Dieta Mediterranea y SM

94
Dietas Mediterráneas y Salud, Dietas Mediterráneas y Salud, relación con el Síndrome Metabólico” relación con el Síndrome Metabólico” Laboratorio de Nutrici Laboratorio de Nutrici ó ó n Molecular n Molecular Pontificia Universidad Católica de Pontificia Universidad Católica de Chile Chile [email protected] Federico Leighton Federico Leighton Universidad de Talca Universidad de Talca Curso Internacional del PIFRECV Curso Internacional del PIFRECV Agosto 22, 2006 Agosto 22, 2006

description

Dieta Mediterranea y SM

Transcript of Dieta Mediterranea y SM

Page 1: Dieta Mediterranea y SM

““Dietas Mediterráneas y Salud, Dietas Mediterráneas y Salud, relación con el Síndrome Metabólico”relación con el Síndrome Metabólico”

““Dietas Mediterráneas y Salud, Dietas Mediterráneas y Salud, relación con el Síndrome Metabólico”relación con el Síndrome Metabólico”

Laboratorio de NutriciLaboratorio de Nutricióón Molecular n Molecular Pontificia Universidad Católica de ChilePontificia Universidad Católica de Chile

[email protected]

Laboratorio de NutriciLaboratorio de Nutricióón Molecular n Molecular Pontificia Universidad Católica de ChilePontificia Universidad Católica de Chile

[email protected]

Federico LeightonFederico LeightonFederico LeightonFederico Leighton

Universidad de TalcaUniversidad de TalcaCurso Internacional del PIFRECVCurso Internacional del PIFRECV

Agosto 22, 2006Agosto 22, 2006

Page 2: Dieta Mediterranea y SM

Dietas Mediterráneas

• DefiniciónDefinición

• Componentes activosComponentes activos

• Actividades biológicas de los polifenoles:Actividades biológicas de los polifenoles:– antioxidantesantioxidantes– otras (GLUT4, eNOS, sirtuinas, etc)otras (GLUT4, eNOS, sirtuinas, etc)

• DefiniciónDefinición

• Componentes activosComponentes activos

• Actividades biológicas de los polifenoles:Actividades biológicas de los polifenoles:– antioxidantesantioxidantes– otras (GLUT4, eNOS, sirtuinas, etc)otras (GLUT4, eNOS, sirtuinas, etc)

Page 3: Dieta Mediterranea y SM

Chile es un país Mediterráneo…

¿¿Qué nos permite hablar de Qué nos permite hablar de “mediterráneo” en Chile?“mediterráneo” en Chile?

¿¿Qué nos permite hablar de Qué nos permite hablar de “mediterráneo” en Chile?“mediterráneo” en Chile?

Page 4: Dieta Mediterranea y SM

Chile es un país Mediterráneo…

1. Clima Mediterráneo

2. Agricultura Mediterránea

3. Cultura Mediterránea

4. Estilo de Vida Mediterráneo

5. Salud Mediterránea

6. Dieta Mediterránea

Page 5: Dieta Mediterranea y SM

CLIMA

MEDITERRÁNEO

Page 6: Dieta Mediterranea y SM

Climas en el Mundo

Page 7: Dieta Mediterranea y SM

1. Clima Mediterráneo

• Se caracteriza por presentar inviernos relativamente húmedos y veranos secos

• Se da entre los 30° y 45° de latitud, en la costa occidental de los continentes. Particularmente frente a aguas frías

• Chile es una de las 5 zonas en el mundo que presentan clima mediterráneo:

– Entorno del Mediterráneo en Europa y África– California Central y Meridional en Norteamérica– Costa chilena en el entorno de Santiago en Sudamérica– Región de Ciudad del Cabo en África– Australia sur-occidental

Page 8: Dieta Mediterranea y SM

1. Clima Mediterráneo

California Entorno del Mediterráneo

Chile Sudáfrica Australia

Fuente: Presentación Inaugural Seminario “Chile Potencia Agroalimentaria”,

Alberto Montanari, Octubre 2004

Page 9: Dieta Mediterranea y SM

Países productores de aceite de olivaPaíses productores de aceite de oliva

Page 10: Dieta Mediterranea y SM

Chile mediterráneo (30º - 45º) y región del Maule

Page 11: Dieta Mediterranea y SM

AGRICULTURA

MEDITERRÁNEA

Page 12: Dieta Mediterranea y SM

2. Agricultura Mediterránea

• La agricultura mediterránea no es específica de un grupo de países en el mediterráneo (España, Grecia, Italia y Portugal)

• Es el resultado de los condicionamientos geográficos, climáticos, demográficos y culturales en los que se asienta

Page 13: Dieta Mediterranea y SM

2. Agricultura Mediterránea

• Se define por sus resultados, los productos mediterráneos:

– Frutas y Verduras frescas

– Cereales

– Leguminosas y Frutos secos

– Vino

– Aceite de Oliva

– y del mar....pescado

• En contraste, la agricultura continental, se define por los siguientes productos:

– Semillas oleaginosas

– Carne y leche de vacuno

– Remolacha azucarera

Referencia: J. Lama de Espinosa en “La agricultura mediterránea en el siglo XXI”, 2000

Page 14: Dieta Mediterranea y SM

Chile Potencia Agroalimentaria

Nº País 2004*

1º Estados Unidos 39,667

2º Francia 28,147

3º Bélgica 23,519

4º Alemania 20,512

5º Holanda 20,269

6º Canadá 18,190

7º China 17,219

8º España 15,379

9º Italia 14,582

10º  Australia 12,998

11º Inglaterra 12,861

12º  Brasil 11,307

13º Dinamarca 9,972

14º Tailandia 9,480

15º  México 8,960

16º  Argentina 8,428

17º  Chile 7,000

18º  Nueva Zelanda 6,328

19º  Irlanda 5,860

20º  India 5,466

Nº País 2010 *

1º Bélgica 52.532

2º Estados Unidos 36.898

3º Francia 23.765

4º Canadá 22.294

5º Alemania 20.771

6º China 19.948

7º Holanda 19.509

8º España 18.152

9º Chile 17.170

10º Italia 16.145

11º Brasil 15.495

12º Australia 13.437

13º México 11.202

14º Inglaterra 10.112

15º Dinamarca 9.981

16º Tailandia 8.995

17º Argentina 8.208

18º Nueva Zelanda 7.315

19º India 5.934

20º Irlanda 4.653

Ranking Mundial de Exportaciones de Alimentos (MM USD)HOY (2004): Para el Bicentenario (2010):

Fuente: Seminario “Chile Potencia Agroalimentaria”, Alberto Montanari, Octubre 2004

y 87%....y 87%....

Page 15: Dieta Mediterranea y SM

CULTURA

MEDITERRÁNEA

Page 16: Dieta Mediterranea y SM

ESTILO DE VIDA

MEDITERRÁNEO

Page 17: Dieta Mediterranea y SM

SALUD

MEDITERRÁNEA

Page 18: Dieta Mediterranea y SM

5. Salud Mediterránea

•Los pueblos Mediterráneos tienen muy buena salud

•Los chilenos tenemos muy buena salud, ciertamente salud a nivel de países desarrollados

Page 19: Dieta Mediterranea y SM

5. Salud Mediterránea

Expectativa de Vida Ajustada por Discapacidad (DALE 2000)

33-29

59,1

66,768,468,670,071,772,572,772,873,174,5

30

40

50

60

70

80

Japón

Franci

a

Españ

aIta

lia

Gre

cia

Reino U

nido

EEUU

ChileCuba

Argen

tina

Brasi

l

África

Sub

-Sah

ara

Fuente: WHO Report 2001

Page 20: Dieta Mediterranea y SM

UKUSA

Years of Life Expectancy for Men 45 Years Old

Trichopoulou & Lagiou, 1997Trichopoulou & Lagiou, 1997

GreeceSpain

33

32

31

30

29

28

27

26

25

1960 1965 1970 1975 1980 1985 1990

Page 21: Dieta Mediterranea y SM

5. Salud Mediterránea

Fuente: CVD infobase, 1997

107

136,3

185,2 191,2

219,1

150,3

233,9

260,6275,3

0

50

100

150

200

250

300

Fran

cia

Españ

aIta

lia

Greci

a

EEUUChi

le

Cuba

Argen

tina

Brasi

l

Tasa Ajustada de Mortalidad por Enfermedades del Aparato Circulatorio(muertes / 100.000)

Page 22: Dieta Mediterranea y SM

Origen del término

Dietas Mediterráneas

Ancel Keys 1957

“el estudio de los siete países”

Page 23: Dieta Mediterranea y SM

Ancel Keys, enero 1961

A.K. muere Noviembre 20, 2004a los 100 años.

Page 24: Dieta Mediterranea y SM

USA

Japan

7 Countries Study1957-, Ancel Keys, Flaminio Fidanza....

7 Countries Study1957-, Ancel Keys, Flaminio Fidanza....

Page 25: Dieta Mediterranea y SM

El Estudio de los Siete Países

Creta Mediterráneo EUA HolandaMort.coronaria* 9 184 420 574 Colesterol (mM) 5.3 5.0 6.1 6.0

Ingesta (g/día)• Pan 380 416 97 252• Legumbres 30 18 1 2• Frutas 464 130 233 82• Pescado 18 34 3 12 • Carne 35 140 273 138• Grasa 95 60 33 79• Alcohol 15 43 6 3

Keys A y cols.; Am J Epidemiol 124: 1986 *= 10 años/10,000 hombres 50-69 a*= 10 años/10,000 hombres 50-69 a

Page 26: Dieta Mediterranea y SM

El Estudio de los Siete Países

Page 27: Dieta Mediterranea y SM

Survival curves for combined cardiac death, nonfatal myocardial infarction, unstable angina, heart failure, stroke, and thromboembolism. Log rank test using only the time of the first event. Note the striking difference between the control and experimental groups within the first year (P < 0.0001). Mediterranean diet recommendation and elevation of plasma 18:3 ω3 in Experimental group. Renaud et al 1995Renaud et al 1995

Lyon Diet Heart Study(mediterranean 18:3 ω3 acid-rich diet)

Page 28: Dieta Mediterranea y SM

DIETA

MEDITERRÁNEA

Page 29: Dieta Mediterranea y SM

•baja en grasas saturadas;

•alta en grasas monoinsaturadas;

•balanceada en ácidos grasos poliinsaturados (omega-6 y omega-3);

•baja en proteína animal;

•rica en antioxidantes: vitaminas y polifenoles;

•rica en fibra.

Características Comunes de las Dietas Mediterráneas

Page 30: Dieta Mediterranea y SM

Frutas y verduras en abundante cantidad

Alimentos frescos minimamente procesados

Aceite de oliva y vegetal comoprincipal fuente de grasa

Cereales integrales, principalmente,pan y pastas, a diario

Legumbres, semillas, nuecesy frutos secos, diariamente

Productos lácteos, principalmentefermentados, yogurt y quesos, consumidos

diariamente en forma moderada

Page 31: Dieta Mediterranea y SM

Huevos: 1-4 por semana

Uso habitual de especias y condimentos variados como limón, vinagre,

ajo, hierbas aromáticas, orégano, etc.

Vino: consumo moderado (1-2 copas día) y en forma regular,

principalmente con las comidas

Carnes rojas grasas: consumo en pequeñacantidad o algunas veces al mes

Ave: consumo moderado(2-4 veces por semana)

Pescado: consumo moderado(2-4 veces por semana)

Page 32: Dieta Mediterranea y SM

General Conclusion:

Present evidences suggest that Wine phenolics, other Plant phenolics, and ω-3 fatty acids

(18:3 ω3) constitute key elements in the healthy effects of the Mediterranean Diets.

Besides their antioxidant capacity, plant phenolics exert many other biochemical effects.

General Conclusion:

Present evidences suggest that Wine phenolics, other Plant phenolics, and ω-3 fatty acids

(18:3 ω3) constitute key elements in the healthy effects of the Mediterranean Diets.

Besides their antioxidant capacity, plant phenolics exert many other biochemical effects.

Page 33: Dieta Mediterranea y SM

Effects on mammalian enzyme systems

Page 34: Dieta Mediterranea y SM

Effects on mammalian enzyme systemsEffects on mammalian enzyme systemsMiddleton et al, Pharmacol Rev 2000Middleton et al, Pharmacol Rev 2000

A. KinasesA. KinasesB. Phospholipase A2B. Phospholipase A2C. ATPasesC. ATPasesD. Lipoxygenases and D. Lipoxygenases and

cyclooxygenasescyclooxygenasesE. Phospholipase CE. Phospholipase CF. Cyclic nucleotide F. Cyclic nucleotide

phosphodiesterasephosphodiesteraseG. Adenylate cyclaseG. Adenylate cyclaseH. Reverse transcriptaseH. Reverse transcriptaseI. HIV-1 proteinaseI. HIV-1 proteinaseJ. HIV-1 integraseJ. HIV-1 integraseK. Ornithine decarboxylaseK. Ornithine decarboxylaseL. TopoisomeraseL. TopoisomeraseM. Glutathione M. Glutathione SS-transferase-transferaseN. Epoxide hydrolaseN. Epoxide hydrolaseO. GlyoxalaseO. GlyoxalaseP. Xanthine oxidaseP. Xanthine oxidaseQ. AromataseQ. Aromatase

R. 11-b-Hydroxysteroid dehydrogenaseR. 11-b-Hydroxysteroid dehydrogenaseS. Catechol-S. Catechol-OO-methyltransferase-methyltransferaseT. Aldose reductaseT. Aldose reductaseU. Monoamine oxidase (FAD-containing)U. Monoamine oxidase (FAD-containing)V. Aldo-keto-reductase family of enzymesV. Aldo-keto-reductase family of enzymesW. HyaluronidaseW. HyaluronidaseX. Histidine decarboxylase and DOPA decarboxyl.X. Histidine decarboxylase and DOPA decarboxyl.Y. Malate dehydrogenaseY. Malate dehydrogenaseZ. Lactic dehydrogenase and pyruvate kinaseZ. Lactic dehydrogenase and pyruvate kinaseAA. Aldehyde and alcohol dehydrogenasesAA. Aldehyde and alcohol dehydrogenasesBB. AmylaseBB. AmylaseCC. RNA and DNA polymerasesCC. RNA and DNA polymerasesDD. Human DNA ligase IDD. Human DNA ligase IEE. RibonucleaseEE. RibonucleaseFF. SialidaseFF. SialidaseGG.Cytochrome P450 systemsGG.Cytochrome P450 systemsHH. ElastaseHH. ElastaseII. Nitric-oxide synthaseII. Nitric-oxide synthaseJJ. ECAJJ. ECA

Page 35: Dieta Mediterranea y SM
Page 36: Dieta Mediterranea y SM

Polyphenols and Aging genes

Page 37: Dieta Mediterranea y SM

Longevity and

decreased Cardiovascular Risk:

are they two partly independent phenomena

resulting from dietary polyphenols?

Page 38: Dieta Mediterranea y SM

Caloric restriction extends life-span in many Caloric restriction extends life-span in many species, including rodents, flies, nematodes species, including rodents, flies, nematodes and yeast. Data for primates due in the next and yeast. Data for primates due in the next

ten years, so far, extremely promising!ten years, so far, extremely promising!

Page 39: Dieta Mediterranea y SM

Weindruch, Science (1996) 273:59

Ad-libitum

85 kcal/week

50 kcal/week

40 kcal/week

Page 40: Dieta Mediterranea y SM

• Caloric Restriction extends life-span in many species, Caloric Restriction extends life-span in many species, including rodents (mice), insects (Drosophila including rodents (mice), insects (Drosophila melanogaster), nematodes (Cenorhabditis elegans), and melanogaster), nematodes (Cenorhabditis elegans), and yeast (Saccharomyces cerevisiae).yeast (Saccharomyces cerevisiae).

• Caloric Restriction in yeast, apparently acts through Caloric Restriction in yeast, apparently acts through activation of sirtuin (Sir2-like proteins) activation of sirtuin (Sir2-like proteins) enzymes which enzymes which deacetylate histones slowing gene expressiondeacetylate histones slowing gene expression. NAD is . NAD is the acetate acceptor.the acetate acceptor.

• Overexpression of sirtuin increases life-span in Overexpression of sirtuin increases life-span in

S. cerevisiae and C. elegans.S. cerevisiae and C. elegans.• Sir2 yeast mutants exhibit decreased life-span. Sir2 yeast mutants exhibit decreased life-span. • Humans have seven sirtuin genesHumans have seven sirtuin genes

Caloric Restriction and LongevityCaloric Restriction and Longevity

Page 41: Dieta Mediterranea y SM

• Sirtuin is an enzyme associated to longevity. Its Sirtuin is an enzyme associated to longevity. Its activity increases lifespan.activity increases lifespan.

• A search of sirtuin activation compounds was A search of sirtuin activation compounds was made, Howitz et al, Nature September 11, made, Howitz et al, Nature September 11, 2003. They tried approximately 50 different 2003. They tried approximately 50 different polyphenols.polyphenols.

• Among polyphenols present in wine and other Among polyphenols present in wine and other vegetals, approximately 15 were shown to vegetals, approximately 15 were shown to activate the enzyime Sirtuin, in yeast and activate the enzyime Sirtuin, in yeast and human cells.human cells.

Page 42: Dieta Mediterranea y SM

......Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the

acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

Nature. 2003 Sep 11;425(6954):191-6

Page 43: Dieta Mediterranea y SM

A quest for longevity. Five hundred years ago, the Spanish explorer Ponce de León A quest for longevity. Five hundred years ago, the Spanish explorer Ponce de León drank his way around the Florida coast during his expedition to find the legendary drank his way around the Florida coast during his expedition to find the legendary fountain of youth.fountain of youth.

A quest for longevity. Five hundred years ago, the Spanish explorer Ponce de León A quest for longevity. Five hundred years ago, the Spanish explorer Ponce de León drank his way around the Florida coast during his expedition to find the legendary drank his way around the Florida coast during his expedition to find the legendary fountain of youth.fountain of youth.

Page 44: Dieta Mediterranea y SM

El Síndrome Metabólico

• DefiniciónDefinición

• ConsecuenciasConsecuencias

• Patogénesis:Patogénesis:– hipótesis hipótesis

frecuentesfrecuentes– estrés oxidativoestrés oxidativo– defecto de eNOSdefecto de eNOS

• DefiniciónDefinición

• ConsecuenciasConsecuencias

• Patogénesis:Patogénesis:– hipótesis hipótesis

frecuentesfrecuentes– estrés oxidativoestrés oxidativo– defecto de eNOSdefecto de eNOS

Page 45: Dieta Mediterranea y SM

““Metabolic Syndrome” definition:Metabolic Syndrome” definition:““Metabolic Syndrome” definition:Metabolic Syndrome” definition:

(Syndrome X)(Syndrome X)

(Insulin Resistance Syndrome)(Insulin Resistance Syndrome)

Alternative denominations:Alternative denominations:

Page 46: Dieta Mediterranea y SM

National Cholesterol Education Program (USA)

((NCEPNCEP) )

Expert Panel on Detection, Evaluation, and Treatment

of High Blood Cholesterol in Adults

((Adult Treatment Panel III, or ATP IIIAdult Treatment Panel III, or ATP III))

Page 47: Dieta Mediterranea y SM

100?100?100?100?

80?80?94?94?

Page 48: Dieta Mediterranea y SM

Inflammatory markers:

Increased white blood cell countIncreased interleukin 6Increased tumour necrosis factor Increased resistinIncreased C-reactive proteinDecreased adiponectin

Vascular:

MicroalbuminuriaIncreased asymmetric dimethylarginine

Other:Increased uric acidIncreased homocysteineNon-alcoholic steatohepatitisPolycystic ovaries syndromeObstructive sleep apnoea(Increased FFA)

Changes associated with insulin resistance,(with metabolic syndrome):

Lifestyle:

Cigarette smokingSedentary behaviour

Lipoproteins:

Increased apo BDecreased apo A-1Small dense LDL and HDLIncreased apo C-III

Prothrombotic:

Increased fibrinogenIncreased plasminogen activator inhibitor 1Increased viscosity

Eckel et al. Lancet 2005

Page 49: Dieta Mediterranea y SM

Prevalence of the metabolic syndrome from ATPIII definitionPrevalence of the metabolic syndrome from ATPIII definition

Eckel et al. Lancet 2005

Prevalence of the Metabolic Syndrome

Page 50: Dieta Mediterranea y SM
Page 51: Dieta Mediterranea y SM

SEMINARIO

Mediterráneas

PAM-Chile Programa Alimentario Mediterráneo en Chile®

Page 52: Dieta Mediterranea y SM
Page 53: Dieta Mediterranea y SM
Page 54: Dieta Mediterranea y SM

Pathogenesis of the Metabolic Syndrome (2004)Pathogenesis of the Metabolic Syndrome (2004)

The metabolic syndrome seems to have 3 potential etiological The metabolic syndrome seems to have 3 potential etiological categories: categories:

-obesity and disorders of adipose tissue-obesity and disorders of adipose tissue

-insulin resistance-insulin resistance

-and a constellation of independent factors -and a constellation of independent factors

that mediate specific components of the that mediate specific components of the

metabolic syndrome (eg, molecules of hepatic, metabolic syndrome (eg, molecules of hepatic,

vascular, and immunologic origin). vascular, and immunologic origin).

Other factors—aging, proinflammatory state, and hormonal Other factors—aging, proinflammatory state, and hormonal

changes—have been implicated as contributors as well.changes—have been implicated as contributors as well.

((Oxidative stress???))((Oxidative stress???))

The metabolic syndrome seems to have 3 potential etiological The metabolic syndrome seems to have 3 potential etiological categories: categories:

-obesity and disorders of adipose tissue-obesity and disorders of adipose tissue

-insulin resistance-insulin resistance

-and a constellation of independent factors -and a constellation of independent factors

that mediate specific components of the that mediate specific components of the

metabolic syndrome (eg, molecules of hepatic, metabolic syndrome (eg, molecules of hepatic,

vascular, and immunologic origin). vascular, and immunologic origin).

Other factors—aging, proinflammatory state, and hormonal Other factors—aging, proinflammatory state, and hormonal

changes—have been implicated as contributors as well.changes—have been implicated as contributors as well.

((Oxidative stress???))((Oxidative stress???))Definition of Metabolic Syndrome. Report of the National Heart, Lung, Definition of Metabolic Syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on and Blood Institute/American Heart Association Conference on Scientific Issues Related to DefinitionScientific Issues Related to Definition

Scott M. Grundy, MD, PhD; H. Bryan Brewer, Jr, MD; James I. Cleeman, MD; Sidney Scott M. Grundy, MD, PhD; H. Bryan Brewer, Jr, MD; James I. Cleeman, MD; Sidney C. Smith, Jr, MD; Claude Lenfant, MD; for the Conference Participants*C. Smith, Jr, MD; Claude Lenfant, MD; for the Conference Participants*

((Circulation. Circulation. 2004;109:433-438.)2004;109:433-438.)

Page 55: Dieta Mediterranea y SM

METABOLIC SYNDROME METABOLIC SYNDROME

PatientPatient ControlControl

Obese WomanObese Woman

Age:Age: 40 yrs40 yrs

Weight:Weight: 113 Kg113 Kg

Height:Height: 1.68 m1.68 m

BMI:BMI: 40.340.3

Normal WomanNormal Woman

Age:Age: 36 years36 years

Weight:Weight: 54 Kg54 Kg

Height:Height: 1.65 m1.65 m

BMI:BMI: 20.020.0

National Geographic, Agosto 2004National Geographic, Agosto 2004

Page 56: Dieta Mediterranea y SM

Relationship among visceral adipose tissue and insulin action

18

16

14

12

10

8

6

4

2

00 1,000 2,000 3,000 4,000 5,000Volume of Visceral Adipose Tissue per unit of surface

(mL/m2)

Glu

cose

Util

iza

tion

(m

g/k

g L

BM

/min

)Banerji et al. Am J Physiol. 1997;273:E425-E432.

Women Men

Page 57: Dieta Mediterranea y SM

A: Free fatty acids (FFA) are released in abundance from an expanded adipose tissue mass. In the liver, FFA lead toan increased production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). Associated

lipid/lipoprotein abnormalities include reductions in high density lipoprotein (HDL) cholesterol and an increaseddensity of low density lipoproteins (LDL). FFA also reduce insulin sensitivity in muscle by inhibiting insulin mediated

glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increasedlipid accumulation in triglyceride (TG). Increases in circulating glucose and to some extent FFA increase pancreatic

insulin secretion resulting in hyperinsulinemia. Hyperinsulinaemia may result in enhanced sodium reabsorptionand increased sympathetic nervous system (SNS) activity and contribute to the hypertension as might increased

levels of circulating FFA.

Eckel, Grundy, Zimmet et al. Lancet vol 365 (April 16, 2005)Eckel, Grundy, Zimmet et al. Lancet vol 365 (April 16, 2005)

Pathophysiology of the metabolic syndrome (insulin resistance)

Page 58: Dieta Mediterranea y SM

Pathogenesis of the MS

Oxidative stress is also a key pathogenic element.Oxidative stress is also a key pathogenic element.

Further comments on Oxidative Stress and Metabolic Syndrome:Further comments on Oxidative Stress and Metabolic Syndrome:

• eNOSeNOS relates to oxidative stress because it can generate superoxide, relates to oxidative stress because it can generate superoxide, when uncoupled, and because its product, NO, requires antioxidant when uncoupled, and because its product, NO, requires antioxidant protection protection

• Oxidative Stress in MS is present, and a special role for adipose tissue Oxidative Stress in MS is present, and a special role for adipose tissue oxidative stressoxidative stress has been proposed has been proposed (Leighton et al, OIV, Vienna, July, 2004; Furukawa et al, December 2004)(Leighton et al, OIV, Vienna, July, 2004; Furukawa et al, December 2004)

Page 59: Dieta Mediterranea y SM

Oxidative Stress in MS Patients, Basal ValuesOxidative Stress in MS Patients, Basal Valuesand Endothelial Functionand Endothelial Function

0,0

0,2

0,4

0,6

0,8

1,0

nm

ol C

O /m

g p

rote

in

Protein Carbonyl

Normal Value

Basal

Men

Women

0

10

20

30

%

Methionine Sulfoxide

0,0

0,4

0,8

1,2

1,6

2,0

8-O

Hd

G/1

00

00

0 d

G

DNA (8-OHdG) Leighton et al, OIV, Vienna, July 4-9, 2004Leighton et al, OIV, Vienna, July 4-9, 2004

Page 60: Dieta Mediterranea y SM

Furukawa et al, Furukawa et al, The Journal of Clinical Investigation The Journal of Clinical Investigation 114 (December) 2004114 (December) 2004

Increased Oxidative Stress in obesity and its impact on the Metabolic

Syndrome

Page 61: Dieta Mediterranea y SM

Pathogenesis of the MS

A breakthrough in the study A breakthrough in the study

of MS pathogenesis!of MS pathogenesis!

Page 62: Dieta Mediterranea y SM

Pathogenesis of the MS

Clustering of cardiovascular risk Clustering of cardiovascular risk factors mimicking the human factors mimicking the human

metabolic syndrome X in eNOS null metabolic syndrome X in eNOS null micemice

Results:Results: .....eNOS–/– mice were hypertensive and insulin resistant, .....eNOS–/– mice were hypertensive and insulin resistant, ....eNOS–/– mice had ....eNOS–/– mice had a 1.5 to 2-fold elevation of the a 1.5 to 2-fold elevation of the cholesterol, triglyceride and free fatty acid plasma cholesterol, triglyceride and free fatty acid plasma concentration. concentration.

Even though body weight was comparable, the leptin plasma Even though body weight was comparable, the leptin plasma level was 30% higher in eNOS–/– than in wild type mice.level was 30% higher in eNOS–/– than in wild type mice.

On a high fat diet, knock-out mice became significantly more On a high fat diet, knock-out mice became significantly more glucoseglucoseintolerant than control mice.intolerant than control mice.

Results:Results: .....eNOS–/– mice were hypertensive and insulin resistant, .....eNOS–/– mice were hypertensive and insulin resistant, ....eNOS–/– mice had ....eNOS–/– mice had a 1.5 to 2-fold elevation of the a 1.5 to 2-fold elevation of the cholesterol, triglyceride and free fatty acid plasma cholesterol, triglyceride and free fatty acid plasma concentration. concentration.

Even though body weight was comparable, the leptin plasma Even though body weight was comparable, the leptin plasma level was 30% higher in eNOS–/– than in wild type mice.level was 30% higher in eNOS–/– than in wild type mice.

On a high fat diet, knock-out mice became significantly more On a high fat diet, knock-out mice became significantly more glucoseglucoseintolerant than control mice.intolerant than control mice.

S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod, S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod, B. Thorens, U. Scherrer B. Thorens, U. Scherrer SWISS MED WKLY 2003;133:360–363SWISS MED WKLY 2003;133:360–363

Page 63: Dieta Mediterranea y SM

S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod, S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod, B. Thorens, U. Scherrer B. Thorens, U. Scherrer SWISS MED WKLY 2003;133:360–363SWISS MED WKLY 2003;133:360–363

Blood pressureBlood pressure

FFAFFA

Glucose infusion Glucose infusion raterate

Fasting insulinFasting insulin

TriglyceridesTriglycerides

CholesterolCholesterol

Page 64: Dieta Mediterranea y SM

Pathogenesis of the MS

Conclusions:Conclusions:

A single gene defect, eNOS deficiency, A single gene defect, eNOS deficiency,

causes a clustering of cardiovascular risk causes a clustering of cardiovascular risk

factors in young mice. We speculate that factors in young mice. We speculate that

defective nitric oxide synthesis could defective nitric oxide synthesis could

trigger many of the abnormalities making trigger many of the abnormalities making

up the metabolic syndrome in humansup the metabolic syndrome in humans..

Conclusions:Conclusions:

A single gene defect, eNOS deficiency, A single gene defect, eNOS deficiency,

causes a clustering of cardiovascular risk causes a clustering of cardiovascular risk

factors in young mice. We speculate that factors in young mice. We speculate that

defective nitric oxide synthesis could defective nitric oxide synthesis could

trigger many of the abnormalities making trigger many of the abnormalities making

up the metabolic syndrome in humansup the metabolic syndrome in humans..

S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod, S. Cook, O. Hugli, M. Egli, P. Vollenweider, R. Burcelin, P. Nicod,

B. Thorens, U. Scherrer B. Thorens, U. Scherrer SWISS MED WKLY 2003;133:360–363SWISS MED WKLY 2003;133:360–363

Page 65: Dieta Mediterranea y SM

A possibility is to explore if polymorphisms (mutations) A possibility is to explore if polymorphisms (mutations) of the eNOS gene in humans, cause defects related to of the eNOS gene in humans, cause defects related to Metabolic Syndrome.Metabolic Syndrome.

The answer is yes, genetic modifications of eNOS The answer is yes, genetic modifications of eNOS associate with changes such as:associate with changes such as:

Ischemic heart diseaseIschemic heart disease

Diabetes type 2Diabetes type 2

HypertensionHypertension

If defective (absent) eNOS causes Metabolic Syndrome in mice, If defective (absent) eNOS causes Metabolic Syndrome in mice, how could we explore it genetically in humans?how could we explore it genetically in humans?

Page 66: Dieta Mediterranea y SM

Pathogenesis of the MS

Scientific data supports Scientific data supports a central role for a central role for eNOSeNOS in the pathogenesis in the pathogenesisof the Metabolic Syndrome:of the Metabolic Syndrome:

• eNOS (-/-) mice: Ins Resist, Hypertension, high TG, high FibrinogeneNOS (-/-) mice: Ins Resist, Hypertension, high TG, high Fibrinogen• eNOS (+/-) mice with high fat: Hypertension and Ins ResisteNOS (+/-) mice with high fat: Hypertension and Ins Resist• eNOS relates to T2Diabetes and Ins Resist in humanseNOS relates to T2Diabetes and Ins Resist in humans•eNOS polymorphism and hypertension in humanseNOS polymorphism and hypertension in humans•eNOS (-/-) mice: muscle mitoch. deficit, reduced phys activityeNOS (-/-) mice: muscle mitoch. deficit, reduced phys activity•eNOS responds to estradiol (HDL)eNOS responds to estradiol (HDL)•eNOS triggers cGMP-dependent mitoch. biogenesiseNOS triggers cGMP-dependent mitoch. biogenesis

•eNOS is a potential source of free radicals (OeNOS is a potential source of free radicals (O22--))

•eNOS involved in MS characteristic erectyle disfunction eNOS involved in MS characteristic erectyle disfunction

•previous speculations for: CV disease, diabetes, late ischemic previous speculations for: CV disease, diabetes, late ischemic preconditioning, platelet activation,preconditioning, platelet activation,inflammatory and ox stress in CV patientsinflammatory and ox stress in CV patients

Page 67: Dieta Mediterranea y SM

Pathogenesis of the MS

Scientific data supports Scientific data supports a central role for a central role for eNOSeNOS in the in the pathogenesis of the Metabolic Syndrome:pathogenesis of the Metabolic Syndrome:

But, the different But, the different mechanisms through which eNOS mechanisms through which eNOS dysfunction could lead to MSdysfunction could lead to MS, as well as the various , as well as the various mechanisms linkingmechanisms linking wine and health to the correct wine and health to the correct function of eNOSfunction of eNOS and consequent positive effects on and consequent positive effects on plasma lipids, haemostasis, endothelial function, and plasma lipids, haemostasis, endothelial function, and reduced oxidative stress, reduced oxidative stress, remain to be established.remain to be established.

Oxidative stress in Metabolic Syndrome is today aOxidative stress in Metabolic Syndrome is today akey question.key question.

Page 68: Dieta Mediterranea y SM

Comparación experimental de laDieta Mediterránea

con la Dieta Occidental

Comparación experimental de laDieta Mediterránea

con la Dieta Occidental

Page 69: Dieta Mediterranea y SM

STUDY DESIGN

0 30 60 90Time (days)

MEDITERRANEAN n=21

HIGH-FAT n=21

DP 08-98

Page 70: Dieta Mediterranea y SM

TOTAL ANTIOXIDANT REACTIVITY (TAR)TOTAL ANTIOXIDANT REACTIVITY (TAR)

200

250

300

350

400

450

00 3030 6060 9090 00 3030 6060 9090

High Fat dietHigh Fat diet Mediterranean dietMediterranean dietTime (days)Time (days)

M T

rolo

x eq

uiv

alen

tM

Tro

lox

equ

ival

ent

AA

AAAA

aa

BB

bb

bb

cc

**

**

**

**

**

**

DP 06/2000

Page 71: Dieta Mediterranea y SM

0

2

4

6

8

10

12

tiempo (days)

AB

A

B

A

a

ab

b

a

Plasma PolyphenolsPlasma Polyphenols

µM

Ru

tin

equ

ival

ent

µM

Ru

tin

equ

ival

ent

High Fat dietHigh Fat diet Mediterranean dietMediterranean diet

Time (days)Time (days)

00 3030 6060 9090 00 3030 6060 9090

PS 6-2000

Page 72: Dieta Mediterranea y SM

-

2

4

6

8

10

12

14

B

A

C

aA

b

c

ab

0

8-O

hd

G/1

08-O

hd

G/1

055 d

G d

GOxidative DNA damageOxidative DNA damage

8-Hydroxydeoxyguanosine8-Hydroxydeoxyguanosine

* *

00 3030 6060 909000 3030 6060 9090

Mediterranean dietMediterranean dietHigh Fat dietHigh Fat diet

Time (days)Time (days)PS 6-2000

Page 73: Dieta Mediterranea y SM

ENDOTHELIAL FUNCTION:ENDOTHELIAL FUNCTION:ENDOTHELIAL FUNCTION:ENDOTHELIAL FUNCTION:

AA link between ethanol effects link between ethanol effects and antioxidants?and antioxidants?

An additional function for wineAn additional function for winephenolics?phenolics?

AA link between ethanol effects link between ethanol effects and antioxidants?and antioxidants?

An additional function for wineAn additional function for winephenolics?phenolics?

Page 74: Dieta Mediterranea y SM

Hyperhomocysteinemia

Diabetes

Hypercholesterolemia(oxidized LDL)Hypertension

Smoking

ATHEROSCLEROSIS

ENDOTHELIAL DYSFUNCTION

.

NONO

Estrogen deficit

Page 75: Dieta Mediterranea y SM

MEASUREMENT OF ENDOTHELIAL FUNCTION MEASUREMENT OF ENDOTHELIAL FUNCTION (flow mediated vascular reactivity)(flow mediated vascular reactivity)

Page 76: Dieta Mediterranea y SM

DIA

ME

TE

R C

HA

NG

E (

%)

WITHOUTWINE

WITHWINE

HIGH FAT DIET

-6

-4

-2

0

2

4

6

8

10

12

ENDOTHELIAL FUNCTIONENDOTHELIAL FUNCTION(measured after 12 hours without wine and food)(measured after 12 hours without wine and food)

Cuevas, Leighton et alCuevas, Leighton et alLipids 35: 143-148, 2000Lipids 35: 143-148, 2000

Page 77: Dieta Mediterranea y SM

PUFAMUFA

12

10

8

6

4

2

0

time

DIET

WHITE W

RED W

F & V

bab

bb

a

a

a

a

Endothelial Function in a HighEndothelial Function in a High-Fat Diet-Fat Diet Intervention study Intervention study Endothelial Function in a HighEndothelial Function in a High-Fat Diet-Fat Diet Intervention study Intervention study

Per

cen

t d

iam

eter

ch

ang

eP

erce

nt

dia

met

er c

han

ge

Page 78: Dieta Mediterranea y SM

eNOSeNOSarginine + O2

citrulline +NADP+

NADPH

NONO O2+ ONOO.. ....

Page 79: Dieta Mediterranea y SM

Red Wine Polyphenol Extract increases NO production

in Human Endothelial Cells Leikert et al, Circulation, 2002

Page 80: Dieta Mediterranea y SM

Red Wine Polyphenol Extract enhances transcription of eNOS in Human Endothelial Cells (Leikert et al, Circulation, 2002)

Page 81: Dieta Mediterranea y SM

NUCLEUS

eNOS NO.

Endothelial function

Thrombosis

NO.

Arginine Arginine

PolyphenolsPolyphenols

Ca++Ca++

LDL

HDL

estrogen

caveolae

CD36

SRBI

estrogenreceptor

?

platelets

Page 82: Dieta Mediterranea y SM

El Síndrome Metabólico y las Dietas Mediterráneas

• Papel central de la eNOSPapel central de la eNOS

• Estudios de intervenciónEstudios de intervención

• Programa de Alimentación LaboralPrograma de Alimentación Laboral

• Papel central de la eNOSPapel central de la eNOS

• Estudios de intervenciónEstudios de intervención

• Programa de Alimentación LaboralPrograma de Alimentación Laboral

Page 83: Dieta Mediterranea y SM

2006; 24(4): 291-2982006; 24(4): 291-298

Page 84: Dieta Mediterranea y SM

Leighton et al, 2005-6Leighton et al, 2005-6

Page 85: Dieta Mediterranea y SM

• Wine as eNOS enhacer Wine as eNOS enhacer

-Wine phenolics -Wine phenolics (Miranda-Rottmann, Leighton et al 2003; (Miranda-Rottmann, Leighton et al 2003;

Leikert et al 2002; Martin et al 2002)Leikert et al 2002; Martin et al 2002)

• Other eNOS enhacersOther eNOS enhacers

-Mediterranean Diet -Mediterranean Diet (Leighton et al 2000; Esposito et al 2004)(Leighton et al 2000; Esposito et al 2004)

-Exercise -Exercise (Green et al 2004)(Green et al 2004)

--PPAR gamma agonists PPAR gamma agonists (Cho et al 2004; Hwang et al 2004)(Cho et al 2004; Hwang et al 2004)

• Wine as eNOS enhacer Wine as eNOS enhacer

-Wine phenolics -Wine phenolics (Miranda-Rottmann, Leighton et al 2003; (Miranda-Rottmann, Leighton et al 2003;

Leikert et al 2002; Martin et al 2002)Leikert et al 2002; Martin et al 2002)

• Other eNOS enhacersOther eNOS enhacers

-Mediterranean Diet -Mediterranean Diet (Leighton et al 2000; Esposito et al 2004)(Leighton et al 2000; Esposito et al 2004)

-Exercise -Exercise (Green et al 2004)(Green et al 2004)

--PPAR gamma agonists PPAR gamma agonists (Cho et al 2004; Hwang et al 2004)(Cho et al 2004; Hwang et al 2004)

Page 86: Dieta Mediterranea y SM

SEMINARIO

Mediterráneas

PAM-Chile Programa Alimentario Mediterráneo en Chile®

• Tenemos evidencias que el Síndrome Metabólico es por falla de una enzima (la eNOS)

• Esta enzima se “activa” con la dieta mediterránea: Flavonoides

AntioxidantesÁcidos grasos omega-3

¿Es reversible el Síndrome Metabólico?

Page 87: Dieta Mediterranea y SM

JAMA, September 22/29, 2004—Vol 292, No. 12

Katherine Esposito et al

Page 88: Dieta Mediterranea y SM

Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular Inflamation

Esposito et al., JAMA 2004

180 patients with Metabolic Syndrome

99 men 81 women

90 assigned to recieve a control prudent diet

90 assigned to recieve a

Mediterranean-style diet

2 years

follow up

Page 89: Dieta Mediterranea y SM

66

20

74

27

76

61

18

7

16 12

8 8 7

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline 2 years Baseline 2 years

Without MS 3 comp. 4 comp. 5 comp.

Changes in number of components of Metabolic Syndrome after 2 years

Mediterranean-style Diet Group

Control Diet Group

from Esposito et al., JAMA 2004

Page 90: Dieta Mediterranea y SM

6 5,9

7,9

6,1

0

1

2

3

4

5

6

7

8

9

Mediterranean-style Diet Group Control Diet Group

En

do

thel

ial F

un

ctio

n S

core

Esposito et al., JAMA 2004

p < 0.001 p = 0.09

Changes in Endothelial Function after 2 years

Baseline

After 2 years

Page 91: Dieta Mediterranea y SM

SEMINARIO

Mediterráneas

PAM-Chile Programa Alimentario Mediterráneo en Chile®

Desarrollos futuros

• Ante las evidencias que la agroindustria chilena puede aportar alimentos saludables, y producir más si es necesario

• Dada la alta incidencia de factores de riesgo propios del Síndrome Metabólico en la población adulta en Chile

• Y considerando nuestro “expertise” y el de nuevos asociados

Page 92: Dieta Mediterranea y SM

SEMINARIO

Mediterráneas

PAM-Chile Programa Alimentario Mediterráneo en Chile®

• En la Universidad Católica (VIII 2005)hemos creado el “Programa de Alimentación Laboral”

– Su objetivo es optimizar los recursos destinados a la alimentación laboral, promoviendo salud, bienestar y estilo de vida

– Luego hemos firmado (VI 2006) con DOLE y la Asociación Chilena de Seguridad un acuerdo para la aplicación de este programa en Chile

Desarrollos futuros

Page 93: Dieta Mediterranea y SM

SEMINARIO

Mediterráneas

PAM-Chile Programa Alimentario Mediterráneo en Chile®

• En el año 2006 hemos puesto en marcha el PAL, un modelo capaz de generar las evidencias científicas necesarias para abordar el problema a nivel nacional. Esto sería posible ya desde 2007, sobre evidencias científicas.

Desarrollos futuros

Page 94: Dieta Mediterranea y SM

Federico Leighton P.

18 de julio de 2006