP)

NHANES1999–2002

(3.601, > 20 aa)

SMNCEP-R34.5%

ObesitàAddom.NCEP

%

780

20

40

60

80

100 85.2 %

SMATP III21.4%

%

78

80.8 %

0

20

40

60

80

100

ObesitàAddom.NCEP

ObesitàAddom.

IDF

97.5 %

SMNCEP21.4%

DISTRIBUZIONE DEI DEPOSITI DI GRASSO

periferica, ginoide

centripeta, androide

Insulina +++

Catecolamine +

Rilascio FFA +

Grasso viscerale+

+++

+++

Insulina ++

Catecolamine

Rilascio FFA ++

++

Insulina

Catecolamine

Rilascio FFA

Funzione lipolitica

Funzione liposintetica

Grasso sottocutaneo Addominale

Grassogluteo - femorale

Insulina +++

Catecolamine +

Rilascio FFA +

Grasso viscerale+

+++

+++

Insulina ++

Catecolamine

Rilascio FFA ++

++

Insulina

Catecolamine

Rilascio FFA

Funzione lipolitica

Funzione liposintetica

Grasso sottocutaneo Addominale

Grassogluteo - femorale

VISCERAL vs SUBCUTANEOUS FAT

insulin antilipolytic effect.

expression of cortiocosteroids receptors.

DEX-induced LPL stimulation.

expression of androgen receptors.

High FFA portal flux increases hepatic glucose production and VLDL synthesis.

cathecolamines lipolytic effect.

TZD effects on preadipocytes.

Energy Homeostasis

LeptinAdiponectin

ResistinVisfatin

1 Glicop.SAA3PTX

InnateImmune System

TNFIL-6

AcutePhase

ReactantResponse

VEGFAngiotensin II

Vascular Remodeling

LPLHSL

Lipoprotein Metabolism Fibrinolysis

PAI-1

PREADIPOCYTE ADIPOCYTE

Adiponectin in IAA

Anti-atherogenic/antidiabetic:

foam cells vascular remodelling insulin sensitivity hepatic glucose output

IL-6 in IAA

Pro-atherogenic/pro-diabetic:

vascular inflammation insulin signalling

TNF in IAA

Pro-atherogenic/pro-diabetic:

insulin sensitivity in adipocytes (paracrine)

PAI-1 in IAA

Pro-atherogenic:

atherothrombotic risk

Properties of key adipokines

IAA: intra-abdominal adiposity

Marette 2002

Adipokine

PAI-1IL-6LeptinAdiponectinTNF-AngiotensinogenResistin

Visceral Adip Tissue (VAT)Vs

Subcutaneous Adip Tissue (SAT)

VAT> SATVAT > SATSAT > VAT

?VAT > SATVAT > SAT

?

Einstein FH et al: Diabetes 54:672, 2005

0

10

20

30

40

50

SC visc.0

2

4

6

SC visc.0

2

4

6

8

SC visc.0

2

4

6

8

SC visc.

0

2

4

6

8

SC visc.0

1

2

3

4

5

SC visc.0

2

4

6

SC visc.0

1

2

3

4

SC visc.

resistina leptina angiot.-geno adiponectina

PAI-1 IL-6 IL-10 TNF-a

digiuno iperglicemia iperinsulinemia

viscerale e sottocutaneorispondono in modo diverso (espressione di geni)

Grasso viscerale

Grasso

Grasso viscerale

sottocutaneo Addominale

Grasso viscerale

Grasso

Grasso viscerale

sottocutaneo Addominale D

IABETE

DIABETE

INS. RES.INS. RES.

0

5

10

15

20

25

30

Young SO no SC no VF CR

Gabriely et al, Diabetes, 51:2951-2958, 2002

Removal of Visceral Fat Prevents Insulin Resistance of Aging

M(m

g/k

g/m

in)

0123456789

10

Young SO no SC no VF CR

HG

P(m

g/k

g/m

in)

*

*

?

Prima Dopo

36%

EFFETTI DELLA RIMOZIONE DI TESSUTO ADIPOSO SOTTOCUTANEO MEDIANTE LIPOSUZIONE

Nessun effetto su:• Sensibilità insulinica• Pressione arteriosa• Glicemia• Colesterolo tot. E HDL• Trigliceridi• FFA• Leptina• Adiponectina• TNFα• IL-6• PCR

Klein et al, N Engl J Med, 350:2549-2557, 2004

Mandibuloacral dysplasia

LIPODISTROFIE PARZIALI

Sbraccia et al, Diabetes (ADA) 2004

WP

Cap

tazi

on

e d

i glu

cosi

o(m

g. K

g-1

. min

- 1)

0

4

5

6

7

8

2

3

1

CLAMP EUGLICEMICO IPERINSULINEMICO

MAD-WP MAD-AFNormali

Cap

tazi

on

e d

i glu

cosi

o(m

g. K

g-1

. min

- 1)

0

4

5

6

7

8

2

3

1

CLAMP EUGLICEMICO IPERINSULINEMICO

MAD-WP MAD-AFNormali

NORMALE

BMI: 21.2Circ. vita: 91 cm

Massa grassa: 24.8%

AFBMI: 14.3

Circ. vita: 68 cmMassa grassa: 15.4%

lipotoxicity: too fat in the wrong tissue

atherosclerosisinsulin-resist. steatosis diabetes

spill-over

Cree MG et al.: J Clin Endocrinol Metab 89:3864, 2004

0

0.1

0.2

0.3

giovani anziani0

0.05

0.10

0.15

giovani anziani

u.a.

TG nel muscolo TG nel fegato

il deposito di trigliceridi determinainsulino-resistenza

Insulin Resistance And Adiposity Correlate With Acute-phase Reaction and Soluble Cell Adhesion Molecules in Type 2 Diabetes. Leinonen E et al, Atherosclerosis 166:387–394, 2003

NIDDM as a Disease of the Innate Immune System: Association of Acute-phase Reactants and Interleukin-6 with Metabolic Syndrome X. Pickup JC et al, Diabetologia 40:1286 –1292, 1997

INFIAMMAZIONE E DIABETE TIPO 2

INFIAMMAZIONE E DT2: STUDI PROSPETTICI

High White Blood Cell Count is Associated With a Worsening of Insulin Sensitivity and Predicts the Development of Type 2 Diabetes. Vozarova B et al, Diabetes 51:455– 461, 2002

The Relation of Markers Of Inflammation To The Development of Glucose Disorders in the Elderly: The Cardiovascular Health Study.Barzilay JI et al, Diabetes 50:2384 –2389, 2001

Low-grade Systemic Inflammation and the Development of Type 2 Diabetes: The Atherosclerosis Risk In Communities Study. Duncan BB et al, Diabetes 52:1799 –1805, 2003

BMI

Mar

kers

Infi

amm

ato

ri

22 23 24 25 26 2722 23 24 25 26 270

2

4

6

8

10

12

14

PCR

IL-6

Fibrinogeno

1-glicoproteina acida

Kern et al, Am J Physiol Endocrinol Metab. 2001Cottam et al, Obes Surg. 2004Yudkin et al, Atherosclerosis. 2000Berg & Sherer, Circulation 2005

Impact of Weight Loss on Inflammatory Proteins and TheirAssociation With the Insulin Resistance Syndrome in

Morbidly Obese Patients

Kopp et al, Arterioscler Thromb Vasc Biol.2003

CRP IL-6 TNF

CRP

Intensive Lifestyle Intervention or Metformin onInflammation and Coagulation in Participants With

Impaired Glucose ToleranceThe Diabetes Prevention Program Research Group

Diabetes 2005

Xu et al, J Clin Invest 2003Weisberg et al, J Clin Invest 2003