Michele O. CarrubaDepartment of Pharmacology, Chemotherapy and Medical

Toxicology

Center for Study and Research on Obesity

SINDROME METABOLICA:PREVENIRE O CURARE?

School of Medicine

Department of Pharmacology, Chemotherapy and Medical Toxicology

CENTER FOR STUDY AND RESEARCH ON OBESITY 

University of Milan, Italy

SINDROME METABOLICA:PREVENIRE O CURARE?

Michele O. CarrubaMichele O. CarrubaDepartment of Pharmacology, Chemotherapy and Medical ToxicologySchool of MedicineVia Vanvitelli, 3220129 – Milan (Italy)

Distribuzione della popolazione italiana nelle varie condizioni di peso

SottopesoNormopesoSovrappesoObeso

4.000.000

16.000.000

1.500.000

Fonte: ISTAT, 4° Rapporto sull’Obesità in Italia. Istituto Auxologico Italiano, 2002

Prevalenza dell’obesità (IMC>30) in funzione dell’età negli UOMINI

0

2

46

810

1214

16

18-24 25-34 35-44 45-54 55-64 65-74 >74

%

Fonte: ISTAT, 4° Rapporto sull’Obesità in Italia. Istituto Auxologico Italiano, 2002

Prevalenza dell’obesità (IMC>30) in funzione dell’età nelle DONNE

0

2

46

810

1214

16

18-24 25-34 35-44 45-54 55-64 65-74 >74

%

Fonte: ISTAT, 4° Rapporto sull’Obesità in Italia. Istituto Auxologico Italiano, 2002

Sovrappeso e obesità aumentano il rischio di MCV e di mortalità per tutte le cause

Dati relativi a 1 milione di uomini e donne seguiti per 16 anni con età media di 57 anni che non hanno mai fumato e non avevano una storia di malattia all’arruolamento.

Calle et al. N Engl J Med. 1999;341:1097-1105

Ris

chio

rel

ativ

o di

mor

talit

àpe

r tu

tte

le

cau

se

Mortalità per tutte le cause

Ris

chio

rel

ativ

o di

m

orta

lità

per

mal

atti

a ca

rdio

vasc

olar

e Mortalità per MCV

0.6

3.0

2.6

2.2

1.8

1.4

1.0

>18 25 30 >40 BMI (kg/m2)

DonneUomini

Normopeso ObesiSovrappeso

BMI (kg/m2)0.6

3.0

2.6

2.2

1.8

1.4

1.0Normopeso Obesi

DonneUomini

sovrappeso

>18 25 30 >40

Peeters et al. Ann Intern Med 2003; 138: 24-32

35

40

45

50

Donne Non-fumatrici Uomini Non-fumatori

Aspettativa di vita a 40 anni di età Normali (18,5-24,9 kg/m2)

Sovrappeso (25-29,9 kg/m2)

Obesi (≥30 kg/m2)

46.3

43.0

39.2

43.4

40.3

37.5

7,1anni

5,8 anni

3,1 anni

3,3anni

Aspettativa di vita a 40 anni: impatto dell’eccesso di peso corporeo

Un parametro fondamentale: la circonferenza addominale

Unmet clinical need associated with abdominal obesity

Patients with abdominal obesity (high waist circumference) often present with one or more additional CV risk factors

NHANES 1999–2000 cohort (data on file)

CV risk factors in a typical patient with abdominal obesity

Abdominal obesity increases the risk of developing type 2

diabetes

<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3

24

20

16

12

8

4

0

Rel

ativ

e ris

k

Waist circumference (cm)

Carey et al 1997

Intra-abdominal adiposity and dyslipidaemia

Pouliot et al 1992

310

248

186

124

62

0

60

45

30m

g/dL

mg/

dL

Triglycerides

Lean

HDL-cholesterol

Visceral fat(obese subjects)

Low High LeanVisceral fat

(obese subjects)

Low High

Abdominal obesity andincreased risk of CHD

Waist circumference was independently associated with increased age-adjusted risk of CHD, even after adjusting for

BMI and other CV risk factors

0.0

0.5

1.0

1.5

2.0

2.53.0

<69.8 69.8-<74.2 74.2-<79.2 79.2-<86.3 86.3-<139.7

1.27

2.06 2.31 2.44

p for trend = 0.007

Rel

ativ

e ris

k

Rexrode et al 1998

Quintiles of waist circumference (cm)

Abdominal obesity and increased risk of cardiovascular events

Dagenais et al 2005

Adj

uste

d re

lativ

e ris

k

1 1 1

1.17 1.16 1.14

1.29 1.271.35

0.8

1

1.2

1.4

CVD death MI All-cause deaths

Tertile 1Tertile 2Tertile 3

Men Women<95

95–103>103

<8787–98>98

Waistcirc. (cm):

Adjusted for BMI, age, smoking, sex, CVD, disease, DM, HDL-C, total-C

The HOPE Study

Elaborazione Centro Studi Ricerca Obesità (CSRO) e Farmacoeconomia UniMI

“STUDIO SPESA” : COSTI DIRETTI ANNUI DELL’OBESITÀ IN ITALIA

Nel 2025 costo Tot (mld) da 11 a 15,7 (+43%)con obesità infantile + 205%

Studio SPESA: composizione dei costidell’Obesità Tot 28,2 mld Euro/anno

Voce di costo PercentualeOspedalizzazioni 64%Diagnostica 12%Farmaci 7%Visite 6%Altro 11%

Centro Studio e Ricerca sull’Obesità (C.S.R.O.)Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica,

Università degli Studi di Milano, Via Vanvitelli 32, MilanoProf. Michele Carruba

Multiple secretoryproducts

LiverPancreas

Muscle

Vasculature

Current View: secretory/endocrine organOld View: inert storage depot

Fatty acids Glucose

Fatty acids Glycerol

Fed

Fasted

TgTg

Tg

The evolving view of adipose tissue:

an endocrine organ

Lyon CJ et al 2003

Adverse cardiometabolic effects of products of adipocytes

Adiposetissue

↑ IL-6

↓ Adiponectin

↑ Leptin

↑ TNFα

↑ Adipsin(Complement D)

↑ Plasminogenactivator inhibitor-1

(PAI-1)

↑ Resistin

↑ FFA↑ Insulin

↑ Angiotensinogen

↑ Lipoprotein lipase

↑ Lactate

Inflammation

Type2 diabetes

Hypertension

Atherogenicdyslipidaemia

ThrombosisAtherosclerosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

Systemic inflammation and adverse cardiovascular

outcomes

0

1

2

3

4

5

Rel

ativ

e ris

k of

MI

Cholesterol/HDL cholesterol ratiohs-CRP

1.0 1.2

2.8

1.11.3 2.5

3.4

4.4

Low LowMedium

High

Medium High

Physicians' Health Study: 9-year follow-up

Ridker et al 1998

2.8

Science 299: 896-899, 2003

Visceral fat depot in eNOS-/- vs. wild-type mice

wt eNOS-/-

4545

55

40403535

3030252520201515

1010

00

4545

55

40403535

3030252520201515

1010

0044 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252 44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252

Bod

y w

eigh

t (g)

Bod

y w

eigh

t (g)

Bod

y w

eigh

t (g)

Bod

y w

eigh

t (g)

MalesMales FemalesFemales

Time (weeks)Time (weeks) Time (weeks)Time (weeks)

aa bb

Growth curves of wildGrowth curves of wild--type and eNOStype and eNOS--//-- micemice

wtwteNOS eNOS --//--

wtwteNOS eNOS --//--

Nisoli et al., Science 299, 896–899, 2003

SWISS MED WKLY 133: 360–363, 2003

eNOS expression is reduced in WAT of obese rodents

Valerio et al., J. Clin. Invest., Oct. 2006

Electron microscopy analysis of WAT, BAT and muscle in ob/ob mice

WAT

Valerio et al., J. Clin. Invest., Oct. 2006

Decreased energy levels can cause and sustain obesity

Food

Fuel

ATP = Energy

Fat

Food

Fuel

ATP = Energy

Fat

Healthy subject Obese subject

Food

Fuel

ATP = Energy

Fat

Low ATPin cells

Brain

Leptin

Sience October 14, 2005

Quindi? Stile di vita!

Abitudini alimentari

eAttività fisica

We conducted a population-based, prospective investigation involving 22,043 adults in Greece who completed an extensive, validated, food-frequency questionnaire at base line.

During a median of 44 months of follow-up, there were 275 deaths. A higher degree of adherence to the Mediterranean diet was associated with a reduction in total mortality.

An inverse association with greater adherence to this diet was evident for both death due to coronary heart disease and death due to cancer.

Conclusions. Greater adherence to the traditional Mediterranean diet is associated with a significant reduction in total mortality.

Adherence to a Mediterranean Diet and Survival in a Greek Population

Antonia Trichopoulou, M.D., Tina Costacou, Ph.D., Christina Bamia, Ph.D., and Dimitrios Trichopoulos, M.D.

The New England Journal of Medicine, 348: 2599-2608, 2003

Livello di attività fisica e rischio di mortalità

Livello di attività fisica e rischio di mortalità

0

1

2

3

4

5R

isk

ratio

I° II° III° IV° V°Fitness level

menwomen

Blair et al, 1989Blair et al, 1989

Integrated Laboratories Network (InLaNe)

Center for Study and Research on Obesity, University of Milan

Michele Carruba, M.D. Ph.D.Enzo Nisoli, M.D. Ph.D. Cristina Tonello, Ph.D.Valeria Cozzi, Ph.D.Laura Tedesco, Ph.D. Annalisa Cardile, Ph.D. studentRenata Bracale, Ph.D. Student

DIBIT, S. Raffaele HMilan (Italy) and University of Milan

Emilio Clementi, M.D.Ph.D.Sestina Falcone, Ph.D.Addolorata Pisconti, Ph.D.

Istituto di Farmacologia e Farmacognosia, University of Urbino “Carlo Bo”, Urbino (Italy)

Orazio Cantoni, M.D. Ph.D.Letizia Palomba, Ph.D.

Department of Biomedical Sciences and Biotechnologies, University of Brescia (Italy)

Alessandra Valerio, M.D. Ph.D.Marta Dossena, Ph.D. student

Diabetes Care 28: 2289-2304, 2005

Diabetes Care 28: 2289-2304, 2005

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

TNFα↑ 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

Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults

Eugenia E. Calle, Ph.D., Carmen Rodriguez, M.D., M.P.H., Kimberly Walker-Thurmond, B.A., and Michael J. Thun, M.D.

The New England Journal of Medicine, 348: 1625-1638, 2003

The heaviest members of this cohort (body-mass index of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight.

In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin's lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women.

Conclusions. Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.

Changes in Body Weight (Kg)( from, DPPRG, 2002)

Study Year

-8

-7

-6

-5

-4

-3

-2

-1

0

ControlMetforminLifestyle

0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0

Cumulative incidence of diabetes( from, DPPRG, 2002)

Study Year

0

5

10

15

20

25

30

35

40

0 0,5 1 1,5 2 2,5 3 3,5 4

PlaceboMetforminLifestyle

Probabilty of remaining free of diabetes

(Tuomilehto et al, 2001)

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

InterventionControl

Study Year

DALLA RICERCA AL TERRITORIOIl Rischio

• Ogni anno 270.000 soggetti vengono colpiti da un attacco cardiaco che è fatale nel 50% dei casi e non arriva neanche al ricovero nel 30% dei casi

• Nell’analisi Framingham Study si èrivoluzionato il concetto di rischio: non piùsingoli fattori (fumo, ipertensione, ipercolesterolemia), ma una valutazione del Rischio Assoluto derivante da un’analisi multifattoriale

Adjusted relative risk for end-stage renal disease (ESRD) by body mass index (BMI)

Ann Intern Med. 144: 21-28, 2006

Obesità viscerale (circonferenza vita † )Uomini >102 cm (>40 pollici)Donne >88 cm (>35 pollici)

Trigliceridi ≥150 mg/dLColesterolo HDL

Uomini <40 mg/dLDonne <50 mg/dL

Pressione arteriosa ≥130 / ≥85 mmHg

Glicemia a digiuno ≥110 mg/dL

† Alcuni pazienti maschi possono sviluppare fattori di rischio metabolici multipli anche se la circonferenza-vita è aumentata solo marginalmente (es., 94–102 cm [37–40 pollici]).

NCEP ATP III. JAMA. 2001;285(19):2486-2497

Diagnosi posta in base alla presenza di 3 o più dei seguenti

NCEP ATP III:identificazione della Sindrome

MetabolicaFattori di rischio Valore

Sindrome metabolica – nuova Consensus IDF (International Diabetes

federation)Obesità centrale (cm)UominiDonne

≥94≥ 80

Più la presenza di altri due tra iseguenti fattori di rischio:Trigliceridi (mg/dL) >150 (o trattamento specifico)

Colesterolo HDL (mg/dL)UominiDonne

<40<50 (o trattamento specifico)

Pressione sistolica/diastolica (mm Hg)

≥ 130/ ≥ 85(o trattamento per ipertensione precedentemente diagnosticata)

Glicemia a digiuno (mg/dL) ≥ 100 (o precedente diagnosi di diabete di tipo 2)

The IDF consensus worldwide definition of the metabolic syndrome, Berlin, PMS, www.idf.org

05

101520253035404550

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

uominidonne

Prevalenza%

PREVALENZA DELLA SINDROME METABOLICA IN ADULTI AMERICANI(8814 soggetti, 1988-1994)

anni Ford et al, 2002

Abdominal obesity predicts the

metabolic syndrome

>30 <30

<102 cm (men)<88 cm (women)

>102 cm (men)>88 cm (women)

Waist circ

.

Body mass index (kg/m2)

8-ye

ar in

cide

nce

ofm

etab

olic

syn

drom

e

Han et al 2002

33

20

2010

0

10

20

30

40

Metabolic syndrome has a negative impact on CV health and mortality

0

5

10

15

20

25

CHD MI Stroke

Prev

alen

ce (%

)

No metabolic syndromeMetabolic syndrome

*p<0.001

Isomaa et al 2001

*

0

5

10

15

20

25

All-cause mortality

Cardiovascular mortality

Mor

talit

y ra

te (%

)

*

*

*

*

*p<0.001

Why is abdominal obesity harmful?

• Abdominal obesity– is often associated with other CV risk factors

– is an independent CV risk factor

• Adipocytes are metabolically active endocrine organs, not simply inert fat storage

Wajchenberg 2000

Intra-Abdominal (Visceral) FatThe dangerous inner fat!

Back

Visceral AT

Subcutaneous AT

Front

Lack of eNOS expression reduces mitochondrial Lack of eNOS expression reduces mitochondrial biogenesis in BAT of eNOSbiogenesis in BAT of eNOS--//-- micemice

wtwt eNOS eNOS --//--

wtwt wtwteNOS

eNOS --//--

mt DNAmt DNA

eNOS

eNOS --//--

MM

22 22 °°CC 4 4 °°CC

Nisoli et al., Science 299, 896–899, 2003

Oxygen consumption, food intake, and food Oxygen consumption, food intake, and food efficiency of wildefficiency of wild--type and eNOStype and eNOS--//-- micemice

Oxy

gen

cons

umpt

ion

(ml K

gO

xyge

n co

nsum

ptio

n (m

l Kg-- 11

min

min

-- 11))

Food

inta

ke (g

Fo

od in

take

(g ··

24h

24h-- 11

100g

bw

100g

bw

-- 11))

Feed

effi

cien

cyFe

ed e

ffici

ency

(wei

ght g

ain

/ foo

d in

take

) x 1

00(w

eigh

t gai

n / f

ood

inta

ke) x

100+/++/+ --//-- +/++/+ --//-- +/++/+ --//--

MalesMales FemalesFemales MalesMales FemalesFemales MalesMales FemalesFemales

aa bb cc

**

2525

2020

1515

1010

55

00

2525

2020

1515

1010

55

00

2525

2020

1515

1010

55

00

Nisoli et al., Science 299, 896–899, 2003

eNOS, PGC-1α, COX IV gene expression, and mtDNA levels are reduced in both WAT

and BAT of obese rodents

Valerio et al., J. Clin. Invest., Oct. 2006

Oxygen consumption and ATP levels are decreased in WAT and BAT of ob/ob mice

Valerio et al., J. Clin. Invest., Oct. 2006

Mitochondrial biogenesis is partially normalized in WAT of ob/obmice in which TNF-αsignaling has been genetically deleted

Valerio et al., J. Clin. Invest., Oct. 2006

Mitochondrial biogenesis is partially normalized in WAT of DIO mice in which TNF-α receptor 1 (p55) has

been genetically deleted

Valerio et al., J. Clin. Invest., Oct. 2006

Nisoli et al., Science 310: 314-317, 2005

CR induces mitochondrialbiogenesis in WAT of wild-type (wt) but not eNOS-/- mice through eNOS expression and cGMP formation.

DIETA MEDITERRANEA

• Calorie• Bilanciamento• Carboidrati (IG)• Lipidi (saturi/insaturi)• Fibra• Vitamine e antiossidanti• Numero pasti• Piramide (QB)

Fabbisogno giornaliero per un apporto bilanciato di nutrienti

I nutrienti della dieta mediterranea

Nutriente Percentuale sul totale dell’apporto calorico

Carboidrati Dal 50 al 55 %

di cui saccarosio Meno del 10 %

Lipidi Dal 25 al 30 %

di cui acidi grassi saturi Meno del 10 %

Proteine Dal 10 al 15 %

(Fonte : FAO/OMS)

Il consumo di grassi alimentari

Dietary Fat

Grassi Totali 37%

La percentuale di grassi sul totale dell’apporto energetico quotidiano si discosta da quella raccomandata dai nutrizionisti:

Sat 14%

Mono 17%

Poly 6%

Eccessi

Zuccheri sempliciGrassi saturiSaleProteine di origine animalePorzioni troppo abbondantiSpuntini troppo frequenti

Carenze

Frutta e verduraFibre Principi nutritivi fondamentaliCarboidrati complessi

La piramide alimentare

Per un corretto approccio nutrizionale è uso comune classificare gli alimenti in 7 gruppi principali in accordo alle specifiche proprietà nutritive di ogni gruppo.