dieta mediterranea y sm
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““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
fleighto@bio.puc.cl
Laboratorio de NutriciLaboratorio de Nutricióón Molecular n Molecular Pontificia Universidad Católica de ChilePontificia Universidad Católica de Chile
fleighto@bio.puc.cl
Federico LeightonFederico LeightonFederico LeightonFederico Leighton
Universidad de TalcaUniversidad de TalcaCurso Internacional del PIFRECVCurso Internacional del PIFRECV
Agosto 22, 2006Agosto 22, 2006
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)
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?
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
CLIMA
MEDITERRÁNEO
Climas en el Mundo
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
1. Clima Mediterráneo
California Entorno del Mediterráneo
Chile Sudáfrica Australia
Fuente: Presentación Inaugural Seminario “Chile Potencia Agroalimentaria”,
Alberto Montanari, Octubre 2004
Países productores de aceite de olivaPaíses productores de aceite de oliva
Chile mediterráneo (30º - 45º) y región del Maule
AGRICULTURA
MEDITERRÁNEA
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
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
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%....
CULTURA
MEDITERRÁNEA
ESTILO DE VIDA
MEDITERRÁNEO
SALUD
MEDITERRÁNEA
5. Salud Mediterránea
•Los pueblos Mediterráneos tienen muy buena salud
•Los chilenos tenemos muy buena salud, ciertamente salud a nivel de países desarrollados
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
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
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)
Origen del término
Dietas Mediterráneas
Ancel Keys 1957
“el estudio de los siete países”
Ancel Keys, enero 1961
A.K. muere Noviembre 20, 2004a los 100 años.
USA
Japan
7 Countries Study1957-, Ancel Keys, Flaminio Fidanza....
7 Countries Study1957-, Ancel Keys, Flaminio Fidanza....
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
El Estudio de los Siete Países
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)
DIETA
MEDITERRÁNEA
•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
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
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)
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.
Effects on mammalian enzyme systems
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
Polyphenols and Aging genes
Longevity and
decreased Cardiovascular Risk:
are they two partly independent phenomena
resulting from dietary polyphenols?
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!
Weindruch, Science (1996) 273:59
Ad-libitum
85 kcal/week
50 kcal/week
40 kcal/week
• 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
• 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.
......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
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.
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
““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:
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))
100?100?100?100?
80?80?94?94?
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
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
SEMINARIO
Mediterráneas
PAM-Chile Programa Alimentario Mediterráneo en Chile®
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.)
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
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
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)
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)
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
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
Pathogenesis of the MS
A breakthrough in the study A breakthrough in the study
of MS pathogenesis!of MS pathogenesis!
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
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
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
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?
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
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.
Comparación experimental de laDieta Mediterránea
con la Dieta Occidental
Comparación experimental de laDieta Mediterránea
con la Dieta Occidental
STUDY DESIGN
0 30 60 90Time (days)
MEDITERRANEAN n=21
HIGH-FAT n=21
DP 08-98
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
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
-
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
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?
Hyperhomocysteinemia
Diabetes
Hypercholesterolemia(oxidized LDL)Hypertension
Smoking
ATHEROSCLEROSIS
ENDOTHELIAL DYSFUNCTION
.
NONO
Estrogen deficit
MEASUREMENT OF ENDOTHELIAL FUNCTION MEASUREMENT OF ENDOTHELIAL FUNCTION (flow mediated vascular reactivity)(flow mediated vascular reactivity)
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
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
eNOSeNOSarginine + O2
citrulline +NADP+
NADPH
NONO O2+ ONOO.. ....
Red Wine Polyphenol Extract increases NO production
in Human Endothelial Cells Leikert et al, Circulation, 2002
Red Wine Polyphenol Extract enhances transcription of eNOS in Human Endothelial Cells (Leikert et al, Circulation, 2002)
NUCLEUS
eNOS NO.
Endothelial function
Thrombosis
NO.
Arginine Arginine
PolyphenolsPolyphenols
Ca++Ca++
LDL
HDL
estrogen
caveolae
CD36
SRBI
estrogenreceptor
?
platelets
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
2006; 24(4): 291-2982006; 24(4): 291-298
Leighton et al, 2005-6Leighton et al, 2005-6
• 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)
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?
JAMA, September 22/29, 2004—Vol 292, No. 12
Katherine Esposito et al
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
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
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
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
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
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
Federico Leighton P.
18 de julio de 2006
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