COMPLICANZE
CAUSE DI MORTE NEGLI U.S.A.
Morti / anno
(migliaia)
400
300
200
100
0
Uso di Incidenti
Armi
Alcool Infezioni Obesità
droghe stradali da fuoco
Fumo
McGinnis et al, JAMA, 1993
RELAZIONE TRA MORTALITÀ E BMI
Mortalità
Rischio relativo
2,5
2,0
1,5
1,0
0,5
Molto
basso
Basso
Moderato
Alto
Molto
alto
0,0
0
20
25
30
35
40
BMI
Bray, Clin Endocrinol Metab, 1999
RELATIONSHIP BETWEEN BMI AND THE RELATIVE RISK OF:
Type 2 Diabetes
Realative risk
6
5
Hypertension
4
Cholelithiasis
3
Coronary heart disease
2
1
0
20 21 22 23 24 25 26 27 28 29 30
BMI
Willet et al, N Engl J Med, 1999
Body Mass Index - B M I (Kg/m )
2
< 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
International Obesity Task Force
RELAZIONE TRA DECILI DI CIRONFERENZA VITA E
BMI E RISCHIO RELATIVO DI DIABETE TIPO 2
RR Diabete tipo 2
21
Circonferenza vita
18
15
BMI
12
9
6
3
0
1
2
3
4
5
6
7
8
9
10
Decili
Wang et al, Am J Clin Nutr, 81: 555-63, 2005
RELATIONSHIP BETWEEN BMI AND CAUSES OF DEATH
Cardiovascular disease
2.8
Cardiovascular disease
2.4
All other
causes
2.0
1.8
Cancer
1.4
1.0
Realative risk
of death
Realative risk
of death
2.4
2.8
2.0
All other causes
1.8
1.4
Cancer
1.0
0.6
20 22 24 26 28 30 32 34 36 38 40
BMI
0.6
20 22 24 26 28 30 32 34 36 38 40
BMI
Calle et al, N Engl J Med, 1999
RELATIONSHIP BETWEEN
CARDIOVASCULAR MORTALITY AND BMI
30-44 aa
Realative risk
of death
45-54 aa
3.0
55-64 aa
65-74 aa
75-84 aa
2.0
> 85 aa
1.0
20
24
28
30
>32
BMI
Stevens et al, N Engl J Med, 1998
MORBILITÀ NELL’OBESITÀ
• 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).
OBESITÀ E RISCHIO
CARDIOVASCOLARE
Cause dirette
Cause indirette
Ipertrofia ventricolo sn.
Morte improvvisa
Ipertensione
Sindrome 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 factor
determining predisposition to diabetes, atherosclerosis, gout, and uric
calculous disease. Am J Clin Nutr.;4:20–34, 1956
Overweight, Obesity, and Mortality in a Large Prospective
Cohort of Persons 50 to 71 Years Old
530.000, 50-71 aa, 10 yrs
Adams et al, NEJM, 2006
ASSOCIATION OF GENERAL AND ABDOMINAL
OBESITY WITH MULTIPLE HEALTH OUTCOMES IN
OLDER WOMAN
The IOWA Woman’s Health Study
Uterine Cancer
31.700 55-69 aa
Folsom AF et al, Arch Internal Med, 2000
RELAZIONE TRA DECILI DI CIRONFERENZA VITA E
BMI E RISCHIO RELATIVO DI DIABETE TIPO 2
RR Diabete tipo 2
21
Circonferenza vita
18
15
BMI
12
9
6
3
0
1
2
3
4
5
6
7
8
9
10
Decili
Wang et al, Am J Clin Nutr, 81: 555-63, 2005
INTERNATIONAL DAY FOR THE EVALUATION OF
ABDOMINAL OBESITY (IDEA)
Frequency (%)
A Study of Waist Circumference, Cardiovascular Disease, and Diabetes
Mellitus in 168 000 Primary Care Patients in 63 Countries
CVD
Frequency (%)
DIABETES
Waist Circunference (cm)
Balkau B et al, Circulation, 2007
Triglycerides
(mg/dl)
LOWER-BODY ADIPOSITY AND METABOLIC
PROTECTION IN POSTMENOPAUSAL WOMEN
180
160
140
120
100
80
60
40
20
0
Higher
Lower
Lower
Higher
Leg Fat
Van Pelt et al, J Clin Endocrinol Metab, 90:4573–4578, 2005
Low sc thigh fat is a risk factor for
unfavourable glucose and lipid levels
The Health ABC Study
5,8
(mmol/l)
Fasting glucose
6
5,6
5,4
1
5,2
2
5
3
4,8
3
3.000, 70-79 aa
2
Visceral Fat
tertiles
1
Snijder et al, Diabetologia, 2005
Prevalenza CHD %
PREVALENZA DI RISCHIO 10-y-CHD > 15%
PER CLASSI DI BMI E WHR:
HEALTH SURVEY FOR ENGLAND
100
90
80
70
60
50
40
30
20
10
0
1,00,9
<0,85
<23
23-
25-
27,5-
30-
BMI
3.000
Nanchahal et al, Int J Obes 29:317, 2005
Obesity and the risk of MI in 27000 participants from 52
countries: a case-control study
INTERHEART study
AMI
BMI quintiles
Waist-to-hip quintiles
Yusuf S et al, Lancet, 366:1640-1649, 2005
Obesity and the risk of MI in 27000 participants from 52
countries: a case-control study
INTERHEART study
AMI
Waist quintiles
Hip quintiles
Yusuf S et al, Lancet, 366:1640-1649, 2005
PREVALENZA DI OBESITÀ ADDOMINALE
NELLA S. METABOLICA (NCEP)
NHANES
1999–2002
“STUDIO LINOSA”:
(364, > 18 aa)
(3.601, > 20 aa)
%
85.2 %
100
97.5 %
%
100
80.8 %
80
80
60
60
40
40
20
20
0
78
SM
NCEP-R
34.5%
Ford ES, Diabetes Care 2005
Obesità
Addom.
NCEP
0
78
SM
SM
NCEP
ATP
III
21.4%
21.4%
Obesità
Addom.
NCEP
Obesità
Addom.
IDF
Bellia et al, Diabetes (ADA) 2004
DISTRIBUZIONE DEI DEPOSITI DI GRASSO
centripeta,
androide
periferica,
ginoide
Grasso
gluteo - femorale
Grasso
sottocutaneo
Addominale
Insulina
++
+
Catecolamine
++
+
Rilascio FFA
++
Insulina
Funzione
Catecolamine
liposintetica
+++
Rilascio FFA
Grasso viscerale
Insulina
Funzione +
Catecolamine
lipolitica +++
Rilascio FFA
+++
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.
Innate
Immune System
Energy
Homeostasis
Leptin
Adiponectin
Resistin
Visfatin
TNF
IL-6
1 Glicop.
SAA3
PTX
PREADIPOCYTE
ADIPOCYTE
LPL
HSL
Acute
Phase
Reactant
Response
VEGF
Angiotensin II
PAI-1
Vascular
Remodeling
Lipoprotein
Metabolism
 Fibrinolysis
Properties of key adipokines
Adiponectin
 in IAA
IL-6
 in IAA
TNF
 in IAA
PAI-1
 in IAA
Anti-atherogenic/antidiabetic:
 foam cells
 vascular remodelling
 insulin sensitivity  hepatic glucose output
Pro-atherogenic/pro-diabetic:
 vascular inflammation  insulin signalling
Pro-atherogenic/pro-diabetic:
 insulin sensitivity in adipocytes (paracrine)
Pro-atherogenic:
 atherothrombotic risk
IAA: intra-abdominal adiposity
Marette 2002
Adipokine
Visceral Adip Tissue (VAT)
Vs
Subcutaneous Adip Tissue (SAT)
PAI-1
IL-6
Leptin
Adiponectin
TNF-
Angiotensinogen
Resistin
VAT> SAT
VAT > SAT
SAT > VAT
?
VAT > SAT
VAT > SAT
?
viscerale e sottocutaneo
rispondono in modo diverso (espressione di geni)
50
resistina
6
leptina
40
4
30
20
2
10
0
8
SC visc.
PAI-1
0
5
SC visc.
IL-6
angiot.-geno
8
8
6
6
4
4
2
2
0
0
6
SC visc.
IL-10
4
6
3
4
2
2
1
0
0
SC visc.
digiuno
adiponectina
4
4
SC visc.
TNF-a
3
2
2
0
1
0
SC visc.
SC visc.
SC visc.
iperinsulinemia
iperglicemia
Einstein FH et al: Diabetes 54:672, 2005
Grasso
Addominale
sottocutaneo
INS. RES.
Grasso viscerale
D
I
A
B
E
T
E
Removal of Visceral Fat Prevents Insulin
Resistance of Aging ?
30
*
(mg/kg/min)
M
25
20
15
10
5
0
(mg/kg/min)
HGP
Young
SO
no SC
10
9
8
7
6
5
4
3
2
1
0
no VF
CR
*
Young
SO
no SC
no VF
CR
Gabriely et al, Diabetes, 51:2951-2958, 2002
EFFETTI DELLA RIMOZIONE DI TESSUTO ADIPOSO
SOTTOCUTANEO MEDIANTE LIPOSUZIONE
Prima
Dopo
 36%
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
LIPODISTROFIE PARZIALI
Mandibuloacral dysplasia
WP
BMI: 21.2
Circ. vita: 91 cm
AF
Massa grassa: 24.8%
BMI: 14.3
Circ. vita: 68 cm
Massa grassa: 15.4%
8
7
(mg.Kg-1.min-1)
Captazione di glucosio
CLAMP EUGLICEMICO IPERINSULINEMICO
6
5
4
3
2
1
0
Normali
NORMALE
MAD-WP MAD-AF
Sbraccia et al, Diabetes (ADA) 2004
lipotoxicity: too fat in the wrong tissue
spill-over
insulin-resist.
steatosis
diabetes
atherosclerosis
il deposito di trigliceridi determina
insulino-resistenza
TG nel muscolo
TG nel fegato
0.15
0.3
0.10
0.2
u.a.
0.05
0
0.1
giovani
anziani
0
giovani
Cree MG et al.: J Clin Endocrinol Metab 89:3864, 2004
anziani
INFIAMMAZIONE E DIABETE TIPO 2
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
Insulin Resistance And Adiposity Correlate With Acutephase Reaction and Soluble Cell Adhesion Molecules in
Type 2 Diabetes.
Leinonen E et al, Atherosclerosis 166:387–394, 2003
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
Markers
Infiammatori
14
PCR
12
IL-6
10
8
Fibrinogeno
6
4
1-glicoproteina acida
2
0
22
23
24
25
BMI
26
27
Kern et al, Am J Physiol Endocrinol Metab. 2001
Cottam et al, Obes Surg. 2004
Yudkin et al, Atherosclerosis. 2000
Berg & Sherer, Circulation 2005
Impact of Weight Loss on Inflammatory Proteins and Their
Association With the Insulin Resistance Syndrome in
Morbidly Obese Patients
CRP
IL-6
TNF
Kopp et al, Arterioscler Thromb Vasc Biol.2003
Intensive Lifestyle Intervention or Metformin on
Inflammation and Coagulation in Participants With
Impaired Glucose Tolerance
The Diabetes Prevention Program Research Group
CRP
Diabetes 2005
Xu et al, J Clin Invest 2003
Weisberg et al, J Clin Invest 2003