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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
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