dieta e prevenção cvd versão slideshare

DIETA E PREVENÇÃO CARDIOVASCULAR !

Pedro Carrera Bastos, 2013!

COLESTEROL DIETÉTICO < 300 MG/DIA

Dietary Guidelines for Americans, USDA, 2005

ALIMENTO (100 G) COLESTEROL (MG)

Queijo de Azeitão 88

Nata 33% gordura 97

Costoleta de Porco (gorda) grelhada 111

Peito de vitela estufado 121

Camarão Cozido 198

Mexilhão cozido 360

Fígado de vitela grelhado 387

Ovo cozido 408

Tabela de Composição dos Alimentos. Centro de Segurança Alimentar e Nutrição. Instituto nacional de Saúde Dr. Ricardo Jorge, 2006

Limite o consumo de gemas de ovo

6

US NATIONAL HEALTH AND NUTRITIONAL SURVEY (1984–1994)

Okuyama H, et al. World Rev Nutr Diet. 2007;96:1-17.

Egg consumption and risk of coronary heart diseaseand stroke: dose-response meta-analysis ofprospective cohort studies

OPEN ACCESS

Ying Rong doctoral student 1 2, Li Chen research fellow 1 2, Tingting Zhu research fellow 1 2, YadongSong research fellow 1 2, Miao Yu research fellow 1 2, Zhilei Shan research fellow 1 2, Amanda Sandsdoctoral student 3, Frank B Hu professor 3, Liegang Liu professor 1 2

1Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University ofScience and Technology, 430030 Wuhan, People’s Republic of China; 2Ministry of Education Key Lab of Environment and Health, School of PublicHealth, Tongji Medical College, People’s Republic of China; 3Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston,MA, USA

AbstractObjective To investigate and quantify the potential dose-responseassociation between egg consumption and risk of coronary heart diseaseand stroke.

Design Dose-response meta-analysis of prospective cohort studies.

Data sources PubMed and Embase prior to June 2012 and referencesof relevant original papers and review articles.

Eligibility criteria for selecting studies Prospective cohort studieswith relative risks and 95% confidence intervals of coronary heart diseaseor stroke for three or more categories of egg consumption.

Results Eight articles with 17 reports (nine for coronary heart disease,eight for stroke) were eligible for inclusion in the meta-analysis (3 081269 person years and 5847 incident cases for coronary heart disease,and 4 148 095 person years and 7579 incident cases for stroke). Noevidence of a curve linear association was seen between eggconsumption and risk of coronary heart disease or stroke (P=0.67 andP=0.27 for non-linearity, respectively). The summary relative risk ofcoronary heart disease for an increase of one egg consumed per daywas 0.99 (95% confidence interval 0.85 to 1.15; P=0.88 for linear trend)without heterogeneity among studies (P=0.97, I2=0%). For stroke, thecombined relative risk for an increase of one egg consumed per daywas 0.91 (0.81 to 1.02; P=0.10 for linear trend) without heterogeneityamong studies (P=0.46, I2=0%). In a subgroup analysis of diabeticpopulations, the relative risk of coronary heart disease comparing thehighest with the lowest egg consumption was 1.54 (1.14 to 2.09; P=0.01).In addition, people with higher egg consumption had a 25% (0.57 to0.99; P=0.04) lower risk of developing hemorrhagic stroke.

Conclusions Higher consumption of eggs (up to one egg per day) isnot associated with increased risk of coronary heart disease or stroke.The increased risk of coronary heart disease among diabetic patientsand reduced risk of hemorrhagic stroke associated with higher eggconsumption in subgroup analyses warrant further studies.

IntroductionCardiovascular disease is now a public health crisis, affectingmillions of people in both developed and developing countries.Although the rate of death attributable to the disease has declinedin developed countries in the past several decades, it is still theleading cause of death and extorts a heavy social and economictoll globally.1-3 In low and middle income countries, theprevalence of cardiovascular disease has increased dramatically.By 2020, the disease is forecasted to be the major cause ofmorbidity and mortality in most developing nations.4

In recent decades, concern has mounted regarding the highprevalence and costs associated with cardiovascular disease,with growing interest in altering risk factors and reversing thisglobal epidemic. Among the known risk factors forcardiovascular disease, levels of low density lipoprotein (LDL)cholesterol have aroused particular attention. In the Women’sHealth Study, after a mean follow-up of eight years, participantswith the highest levels of LDL cholesterol showed a notablyhigher risk of cardiovascular events than those with the lowestlevels.5 In addition, several meta-analyses of observationalstudies and randomized controlled trials have found that areduction in concentrations of LDL cholesterol couldsignificantly reduce the risk of coronary heart disease and stroke

Correspondence to: L Liu [email protected]

Extra material supplied by the author (see http://www.bmj.com/content/346/bmj.e8539?tab=related#webextra)Web appendix: Web tables

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2013;346:e8539 doi: 10.1136/bmj.e8539 (Published 7 January 2013) Page 1 of 13

Research

RESEARCH

Fig 3 Forest plot of egg consumption and risk of coronary heart disease

Fig 4 Dose-response analyses of egg consumption and risk of stroke

Fig 5 Forest plot of egg consumption and risk of stroke



RESEARCH

RISCO DE DOENÇA CARDÍACA CORONÁRIA

Egg consumption and risk of coronary heart diseaseand stroke: dose-response meta-analysis ofprospective cohort studies

OPEN ACCESS

Ying Rong doctoral student 1 2, Li Chen research fellow 1 2, Tingting Zhu research fellow 1 2, YadongSong research fellow 1 2, Miao Yu research fellow 1 2, Zhilei Shan research fellow 1 2, Amanda Sandsdoctoral student 3, Frank B Hu professor 3, Liegang Liu professor 1 2

1Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University ofScience and Technology, 430030 Wuhan, People’s Republic of China; 2Ministry of Education Key Lab of Environment and Health, School of PublicHealth, Tongji Medical College, People’s Republic of China; 3Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston,MA, USA

AbstractObjective To investigate and quantify the potential dose-responseassociation between egg consumption and risk of coronary heart diseaseand stroke.

Design Dose-response meta-analysis of prospective cohort studies.

Data sources PubMed and Embase prior to June 2012 and referencesof relevant original papers and review articles.

Eligibility criteria for selecting studies Prospective cohort studieswith relative risks and 95% confidence intervals of coronary heart diseaseor stroke for three or more categories of egg consumption.

Results Eight articles with 17 reports (nine for coronary heart disease,eight for stroke) were eligible for inclusion in the meta-analysis (3 081269 person years and 5847 incident cases for coronary heart disease,and 4 148 095 person years and 7579 incident cases for stroke). Noevidence of a curve linear association was seen between eggconsumption and risk of coronary heart disease or stroke (P=0.67 andP=0.27 for non-linearity, respectively). The summary relative risk ofcoronary heart disease for an increase of one egg consumed per daywas 0.99 (95% confidence interval 0.85 to 1.15; P=0.88 for linear trend)without heterogeneity among studies (P=0.97, I2=0%). For stroke, thecombined relative risk for an increase of one egg consumed per daywas 0.91 (0.81 to 1.02; P=0.10 for linear trend) without heterogeneityamong studies (P=0.46, I2=0%). In a subgroup analysis of diabeticpopulations, the relative risk of coronary heart disease comparing thehighest with the lowest egg consumption was 1.54 (1.14 to 2.09; P=0.01).In addition, people with higher egg consumption had a 25% (0.57 to0.99; P=0.04) lower risk of developing hemorrhagic stroke.

Conclusions Higher consumption of eggs (up to one egg per day) isnot associated with increased risk of coronary heart disease or stroke.The increased risk of coronary heart disease among diabetic patientsand reduced risk of hemorrhagic stroke associated with higher eggconsumption in subgroup analyses warrant further studies.

IntroductionCardiovascular disease is now a public health crisis, affectingmillions of people in both developed and developing countries.Although the rate of death attributable to the disease has declinedin developed countries in the past several decades, it is still theleading cause of death and extorts a heavy social and economictoll globally.1-3 In low and middle income countries, theprevalence of cardiovascular disease has increased dramatically.By 2020, the disease is forecasted to be the major cause ofmorbidity and mortality in most developing nations.4

In recent decades, concern has mounted regarding the highprevalence and costs associated with cardiovascular disease,with growing interest in altering risk factors and reversing thisglobal epidemic. Among the known risk factors forcardiovascular disease, levels of low density lipoprotein (LDL)cholesterol have aroused particular attention. In the Women’sHealth Study, after a mean follow-up of eight years, participantswith the highest levels of LDL cholesterol showed a notablyhigher risk of cardiovascular events than those with the lowestlevels.5 In addition, several meta-analyses of observationalstudies and randomized controlled trials have found that areduction in concentrations of LDL cholesterol couldsignificantly reduce the risk of coronary heart disease and stroke

Correspondence to: L Liu [email protected]

Extra material supplied by the author (see http://www.bmj.com/content/346/bmj.e8539?tab=related#webextra)Web appendix: Web tables



Research

RESEARCH

RISCO DE AVC

Fig 3 Forest plot of egg consumption and risk of coronary heart disease

Fig 4 Dose-response analyses of egg consumption and risk of stroke

Fig 5 Forest plot of egg consumption and risk of stroke



RESEARCH

9

EFEITOS NO CURTO PRAZO

INCREMENTO DE 100 MG/D DE COLESTEROL DIETÉTICO AUMENTOU: ü  CT: 2.2 mg/dl ü  C- HDL: 0.3 mg/dl

Okuyama H, et al. World Rev Nutr Diet. 2007;96:1-17.

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 225

C

CE

C

LDL(apo B-100, E)

receptor

EXTRAHEPATICTISSUES

Synthesis

LDL

CE

TG

TG

CE

LRP receptor

IDL(VLDL remnant)

Chylomicronremnant

CC

C

CE

SynthesisBile acids

(total pool, 3–5 g)

BILE DUCT

VLDL Chylomicron

Bileacids

CE

CCE

Diet (0.4 g/d)HEPATIC PORTAL VEIN

GALLBLADDER

ENTEROHEPATIC CIRCULATION

C(0.6 g/d)

Bile acids(0.4 g/d)

Feces

ILEUM

Unesterifiedcholesterol

pool

CE

HDLA-ILC

AT

CETP

LPL

ACAT

HL

CEC

TGCEC

LIVERTGCEC

TGCEC

CE

TG, CE

TG

TGCEC

C

–8999 %

CEC

––

C

LDL(apo B-100, E)

receptor

Figure 26–6. Transport of cholesterol between the tissues in humans. (C, unesterified cholesterol; CE, cho-lesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein; LDL,low-density lipoprotein; HDL, high-density lipoprotein; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT,lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; LPL, lipopro-tein lipase; HL, hepatic lipase; LRP, LDL receptor-related protein.)

CHOLESTEROL IS EXCRETED FROM THEBODY IN THE BILE AS CHOLESTEROL ORBILE ACIDS (SALTS)About 1 g of cholesterol is eliminated from the bodyper day. Approximately half is excreted in the feces afterconversion to bile acids. The remainder is excreted ascholesterol. Coprostanol is the principal sterol in the

feces; it is formed from cholesterol by the bacteria inthe lower intestine.

Bile Acids Are Formed From Cholesterol

The primary bile acids are synthesized in the liver fromcholesterol. These are cholic acid (found in the largestamount) and chenodeoxycholic acid (Figure 26–7).

ch26.qxd 3/16/04 10:58 AM Page 225

Murray R, et al. Harper’s Illustrated Biochemistry 26th Edition. McGraw-Hill, 2003

LDL PEQUENAS E DENSAS

ü  > Entrada no espaço subendotelial

ü Menos Vit E

ü  + Susceptível à oxidação

ü  Elevado TG/HDL-C é um bom preditor de sdLDL

Griffin BA. Proc Nutr Soc 1999;58:163-69

Revisiting Dietary Cholesterol Recommendations:Does the Evidence Support a Limit of 300 mg/d?

Maria Luz Fernandez & Mariana Calle

Published online: 4 August 2010# Springer Science+Business Media, LLC 2010

Abstract The perceived association between dietary cho-lesterol (DC) and risk for coronary heart disease (CHD) hasresulted in recommendations of no more than 300 mg/d forhealthy persons in the United States. These dietaryrecommendations proposed in the 1960s had little scientificevidence other than the known association betweensaturated fat and cholesterol and animal studies wherecholesterol was fed in amounts far exceeding normalintakes. In contrast, European countries, Asian countries,and Canada do not have an upper limit for DC. Further,current epidemiologic data have clearly demonstrated thatincreasing concentrations of DC are not correlated withincreased risk for CHD. Clinical studies have shown thateven if DC may increase plasma low-density lipoprotein(LDL) cholesterol in certain individuals (hyper-responders),this is always accompanied by increases in high-densitylipoprotein (HDL) cholesterol, so the LDL/HDL cholesterolratio is maintained. More importantly, DC reduces circu-lating levels of small, dense LDL particles, a well-definedrisk factor for CHD. This article presents recent evidencefrom human studies documenting the lack of effect of DCon CHD risk, suggesting that guidelines for DC should berevisited.

Keywords Dietary cholesterol . LDL cholesterol .

HDL cholesterol . LDL size . Clinical studies .

Epidemiologic data . Eggs

Introduction

The American Heart Association (AHA) recommends nomore than 300 mg/d of dietary cholesterol (DC) for healthypersons to prevent increased risk for coronary heart disease(CHD) [1]. These recommendations are mostly based onthe presence of both saturated fat and cholesterol in manyfoods and on data derived from animal studies wheresupraphysiologic doses of cholesterol, ranging from theequivalent of 1,000 mg to 20,000 mg/d for humans, werefed in order to produce atherosclerosis [2].

It is important to note that many other countries do nothave the same guidelines for DC. Canada [3••], Korea [4•],New Zealand [5], and India [6], for example, do not set anupper limit for DC, focusing instead on controlling theintake of saturated fat and trans fat, which are the majordeterminants of blood cholesterol concentrations. Similarly,the European guidelines on cardiovascular disease preven-tion have the following recommendations regarding healthyfood choices: “consume a wide variety of foods, adjustenergy intake to maintain a healthy weight, encourageconsumption of fruits and vegetables, replace saturated fatwith mono or polyunsaturated fatty acids and reduce saltintake” [7]. In contrast to US policies, Europeans have nodietary guidelines for DC [7]. A summary of the dietaryrecommendations for DC in different countries, includingtwo recent reports from the AHA, is presented in Table 1.

Epidemiologic studies do not support an associationbetween cholesterol intake and CHD [8–12]. This couldpartly be explained by the fluctuations in response to dietarycholesterol among all individuals, which varies from nochanges to large increases in plasma cholesterol. In addition,it is critical to note that for those individuals who havehypercholesterolemic response to dietary cholesterol (aboutone third of the population), the rise is typically due to

M. L. Fernandez (*) :M. CalleDepartment of Nutritional Sciences,the University of Connecticut,3624 Horsebarn Road Extension,Storrs, CT 06269, USAe-mail: [email protected]

Curr Atheroscler Rep (2010) 12:377–383DOI 10.1007/s11883-010-0130-7

an increase in CHD in patients diagnosed with diabetes atthe highest level of egg consumption [21]. Other studiesalso suggest that individuals with diabetes should limit eggintake [22, 23•]. In summary, the preponderance of theepidemiologic evidence from the past 14 years does notsupport a relationship between dietary cholesterol (or eggintake) and risk for CHD [4•, 8–14], [15•, 16••, 17••].Accordingly, neither Europe [7], Canada [3••], nor Asiancountries [4•, 5] restrict dietary cholesterol as part of therecommendations for a heart-healthy diet.

Eggs and Dietary Cholesterol

The AHA still recommends limiting other food items highin cholesterol if eggs are to be consumed [1] in spite ofrecent reports that show no association between egg intakeand risk for heart disease [8–11, 18••, 19–21]. In fact, thereare no studies with substantial evidence supporting theclaims of egg consumption involved in CHD risk. Incontrast, a recent analysis in which a risk-apportionmentapproach was used on the risk factors for CHD revealedthat egg intake contributes to less than 1% of the risk, andthe authors conclude that AHA dietary guidelines possiblyshould be revised [18••]. Eggs are the only food that is bothrich in cholesterol and low in saturated fat, perhapsexplaining why eggs are often used to evaluate the effectsof dietary cholesterol on plasma lipids and CHD risk [8–11,24, 25]. Other cholesterol-containing foods, such as dairyproducts, also contain high concentrations of saturated fat,which is a confounder for dietary cholesterol effects. Thismight be the reason why controversial results existregarding the effects of dairy products on CHD risk [26].

Clinical trials conducted in children [27], younger adults[24, 25], and the elderly [28, 29] have clearly demonstratedthat although dietary cholesterol provided by eggs signifi-cantly increases LDL-C in one third of the population, thoseindividuals considered hyper-responders to a cholesterolchallenge exhibit increases in both LDL-C and HDL-C, with

the result of no changes in the LDL-C/HDL-C ratio, a majorpredictor of CHD [30•]. These results indicate thatindividuals with initial plasma cholesterol concentrationsthat place them at a low risk for CHD do not develop anatherogenic lipoprotein profile following the consumptionof additional dietary cholesterol, regardless of theirresponse classification.

It is well established that nutritional interventions aimedat managing plasma lipids are known to be less effective inobese and overweight individuals [31]. During a weightloss intervention, intake of 3 eggs per day for 12 weeks wasshown to selectively increase plasma HDL-C withoutincreasing LDL-C in overweight men [32••]. Harman etal. [33•] also reported no changes in LDL-C afterconsuming 2 eggs per day for 12 weeks in a weight lossintervention study. Intake of only 1 egg per day increasedHDL-C without increasing LDL-C in men and women aged40–60 years, resulting in a lower LDL-C/HDL-C ratio [34].Similarly, in a study in which 56 participants with a meanage of 35 years were given an additional egg per day during12 weeks, significant increases were reported for HDL-Cwith no changes in LDL-C [35•]. A summary of plasmaLDL-C and HDL-C concentrations as a response to eggintake in recent clinical studies is presented in Table 2.

To evaluate whether insulin resistance, with or withoutobesity, influences the response to dietary cholesterol, Knoppet al. [36] recruited 197 healthy individuals into a random-ized crossover study in which 0, 2, and 4 eggs per day werefed for 4 weeks with a 1-month washout period in between.The participants were classified as insulin sensitive (n=65),insulin resistant (n=75), and obese insulin resistant (OIR,n=58). Insulin-resistant and insulin-sensitive individuals hadsignificant increases in LDL-C of 7.8% and 3.3%, respec-tively, after consuming 4 eggs per day, whereas OIRindividuals had no changes in LDL-C at any intake level.In contrast, HDL-C was significantly increased for all groupseven after the consumption of only 2 eggs per day. Thesestudies suggest that dietary management of OIR individualsneed not include restrictions on eggs.

Table 2 Changes in LDL-C, HDL-C, LDL size, and HDL size as a response to dietary cholesterol provided by eggs in various populations

Population Duration Additional dietary cholesterol LDL-C HDL-C LDL-C/HDL-C ratio LDL size HDL size

Children (n=54) [27] 4 wk 518 mg/d Increase Increase No change Increase ND

Women (n=51) [25] 4 wk 640 mg/d Increase Increase No change Increase ND

Men (n=28) [32••] 12 wk 640 mg/d No change Increase Decrease Increase Increase

Men/women (n=42) [34] 12 wk 215 mg/d No change Increase No change Increase Increase

Men/women (n=34) [28] 4 wk 640 mg/d Increase Increase No change Increase Increase

Men/women (n=56) [35•] 12 wk 250 mg/d No change Increase Decrease ND ND

Men/women (n=45) [33•] 12 wk 400 mg/d No change No change No change ND ND

HDL-C high-density lipoprotein cholesterol; LDL-C low-density lipoprotein cholesterol; ND not determined.

Curr Atheroscler Rep (2010) 12:377–383 379

REDUZIR INGESTÃO DE GORDURA TOTAL DIMINUI RISCO DE DCV

970 G.J. NELSON ETAL.

(13-20). Thus, it is difficult to determine if simply reducing the fat content of the diet without changing the dietary FAC changes the tissue FAC or alters plasma lipid levels. Further- more, people eat natural and processed food as complex mix- tures that vary day to day and year to year. They rarely eat pure fats or oils, and certainly not continuously for weeks. In most previous studies (13-20) that have examined this issue, the FAC of the diet was changed markedly as well as the amount of calories from fat; thus, the experimental diets had different ratios of saturated and unsaturated FA in them. This confounds the interpretation of the results; one does not know if the changes observed are the result of changes in the caloric intake or changes in the type of FA in the diet. In an effort to clarify this point, we fed LF (22 en% fat) and HF (39 en% fat) diets to healthy volunteers for 50 d. The diets had FAC that were identical despite the intentional differences in the fat content in the diet.

MATERIALS A N D M E T H O D S

Materials. All natural foods were purchased at local food markets. FA standards were purchased from Nu-Chek-Prep (Elysian, MN). Organic solvents were obtained from Baxter Scientific, Burdick and Jackson Brand (McGaw Park, IL). The reagents for the enzymatic determination of plasma cholesterol and triglycerides were purchased from Sigma Diag- nostics (St. Louis, MO).

Subjects. The volunteers were recruited from the West Coast, and consisted of men between the ages of 20 and 35. The physical characteristics of the eleven male volunteers (HNS-27) who completed the study were age (years), 32.9 _+ 4.5; weight (kg), 72.9 _+ 8.2; body mass index (kg/M2), 23.1 _+ 1.6; blood pressure systolic, 115.9 _+ 9.5; blood pressure diastolic, 73.2 _+ 7.8; smokers, none. Initially twelve volunteers were included in the study, but one was unable to complete the protocol. The volunteers were given complete physical examinations. Body weights had to be within -10 to +20 per- cent of ideal body weights using the Metropolitan Life Insur- ance Company tables (medium frame values from the 1983 edition). Evidence of existing illness or chronic disease was an exclu~on criterion. Mild hypertension was not an exclusion criterion, but the group that was recruited tended to have blood pressures slightly below average for men in this age group. Smoking, excessive alcohol consumption, and evidence of narcotic abuse were also exclusionary.

Experimental design. All the volunteers were confined to the Nutrition Research Suite of the Western Human Nutrition Research Center (San Francisco, CA) for the duration of the study. As the subjects stay within the confines of the Nutri- tion Suite except for occasional supervised outings, they had no opportunity to consume any food except that provided by the Center. Thus, compliance with the protocol was, of neces- sity, 100%. In addition, all food intake was monitored, por- tions were weighed, and subjects were required to consume everything provided to them during their meals. (A rubber spatula was provided to ensure that all food was scraped from

the plates and eaten.) Food spills were carefully monitored and recorded, and fluid intake, while ad libitum, was also measured precisely.

The protocol for this study was approved by the Institu- tional Review Boards of the University of California at Davis (Davis, CA) and the USDA (Washington, D.C.). A crossover design was used so that the subjects acted as their own con- trols. The subjects were fed a stabilization diet, containing 39% of calories from fat for 20 d. The HF diet had a macronutrient composition of 39 en% fat, 16 en% protein, and 45 en% CHO. On day 20 of the study, they were divided randomly into two groups: Group A remained on the HF diet (39% of calories from fat) for 50 d; Group B was placed on a LF diet (22% of calories from fat). The LF diet had a macronutrient composition of 22 en% fat, 16 en% protein, and 62 en% CHO. After 50 d, day 70 of the study, the groups switched diets for the remaining 50 d of the study. After 120 d, all the volunteers were discharged from the Nutrition Suite and re- turned to an ad libitum diet.

During the confinement period, there were blood draws on study days 2, 20, 45, 70, 95, and 120. As measured parameters on the intermediate blood draws (study days 45 and 95) showed insignificant differences from the endpoints (study days 70 and 120), only data obtained from the endpoint blood draws were used for statistical analysis. Statistical comparisons of the measured parameters were made using day 20 as the baseline values for each subject.

Diets. The diets consisted of natural foods. No dietary supplements were given. The macronutrient composition of the diets is given in Table 1. (A complete description of the diets, listing all the major and minor nutrients, is available upon re- quest.) A seven-day menu cycle was used throughout the study. Proximate analysis was made on seven individual diet composite samples taken from each menu once during the study for both the stabilization diet and intervention diets. The results for the seven composite samples were averaged to find the actual composition of the diets. No alcohol was in-

TABLE 1 Composition of HNS*27 Diets, Proximal Analysis a

Low-fat diets High-fat diets (% of total calories) Target Target

Measured value Measured value

Macronutrient energy distribution

Protein 15.9 16.0 15.7 16.0 Fat 22.2 20.0 38.7 40.0 Carbohydrate 61.9 64.0 45.7 44.0

Cholesterol content (mean, mg/day) - - 360 - - 360

Fatty acid energy distribution

Saturated 6.4 5 10.6 10 Monounsaturated 9.2 10 15.5 20 Polyunsaturated 6.6 5 12.6 10

P/S ratio 1.0 1.0 1.2 1.0 ap/s, polyunsaturated/saturated; HNS-2 7 diet.

Lipids, Vol. 30, no. 11 (1995)

Nelson GJ, Schmidt PC, Kelley DS. Lipids. 1995 Nov;30(11):969-76

Nelson GJ, Schmidt PC, Kelley DS. Lipids. 1995 Nov;30(11):969-76

EFFECT OF DIETARY FAT ON BLOOD LIPIDS 973

TABLE 5 Red Blood Cell Fatty Acid Composition (wt%) a

High-fat diet Low-fat diet FAME (means _+ SD) (means _+ SD) Pvalues

14:0 (myristate) 0.20 _+ 0.05 0.19 • 0.03 16:0 D M A 1.51 • 1 .62+0 .11 16:0 (palmitate) 16.57 • 1.57 16.16 + 0.38 16:1n-9 0 . 3 5 • 0.33_+0.02 17:0 2 . 8 7 • 3 . 0 4 • 18:0 D M A 0.35 • 0.05 0.38 _+ 0.04 18:1 n-7 D M A 1.64 • 0.28 1.75 _+ 0.22 18:0 (stearate) 10.25 + 0.58 9.74 + 0.36 0.01 18:1n-7t 1.11 • 1.06_+0.1 18:1n-9 (oleate) 9.51 _+0.82 9.11 _+0.8 18:1 n-7 0.85 _+ 0.06 0.88 • 0.08 18:1n-5 0.44 _+ 0.05 0.47 _+ 0.07 18:2t tand 19:0 0.11 _+0.02 0.11 _+0.01 18:2n-6 (l inoleate) 9.99 _+ 0.61 8.37 _+ 0.46 0.000004 20:0 (arachidate) 0.61 _+ 0.11 0.54 _+ 0.05 18:3n-3 (@-Iinolenate) 0.30 • 0.05 0.25 • 0.04 0.0005 20:3n-6 (homo-T-linolenate) 1.12 _+ 0.23 1.34 • 0.24 0.00003 22:0 (behenate) 2.22 • 0.47 2 _+ 0.19 20:4n-6 (arachidonate) 12.11 + 2.34 13.85 -+ 0.47 0.04 23:0 0.47 _+ 0.1 0.42 _+ 0.04 20:5n-3 (EPA) 0.52 _+ 0.14 0.61 • 0.11 24:0 (l ignocerate) 6.54 -+ 1.56 5.94 -+ 0.59 24:4n-6 3.12 • 0.73 3.49 _+ 0.34 24:1 n-9 (nervonate) 6.38 _+ 1.32 6.03 _+ 0.5 22:4n-3 0.56 • 0.15 0.74 _+ 0.13 0.007 24:2n-6 1.05 _+ 0.16 1.05 • 0.09 22:5n-3 2.6 _+ 0.69 2.99 • 0.3 22:6n-3 (DHA) 4.02 _+ 1.3 4.87 _+ 0.81 26:0 0.44 _+ 0.11 0.41 _+ 0.05

Total 99.04 _+ 0.16 98.95 _+ 0.13 Unknown 0.96 _+ 0.16 1.05 _+ 0.13

aSee Tables 2 and 3 for abbreviations.

ous lipoprotein fractions were not altered significantly, there was a redistribution of the lipoprotein spectrum during the two diet periods. The increase in the plasma triglyceride level indicated an increase in the plasma very low density lipoprotein (VLDL) level and a decrease in both the plasma HDL and LDL levels. Thus, the total cholesterol level remained con- stant because the increase in plasma VLDL cholesterol com- pensated for the reduction in HDL-cholesterol and LDL-cholesterol. Because of individual variations, the standard devia-

tion was large enough to prevent these values from reaching statistical significance.

D I S C U S S I O N

It has almost been dogma for the last forty years in the field of dietary fat effects on blood lipids that HF diets will raise blood cholesterol levels while LF diets will lower blood cholesterol (1-4). A problem one encounters when examining the scientific basis for this concept is that the FAC of LF and HF diets was rarely the same. The Keys et al. (5) and Hegsted et al. (6) formulas for the effect of dietary fat on blood cholesterol levels were published thirty years ago. Those equations say nothing about the total percentage of fat calories in the diet, but they imply that HF diets will raise blood cholesterol because they relate grams of fat ingested to blood cholesterol level, positively for saturated FA, except stearic (7,8), and negatively for polyunsaturated fat (n-3 FA are ignored). Di- etary cholesterol has only a small influence on blood cholesterol levels. If one uses the Keys equation (5) or the Hegsted equation (6) to calculate the change in blood cholesterol that one would expect with the protocol used in this study, there should have been an average difference between the HF and LF diets o f -2 3 mg/dl. The subjects' LF diet cholesterol level was 173 mg, and should have risen to 196 mg/dl if the Keys et al. (5) and Hegsted et al. (6) equations were an appropriate explanation for the physiological response to changes in dietary fat intakers. The observed total cholesterol value when the participants consumed the HF was 177 mg/dl, not significantly different from the value obtained when they consumed the LF diet.

There are several possible reasons that the Keys et al. (5) and Hegsted et aL (6) equations do not hold in this particular experiment: (i) The equations were developed using large population data bases (11,20). Here the sample number is too small to detect the effect. This answer is unlikely and unsatis- factory because the conditions of this experiment were carefully controlled and the statistical power of the protocol was excellent.

(ii) The average cholesterol level in the subjects was con- siderably below that in the European and American populations used to develop the Keys et aL (5) and Hegsted et al. (6)

TABLE 6 High- and Low-Fat Diets, Blood Cholesterol, Triglycerides, and Lipoprotein Values

Total HDL- LDL- cholesterol Triglycerides cholesterol cholesterol

Period Diet mean + SD mean _+ SD mean • SD mean • SD

Entry A d l ib i tum 176.3 + 33.1 85.8 + 28.4 46.3 _+ 14.0 112.8 • 26.8 Stabil ization High-fat 172.5 + 30.3 75.3 • 46.4 44.8 • 11.6 112.6 • 21.9 Intervention Low-fat 173.2 _+ 27.3 91.5 • 38.0 40.5 • 12.4 114.5 • 21.3 Intervention High-fat 176.9 _+ 32.9 66.4 • 41.7 43.2 + 13.4 119.5 _+ 24.3 Paired t-test, Pvalues a 0.425 0.002 0.258 0.238

~lhe t-test compares only the values at the end of the high- or low-fat diets with the values obtained at the end of the stabilization period, study day 20. Groups A and B values were taken at study day 70 and day 120, depending on the leg of the intervention diet for the each group; HDL, high density lipoprotein; LDL, low density lipoprotein.

Lipids, Vol. 30, no. 11 (1995)

American Institute for Cancer Research 11th Annual

Research Conference on Diet, Nutrition and Cancer

The Mediterranean Diets: What Is So Special about the Diet of Greece?

The Scientific Evidence

1

Artemis P. Simopoulos2

The Center for Genetics, Nutrition and Health, Washington, DC

ABSTRACT The term “Mediterranean diet,” implying that all Mediterranean people have the same diet, is amisnomer. The countries around the Mediterranean basin have different diets, religions and cultures. Their dietsdiffer in the amount of total fat, olive oil, type of meat and wine intake; milk vs. cheese; fruits and vegetables; andthe rates of coronary heart disease and cancer, with the lower death rates and longer life expectancy occurring inGreece. Extensive studies on the traditional diet of Greece (the diet before 1960) indicate that the dietary patternof Greeks consists of a high intake of fruits, vegetables (particularly wild plants), nuts and cereals mostly in the formof sourdough bread rather than pasta; more olive oil and olives; less milk but more cheese; more fish; less meat;and moderate amounts of wine, more so than other Mediterranean countries. Analyses of the dietary pattern of thediet of Crete shows a number of protective substances, such as selenium, glutathione, a balanced ratio of(n-6):(n-3) essential fatty acids (EFA), high amounts of fiber, antioxidants (especially resveratrol from wine andpolyphenols from olive oil), vitamins E and C, some of which have been shown to be associated with lower risk ofcancer, including cancer of the breast. These findings should serve as a strong incentive for the initiation ofintervention trials that will test the effect of specific dietary patterns in the prevention and management of patientswith cancer. J. Nutr. 131: 3065S–3073S, 2001.

KEY WORDS: c diet of Crete c (n-3) fatty acids c wild plants c antioxidants c cancer c (n-6) fatty acids

The health of the individual and the population in generalis the result of interactions between genetics and a number ofenvironmental factors. Nutrition is an environmental factor ofmajor importance (1–4). Our genetic profile has not changedover the past 10,000 y, whereas major changes have takenplace in our food supply and in energy expenditure and phys-ical activity (5–17). Today industrialized societies are charac-terized by the following: 1) an increase in energy intake anddecrease in energy expenditure; 2) an increase in saturated fat,(n-6) fatty acids and trans fatty acids and a decrease in (n-3)fatty acid intake; 3) a decrease in complex carbohydrates andfiber intake; 4) an increase in cereal grains and a decrease infruit and vegetable intake; and 5) a decrease in protein, anti-oxidant and calcium intake (5–17). Furthermore, the ratio of(n-6) to (n-3) fatty acids is 16.74:1, whereas during evolutionit was 2–1:1 (Table 1, Fig. 1).

Recent investigations of the dietary patterns and healthstatus of the countries surrounding the Mediterranean basinclearly indicate major differences among them in both dietary

intake and health status. Therefore, the term “Mediterraneandiet” is a misnomer. There is not just one Mediterranean dietbut in fact many Mediterranean diets (18), which is notsurprising because the countries along the Mediterranean ba-sin have different religions, economic and cultural traditionsand diets. Diets are influenced by religious habits, that is,Muslims do not eat pork or drink wine and other alcoholicdrinks, whereas Greek Orthodox populations usually do noteat meat on Wednesdays and Fridays but drink wine, and soon. Although Greece and the Mediterranean countries areusually considered to be areas of medium-high death rates(14.0–18.0 per 1000 inhabitants), death rates on the island ofCrete have been below this level continuously since before1930 (19). No other area in the Mediterranean basin has hadas low a death rate as Crete, according to data compiled by theUnited Nations in their demographic yearbook for 1948. Itwas 11.3–13.7 per 1000 inhabitants before World War II and;10.6 in 1946–1948 (19). Cancer and heart disease causedalmost three times as many deaths proportionally in theUnited States as in Crete (19). The diet of Crete representsthe traditional diet of Greece before 1960. The Seven Coun-tries Study was the first to establish credible data on cardio-vascular disease prevalence rates in contrasting populations(United States, Finland, The Netherlands, Italy, former Yu-goslavia, Japan and Greece), with differences found on theorder of 5- to 10-fold in coronary heart disease (20). In 1958,the field work started in Dalmatia in the former Yugoslavia.

1 Presented as part of the 11th Annual Research Conference on Diet, Nutritionand Cancer held in Washington, DC, July 16–17, 2001. This conference wassponsored by the American Institute for Cancer Research and was supported bythe California Dried Plum Board, The Campbell Soup Company, General Mills,Lipton, Mead Johnson Nutritionals, Roche Vitamins Inc. and Vitasoy USA. Guesteditors for this symposium publication were Ritva R. Butrum and Helen A.Norman, American Institute for Cancer Research, Washington, DC.

2 To whom correspondence should be addressed.E-mail: [email protected]

0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.

3065S

by on September 27, 2006

jn.nutrition.orgD

ownloaded from





1











3065S


jn.nutrition.orgD

ownloaded from

GORDURA DIETÉTICA: 37% DA ENERGIA TOTAL CONSUMIDA





1











3065S


jn.nutrition.orgD

ownloaded from

Burr ML, Fehily AM, Gilbert JF, et al. Lancet 1989; 2:757-761.

DIMINUIÇÃO DA GORDURA TOTAL DE 35% PARA 32.3%

0% 5% 10% 15% 20% 25% DAC Total DCV RISCO RELATIVO

ORIGINAL CONTRIBUTION

Low-Fat Dietary Patternand Risk of Cardiovascular DiseaseThe Women’s Health Initiative Randomized ControlledDietary Modification TrialBarbara V. Howard, PhD; LindaVan Horn, PhD; Judith Hsia, MD;JoAnn E. Manson, MD; Marcia L.Stefanick, PhD; SylviaWassertheil-Smoller, PhD; Lewis H.Kuller, MD; Andrea Z. LaCroix, PhD;Robert D. Langer, MD; Norman L.Lasser, MD; Cora E. Lewis, MD;Marian C. Limacher, MD; Karen L.Margolis, MD; W. Jerry Mysiw, MD;Judith K. Ockene, PhD; Linda M.Parker, DSc; Michael G. Perri, PhD;Lawrence Phillips, MD; Ross L.Prentice, PhD; John Robbins, MD;Jacques E. Rossouw, MD; Gloria E.Sarto, MD; Irwin J. Schatz, MD; Linda G.Snetselaar, PhD; Victor J. Stevens, PhD;Lesley F. Tinker, PhD; MaurizioTrevisan, MD; Mara Z. Vitolins, DrPH;Garnet L. Anderson, PhD; Annlouise R.Assaf, PhD; Tamsen Bassford, MD;Shirley A. A. Beresford, PhD; Henry R.Black, MD; Robert L. Brunner, PhD;Robert G. Brzyski, MD; BetteCaan, DrPH; Rowan T. Chlebowski, MD;Margery Gass, MD; Iris Granek, MD;Philip Greenland, MD; JenniferHays, PhD; David Heber, MD;Gerardo Heiss, MD; Susan L.Hendrix, DO; F. Allan Hubbell, MD;Karen C. Johnson, MD;Jane Morley Kotchen, MD

CLINICAL TRIALS AND OBSERVA-tional studies have identifiedstrong associations betweenlow-density lipoprotein cho-

lesterol (LDL-C) level and other cardio-vascular disease (CVD) risk factors anddietary intake of fats, particularly

See also pp 629, 643, and 693.Author Affiliations are listed at the end of thisarticle.Corresponding Author: Barbara V. Howard, PhD,

MedStar Research Institute, 6495 New Hampshire Ave,Suite 201, Hyattsville, MD 20783 ([email protected]).

Context Multiple epidemiologic studies and some trials have linked diet with car-diovascular disease (CVD) prevention, but long-term intervention data are needed.Objective To test the hypothesis that a dietary intervention, intended to be low infat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk.Design, Setting, and Participants Randomized controlled trial of 48 835 post-menopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, whoparticipated in the Women’s Health Initiative Dietary Modification Trial. Women wererandomly assigned to an intervention (19 541 [40%]) or comparison group (29 294[60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in40 US clinical centers; mean follow-up in this analysis was 8.1 years.Intervention Intensive behavior modification in group and individual sessions de-signed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group receiveddiet-related education materials.Main Outcome Measures Fatal and nonfatal coronary heart disease (CHD), fataland nonfatal stroke, and CVD (composite of CHD and stroke).Results By year 6, mean fat intake decreased by 8.2% of energy intake in the inter-vention vs the comparison group, with small decreases in saturated (2.9%), monoun-saturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of veg-etables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterollevels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cho-lesterol, triglycerides, glucose, and insulin did not significantly differ in the interventionvs comparison groups. The numbers who developed CHD, stroke, and CVD (annual-ized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the in-tervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group.The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95%confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR,0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs(95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respec-tively. Trends toward greater reductions in CHD risk were observed in those with lowerintakes of saturated fat or trans fat or higher intakes of vegetables/fruits.Conclusions Over a mean of 8.1 years, a dietary intervention that reduced total fatintake and increased intakes of vegetables, fruits, and grains did not significantly re-duce the risk of CHD, stroke, or CVD in postmenopausal women and achieved onlymodest effects on CVD risk factors, suggesting that more focused diet and lifestyleinterventions may be needed to improve risk factors and reduce CVD risk.Clinical Trials Registration ClinicalTrials.gov Identifier NCT00000611JAMA. 2006;295:655-666 www.jama.com

©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, February 8, 2006—Vol 295, No. 6 655

by PEDROBASTOS, on January 18, 2007 www.jama.comDownloaded from



















HORTALIÇAS/FRUTA: +30%

TRANS: - 22%

FIBRA: + 16% CEREAIS: +11%

Howard BV, et al. JAMA. 2006 Feb 8;295(6):655-66

0% 5% 10% 15% 20% 25% DAC Total DCV RISCO RELATIVO


0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

DAC Total DCV

RISCO RELATIVO EM MULHERES

QUE TINHAM DCV


0

20

40

60

80

0 10 20 30 40 50

% P

esso

as c

/ Sd

LDL

% Gordura % CHO 75 65 55 45 35

r = -0.95 P< 0.001

Krauss RM. J Nutr 2001;131:340s-43s

ÁCIDOS GORDOS SATURADOS

USDA, AHA: < 10% DO TOTAL CALÓRICO

Dietary Guidelines for Americans, USDA, 2010

Mensink RP, Zock PL, Kester AD, Katan MB. Am J Clin Nutr. 2003 May;77(5):1146-55

Δ de LDL-C Δ de HDL-C Δ de TC/HDL-C

1150 MENSINK ET AL

TABLE 2Estimated regression coefficients for mean changes (!) in serum lipids and lipoproteins when carbohydrates constituting 1% of dietary energy arereplaced isoenergetically with lauric acid (Carbohydrates ! 12:0), myristic acid (Carbohydrates ! 14:0), palmitic acid (Carbohydrates ! 16:0), orstearic acid (Carbohydrates ! 18:0)1

No. of diets;Lipid or lipoprotein no. of studies Carbohydrates ! 12:0 Carbohydrates ! 14:0 Carbohydrates ! 16:0 Carbohydrates ! 18:0

!Total:HDL cholesterol 91; 35 "0.037 ("0.057, "0.017) "0.003 ("0.026, 0.021) 0.005 ("0.008, 0.019) "0.013 ("0.030, 0.003)P <0.001 0.832 0.431 0.119

!Total cholesterol (mmol/L) 90; 35 0.069 (0.040, 0.097) 0.059 (0.036, 0.082) 0.041 (0.028, 0.054) "0.010 ("0.026, 0.006)P <0.001 <0.001 < 0.001 0.227

!LDL cholesterol (mmol/L) 90; 35 0.052 (0.026, 0.078) 0.048 (0.027, 0.069) 0.039 (0.027, 0.051) "0.004 ("0.019, 0.011)P <0.001 <0.001 < 0.001 0.464

!HDL cholesterol (mmol/L) 90; 35 0.027 (0.021, 0.033) 0.018 (0.013, 0.023) 0.010 (0.007, 0.013) 0.002 ("0.001, 0.006)P <0.001 0.841 0.418 0.390

!Triacylglycerol (mmolL) 91; 35 "0.019 ("0.028, "0.011) "0.017 ("0.027, "0.006) "0.017 ("0.023, "0.011) "0.017 ("0.024, "0.010)P <0.001 0.002 < 0.001 <0.001

!Apo B (mg/L) 66; 25 5.6 ("2.6, 13.8) 1.9 ("4.6, 8.5) 4.2 ("0.5, 8.9) "3.8 ("9.2, 1.5)P 0.173 0.552 0.078 0.152

!Apo A-I (mg/L) 65; 25 13.8 (1.8, 25.8) 10.4 (5.0, 15.7) 7.5 (3.7, 11.4) "1.6 ("6.0, 2.8)P <0.001 <0.001 <0.001 0.371

1 95% CI in parentheses. Apo, apolipoprotein.

FIGURE 3. Predicted changes (!) in the ratio of serum total to HDLcholesterol and in LDL- and HDL-cholesterol concentrations when car-bohydrates constituting 1% of energy are replaced isoenergetically withlauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), or stearic acid(18:0). *P < 0.001.

36% in women (87). For the Veterans Administration trial, the pre-dicted and observed changes are 20% and 24%, respectively (88).Predicted effects are thus somewhat lower than observed effects,which suggests that dietary fatty acids also affect other risk factorsfor CAD. Epidemiologic observations, however, suggest a muchlarger effect of changes in the amount and quality of dietary fatand carbohydrates on CAD risk (89), and the possible reasons forthis were discussed elsewhere (90, 91).

Effects of fatty acids and carbohydrates on serum lipids andlipoproteins

Our results suggest that isoenergetic replacement of SFAs withcarbohydrates does not improve the serum total:HDL cholesterol.All natural fats contain both SFAs, which do not change this ratio,and unsaturated fatty acids, which lower it. As a result, even thereplacement of dairy fat and tropical fats with carbohydrates will

increase the ratio of total to HDL cholesterol (Figure 4). Theproducts with the most favorable effect on this ratio are oils thatare rich in cis unsaturated fatty acids, such as rapeseed, soy-bean, sunflower, and olive oils. The effects of the PUFAs, whichin our analyses consisted mainly of linoleic acid plus some#-linolenic acid, are more favorable than those of MUFAs suchas oleic acid, but the difference is slight. Our study did notaddress the effects of n"3 PUFAs from fish. Their major effecton plasma lipids is to lower triacylglycerols (12), but theirfavorable effects on CAD mortality may also involve pathwaysother than plasma lipoproteins (92).

Apolipoprotein B and LDL particle size

There is evidence that not only the amount of cholesterol trans-ported by LDL particles but also the size and density of these par-ticles and their apo B content affect CAD risk (93). Effects of car-bohydrates on apo B were less favorable than those of unsaturatedfatty acids (Table 1), which may agree with the findings of stud-ies in which high-carbohydrate diets not only increased triacyl-glycerol concentrations but also induced a shift toward smaller,denser LDL particles (93).

Individual saturated fatty acids

Lauric acid markedly increases cholesterol, whereas stearicacid lowers it somewhat when it is used to replace carbohydrates.However, the picture reverses if one looks at total:HDL choles-terol: both lauric and stearic acid are now more favorable than car-bohydrates. Lauric acid—a major component of tropical oils suchas coconut and palm kernel fat—has the largest cholesterol-rais-ing effect of all fatty acids, but much of this is due to HDL cho-lesterol. As a result, lauric acid had a more favorable effect ontotal:HDL cholesterol than any other fatty acid, either saturatedor unsaturated.

trans Fatty acids

The trans MUFAs were the most harmful macronutrient interms of the ratio of total to HDL cholesterol. If trans MUFAsconstituting 1% of energy are isoenergetically replaced with a1:1:1 mix of carbohydrates, cis MUFAs, and cis PUFAs, then the

by on Novem

ber 26, 2009 w

ww

.ajcn.orgD

ownloaded from

1150 MENSINK ET AL

TABLE 2Estimated regression coefficients for mean changes (!) in serum lipids and lipoproteins when carbohydrates constituting 1% of dietary energy arereplaced isoenergetically with lauric acid (Carbohydrates ! 12:0), myristic acid (Carbohydrates ! 14:0), palmitic acid (Carbohydrates ! 16:0), orstearic acid (Carbohydrates ! 18:0)1

No. of diets;Lipid or lipoprotein no. of studies Carbohydrates ! 12:0 Carbohydrates ! 14:0 Carbohydrates ! 16:0 Carbohydrates ! 18:0

!Total:HDL cholesterol 91; 35 "0.037 ("0.057, "0.017) "0.003 ("0.026, 0.021) 0.005 ("0.008, 0.019) "0.013 ("0.030, 0.003)P <0.001 0.832 0.431 0.119

!Total cholesterol (mmol/L) 90; 35 0.069 (0.040, 0.097) 0.059 (0.036, 0.082) 0.041 (0.028, 0.054) "0.010 ("0.026, 0.006)P <0.001 <0.001 <0.001 0.227

!LDL cholesterol (mmol/L) 90; 35 0.052 (0.026, 0.078) 0.048 (0.027, 0.069) 0.039 (0.027, 0.051) "0.004 ("0.019, 0.011)P <0.001 <0.001 <0.001 0.464

!HDL cholesterol (mmol/L) 90; 35 0.027 (0.021, 0.033) 0.018 (0.013, 0.023) 0.010 (0.007, 0.013) 0.002 ("0.001, 0.006)P <0.001 0.841 0.418 0.390

!Triacylglycerol (mmolL) 91; 35 "0.019 ("0.028, "0.011) "0.017 ("0.027, "0.006) "0.017 ("0.023, "0.011) "0.017 ("0.024, "0.010)P <0.001 0.002 <0.001 <0.001

!Apo B (mg/L) 66; 25 5.6 ("2.6, 13.8) 1.9 ("4.6, 8.5) 4.2 ("0.5, 8.9) "3.8 ("9.2, 1.5)P 0.173 0.552 0.078 0.152

!Apo A-I (mg/L) 65; 25 13.8 (1.8, 25.8) 10.4 (5.0, 15.7) 7.5 (3.7, 11.4) "1.6 ("6.0, 2.8)P <0.001 <0.001 <0.001 0.371

1 95% CI in parentheses. Apo, apolipoprotein.

FIGURE 3. Predicted changes (!) in the ratio of serum total to HDLcholesterol and in LDL- and HDL-cholesterol concentrations when car-bohydrates constituting 1% of energy are replaced isoenergetically withlauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), or stearic acid(18:0). *P < 0.001.

36% in women (87). For the Veterans Administration trial, the pre-dicted and observed changes are 20% and 24%, respectively (88).Predicted effects are thus somewhat lower than observed effects,which suggests that dietary fatty acids also affect other risk factorsfor CAD. Epidemiologic observations, however, suggest a muchlarger effect of changes in the amount and quality of dietary fatand carbohydrates on CAD risk (89), and the possible reasons forthis were discussed elsewhere (90, 91).

Effects of fatty acids and carbohydrates on serum lipids andlipoproteins

Our results suggest that isoenergetic replacement of SFAs withcarbohydrates does not improve the serum total:HDL cholesterol.All natural fats contain both SFAs, which do not change this ratio,and unsaturated fatty acids, which lower it. As a result, even thereplacement of dairy fat and tropical fats with carbohydrates will

increase the ratio of total to HDL cholesterol (Figure 4). Theproducts with the most favorable effect on this ratio are oils thatare rich in cis unsaturated fatty acids, such as rapeseed, soy-bean, sunflower, and olive oils. The effects of the PUFAs, whichin our analyses consisted mainly of linoleic acid plus some#-linolenic acid, are more favorable than those of MUFAs suchas oleic acid, but the difference is slight. Our study did notaddress the effects of n"3 PUFAs from fish. Their major effecton plasma lipids is to lower triacylglycerols (12), but theirfavorable effects on CAD mortality may also involve pathwaysother than plasma lipoproteins (92).

Apolipoprotein B and LDL particle size

There is evidence that not only the amount of cholesterol trans-ported by LDL particles but also the size and density of these par-ticles and their apo B content affect CAD risk (93). Effects of car-bohydrates on apo B were less favorable than those of unsaturatedfatty acids (Table 1), which may agree with the findings of stud-ies in which high-carbohydrate diets not only increased triacyl-glycerol concentrations but also induced a shift toward smaller,denser LDL particles (93).

Individual saturated fatty acids

Lauric acid markedly increases cholesterol, whereas stearicacid lowers it somewhat when it is used to replace carbohydrates.However, the picture reverses if one looks at total:HDL choles-terol: both lauric and stearic acid are now more favorable than car-bohydrates. Lauric acid—a major component of tropical oils suchas coconut and palm kernel fat—has the largest cholesterol-rais-ing effect of all fatty acids, but much of this is due to HDL cho-lesterol. As a result, lauric acid had a more favorable effect ontotal:HDL cholesterol than any other fatty acid, either saturatedor unsaturated.

trans Fatty acids

The trans MUFAs were the most harmful macronutrient interms of the ratio of total to HDL cholesterol. If trans MUFAsconstituting 1% of energy are isoenergetically replaced with a1:1:1 mix of carbohydrates, cis MUFAs, and cis PUFAs, then the

by on Novem

ber 26, 2009 w

ww

.ajcn.orgD

ownloaded from


Coronary heart disease (CHD) incidence and mor-tality re! ect complex interactions between genetic susceptibilities and environmental factors. Although several CHD susceptibility genes have been identi" ed [1], several lines of evidence indicate that environ-ment rather than genetics is the main driver of CHD risk [2]. Globally, age-adjusted CHD incidence and mortality vary as much as 10-fold across populations [3,4]. CHD incidence and risk factors are sensitive to lifestyle changes. When immigrants from traditionally low-risk regions adopt the habits of high-risk popula-tions, their CHD incidence rises to approach that of

resident inhabitants, especially with increasing dura-tion of residence [5–7].

For instance, CHD is historically far more common in the United States than in Japan [4]. Among men of Japa-nese ancestry, CHD risk is lowest in Japan, intermediate in Hawaii, and highest in California [8,9]. These differences appear to re! ect the replacement of traditional Japanese cultural traditions with Western habits [8]. Indeed, Japa-nese Americans who maintained traditional customs and habits had a CHD risk similar to that of their counterparts residing in Japan, whereas those who adopted Western cul-ture had a three- to " vefold excess in CHD prevalence [8].

Dietary Fat Quality and Coronary Heart Disease Prevention: A Unifi ed Theory Based on Evolutionary, Historical, Global, and Modern PerspectivesChristopher E. Ramsden, MDKeturah R. Faurot, PA, MPHPedro Carrera-Bastos, BALoren Cordain, PhDMichel De Lorgeril, MD, PhDLaurence S. Sperling, MDCorresponding authorChristopher E. Ramsden, MDDepartment of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina–Chapel Hill School of Medicine, CB# 7200, Chapel Hill, NC 27599, USA.E-mail: [email protected]

Current Treatment Options in Cardiovascular Medicine 2009, 11:289–301Current Medicine Group LLC ISSN 1092-8464Copyright © 2009 by Current Medicine Group LLC

Opinion statementA large and growing body of evidence indicates that dietary fatty acids regulate crucial metabolic processes involved in the pathogenesis of coronary heart disease (CHD). Despite this evidence, optimal dietary fatty acid intakes for CHD preven-tion remain unclear. Signifi cant gaps in the modern nutrition literature and contra-dictions in its interpretation have precluded broad consensus. These shortcomings can be addressed through the incorporation of evolutionary, historical, and global perspectives. The objective of this review is to propose a unifi ed theory of optimal dietary fatty acid intake for CHD prevention that integrates critical insights from evolutionary, historical, global, and modern perspectives. This broad approach may be more likely than previous methods to characterize optimal fatty acid intakes.

Introduction

Coronary heart disease (CHD) incidence and mor-tality re! ect complex interactions between genetic susceptibilities and environmental factors. Although several CHD susceptibility genes have been identi" ed [1], several lines of evidence indicate that environ-ment rather than genetics is the main driver of CHD risk [2]. Globally, age-adjusted CHD incidence and mortality vary as much as 10-fold across populations [3,4]. CHD incidence and risk factors are sensitive to lifestyle changes. When immigrants from traditionally low-risk regions adopt the habits of high-risk popula-tions, their CHD incidence rises to approach that of

resident inhabitants, especially with increasing dura-tion of residence [5–7].

For instance, CHD is historically far more common in the United States than in Japan [4]. Among men of Japa-nese ancestry, CHD risk is lowest in Japan, intermediate in Hawaii, and highest in California [8,9]. These differences appear to re! ect the replacement of traditional Japanese cultural traditions with Western habits [8]. Indeed, Japa-nese Americans who maintained traditional customs and habits had a CHD risk similar to that of their counterparts residing in Japan, whereas those who adopted Western cul-ture had a three- to " vefold excess in CHD prevalence [8].

Dietary Fat Quality and Coronary Heart Disease Prevention: A Unifi ed Theory Based on Evolutionary, Historical, Global, and Modern PerspectivesChristopher E. Ramsden, MDKeturah R. Faurot, PA, MPHPedro Carrera-Bastos, BALoren Cordain, PhDMichel De Lorgeril, MD, PhDLaurence S. Sperling, MDCorresponding authorChristopher E. Ramsden, MDDepartment of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina–Chapel Hill School of Medicine, CB# 7200, Chapel Hill, NC 27599, USA.E-mail: [email protected]

Current Treatment Options in Cardiovascular Medicine 2009, 11:289–301Current Medicine Group LLC ISSN 1092-8464Copyright © 2009 by Current Medicine Group LLC

Opinion statementA large and growing body of evidence indicates that dietary fatty acids regulate crucial metabolic processes involved in the pathogenesis of coronary heart disease (CHD). Despite this evidence, optimal dietary fatty acid intakes for CHD preven-tion remain unclear. Signifi cant gaps in the modern nutrition literature and contra-dictions in its interpretation have precluded broad consensus. These shortcomings can be addressed through the incorporation of evolutionary, historical, and global perspectives. The objective of this review is to propose a unifi ed theory of optimal dietary fatty acid intake for CHD prevention that integrates critical insights from evolutionary, historical, global, and modern perspectives. This broad approach may be more likely than previous methods to characterize optimal fatty acid intakes.

Introduction

CHINA RURAL: < 5%

TOKELAU: 40%

EUA: 11-12% CRS: 4-18%

MAASAI: 30-35% KITAVA: 17%

A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD


DIMINUIÇÃO DA GORDURA TOTAL DE 35% PARA 32.3%

AUMENTO DO RÁCIO PUFA/SAFA EM 100%

Differential Effects of Cream, Glucose, andOrange Juice on Inflammation, Endotoxin,and the Expression of Toll-Like Receptor-4and Suppressor of Cytokine Signaling-3RUPALI DEOPURKAR, PHD

HUSAM GHANIM, PHD

JAY FRIEDMAN, PHD

SANAA ABUAYSHEH, BSC

CHANG LING SIA, BSC

PRIYA MOHANTY, MD

PRABHAKAR VISWANATHAN, PHD

AJAY CHAUDHURI, MD

PARESH DANDONA, MD, PHD

OBJECTIVE — We have recently shown that a high-fat high-carbohydrate (HFHC) mealinduces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and theexpression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) inmononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturatedfat and carbohydrates, components of the HFHC meal, known to induce oxidative stress andinflammation, also induce an increase in LPS, TLR-4, and SOCS3.

RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300-calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Bloodsamples were obtained at 0, 1, 3, and 5 h for analysis.

RESULTS — Indexes of inflammation including nuclear factor-!B (NF-!B) binding, and theexpression of SOCS3, tumor necrosis factor-" (TNF-"), and interleukin (IL)-1# in MNCs,increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPSconcentrations increased only after cream intake. The intake of orange juice or water did notinduce any change in any of the indexes measured.

CONCLUSIONS — Although both glucose and cream induce NF-!B binding and an in-crease in the expression of SOCS3, TNF-", and IL-1# in MNCs, only cream caused an increasein LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did notinduce a change in any of these indexes. These changes are relevant to the pathogenesis ofatherosclerosis and insulin resistance.

Diabetes Care 33:991–997, 2010

Our recent work has shown that ahigh-fat high-cholesterol (HFHC)meal induces oxidative and inflam-

matory stress in addition to inducing anincrease in plasma endotoxin (lipopoly-saccharide [LPS]) levels and the expres-sion of Toll-like receptor (TLR)-4, thespecific receptor for LPS (1). In contrast, ahigh-fiber and fruit meal does not induceany of these changes. These data are of

great interest because the content of LPSin these meals is not significantly differ-ent, and, thus, it would appear that theinflammatory nature of the meal may leadto a partial breakdown of the intestinalbarrier that normally protects the bodyfrom invasion of bacteria and the entry ofLPS from the gut. The concept of this im-munological barrier of the gut has devel-oped rapidly over the past few years and is

vital to the protection from bacterial tox-ins and immunological responses to thecommensal and pathogenic intestinalbacteria.

In this context, we wanted to analyzewhich macronutrient was responsible forthe induction of oxidative stress and in-flammation, on the one hand, and the in-crease in LPS concentrations and theexpression of TLR-4 and suppresser of cy-tokine signaling (SOCS)-3 on the other.To elucidate this, we investigated the ef-fect of glucose, the most important carbo-hydrate, cream, a saturated fat, andorange juice, a carbohydrate-containingfood product, which does not induce ei-ther oxidative stress or inflammation.

SOCS3 is a protein that has beenshown to interfere with insulin and leptinsignal transduction (2–5). Our recentwork has shown that SOCS3 expressionin the circulating mononuclear cells(MNCs) of the obese human is markedlyincreased when compared with that innormal subjects (6). In addition, ourwork demonstrated that SOCS3 expres-sion in MNCs is inversely related to thetyrosine phosphorylation of the insulinreceptor and directly related to BMI andinsulin resistance (homeostasis model as-sessment of insulin resistance [HOMA-IR]), consistent with its role in thepathogenesis of insulin resistance. Leptinresistance in human obesity leads to theinability of leptin to cause satiety andweight loss, whereas insulin resistancemakes the obese vulnerable to diabetes.Human obesity is also a state of chronicinflammation characterized by an in-crease in inflammatory mediators inplasma, in adipose tissue, and in circulat-ing mononuclear cells (7,8). BecauseSOCS3 is induced in animal models byproinflammatory stimuli like the cyto-kines, TNF-", IL-6, and IL-1# (3,4,9) andbecause macronutrient intake causes oxi-dative stress (10,11) and inflammation(12,13), it is possible that the intake ofglucose and saturated fat (cream) inducesan increase in the expression of SOCS3 asa part of macronutrient-induced inflam-

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

From the Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo andKaleida Health, Buffalo, New York.

Corresponding author: Paresh Dandona, [email protected] 2 September 2009 and accepted 5 January 2010. Published ahead of print at http://care.

diabetesjournals.org on 12 January 2010. DOI: 10.2337/dc09-1630.R.D., H.G., and J.F. contributed equally to this study.© 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c hO R I G I N A L A R T I C L E

care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 5, MAY 2010 991


HUSAM GHANIM, PHD

JAY FRIEDMAN, PHD


CHANG LING SIA, BSC

PRIYA MOHANTY, MD


AJAY CHAUDHURI, MD













! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !









HUSAM GHANIM, PHD

JAY FRIEDMAN, PHD


CHANG LING SIA, BSC

PRIYA MOHANTY, MD


AJAY CHAUDHURI, MD













! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !









HUSAM GHANIM, PHD

JAY FRIEDMAN, PHD


CHANG LING SIA, BSC

PRIYA MOHANTY, MD


AJAY CHAUDHURI, MD













! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !








flected in these indexes and the overallmagnitude of the inflammatory process.Previously, Dasu et al. (25) reported thathigh glucose concentrations upregulatedTLR-4 expression and its downstream sig-naling in a monocytic cell line. However,the excursions of glucose concentrationsin normal and even obese subjects do notachieve those concentrations postprandi-ally. Thus, the observations of Dasu et al.are relevant to diabetic individuals. Ourinvestigation deals with postprandialchanges in normal subjects. As far as theeffects of cream intake are concerned, theamount taken is modest, and the increase

in triglycerides is consistent with that inprevious studies. It should, therefore, benoted that although the amounts of creamand glucose taken induced similar in-creases in reactive oxygen species genera-tion and NF-!B binding, glucose was notable to induce an increase in the expres-sion of TLR-4.

In summary, the intake of a modestamount of glucose or cream results in asignificant induction of SOCS3 mRNAand protein in parallel with the inductionof an inflammatory response character-ized by an increase in NF-!B binding inMNCs and the induction of two of the

cytokines, TNF-" and IL-1#, which areknown to induce SOCS3 in experimentalanimals. In addition, the intake of creambut not of glucose also induces an in-crease in the expression of TLR-4 mRNAand protein while also inducing an in-crease in plasma LPS concentrations. BothSOCS3 and TLR-4 are putative mediatorsof insulin resistance. In contrast, orangejuice intake does not induce oxidativestress, inflammation, SOCS3, TLR-4, oran increase in plasma LPS concentrations.

Acknowledgments— The study was sup-ported in part by a grant from the State ofFlorida, Department of Citrus. P.D. was alsosupported by the National Institutes of Health(R01-DK-069805 and R01-DK-075877) andthe American Diabetes Association (708CR13).The data were obtained from our laboratoryand were under our control, and the inter-pretations and conclusions are those of theinvestigators. Furthermore, the Principal In-vestigator (P.D.) takes the full responsibilityfor them.

No potential conflicts of interest relevant tothis article were reported.

References1. Ghanim H, Abuaysheh S, Sia CL, Korze-

niewski K, Chaudhuri A, Fernandez-RealJM, Dandona P. Increase in plasma endo-toxin concentrations and the expressionof Toll-like receptors and suppressor ofcytokine signaling-3 in mononuclear cellsfollowing a high-fat high-carbohydratemeal: implications for insulin resistance.Diabetes Care 2009;32:2281–2287

2. Rui L, Yuan M, Frantz D, Shoelson S,White MF. SOCS-1 and SOCS-3 block in-sulin signaling by ubiquitin-mediateddegradation of IRS1 and IRS2. J BiolChem 2002;277:42394–42398

3. Senn JJ, Klover PJ, Nowak IA, ZimmersTA, Koniaris LG, Furlanetto RW, MooneyRA. Suppressor of cytokine signaling-3(SOCS-3), a potential mediator of inter-leukin-6-dependent insulin resistance inhepatocytes. J Biol Chem 2003;278:13740–13746

4. Emanuelli B, Peraldi P, Filloux C, ChaveyC, Freidinger K, Hilton DJ, HotamisligilGS, Van Obberghen E. SOCS-3 inhibitsinsulin signaling and is up-regulated inresponse to tumor necrosis factor-alpha inthe adipose tissue of obese mice. J BiolChem 2001;276:47944–47949

5. Bjørbaek C, El-Haschimi K, Frantz JD,Flier JS. The role of SOCS-3 in leptin sig-naling and leptin resistance. J Biol Chem1999;274:30059–30065

6. Ghanim H, Aljada A, Daoud N, DeopurkarR, Chaudhuri A, Dandona P. Role of inflam-matory mediators in the suppression ofinsulin receptor phosphorylation in circu-

Figure 3—Change in NF!B binding activity in MNC (A) and plasma endotoxin concentrations(B) in normal subjects after a 300-calorie drink of cream (E), glucose (Œ), orange juice (OJ, ‚),or water (F). Data are means $ SEM. * and !, P % 0.05 with RMANOVA comparing changes inrelation to baseline after cream and glucose challenges; # and $, P % 0.05 with two-wayRMANOVA for comparisons of cream and glucose changes, respectively, to water (n & 12).

Macronutrients, oxidative stress, and inflammation

996 DIABETES CARE, VOLUME 33, NUMBER 5, MAY 2010 care.diabetesjournals.org

Sumo de Laranja

Nata

LIGANDOS DOS TLRS

IkB Cinase

P

LPS

TLR

•  Citoquinas •  Enzimas •  Moléculas de adesão


HUSAM GHANIM, PHD

JAY FRIEDMAN, PHD


CHANG LING SIA, BSC

PRIYA MOHANTY, MD


AJAY CHAUDHURI, MD













! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !








flected in these indexes and the overallmagnitude of the inflammatory process.Previously, Dasu et al. (25) reported thathigh glucose concentrations upregulatedTLR-4 expression and its downstream sig-naling in a monocytic cell line. However,the excursions of glucose concentrationsin normal and even obese subjects do notachieve those concentrations postprandi-ally. Thus, the observations of Dasu et al.are relevant to diabetic individuals. Ourinvestigation deals with postprandialchanges in normal subjects. As far as theeffects of cream intake are concerned, theamount taken is modest, and the increase

in triglycerides is consistent with that inprevious studies. It should, therefore, benoted that although the amounts of creamand glucose taken induced similar in-creases in reactive oxygen species genera-tion and NF-!B binding, glucose was notable to induce an increase in the expres-sion of TLR-4.

In summary, the intake of a modestamount of glucose or cream results in asignificant induction of SOCS3 mRNAand protein in parallel with the inductionof an inflammatory response character-ized by an increase in NF-!B binding inMNCs and the induction of two of the

cytokines, TNF-" and IL-1#, which areknown to induce SOCS3 in experimentalanimals. In addition, the intake of creambut not of glucose also induces an in-crease in the expression of TLR-4 mRNAand protein while also inducing an in-crease in plasma LPS concentrations. BothSOCS3 and TLR-4 are putative mediatorsof insulin resistance. In contrast, orangejuice intake does not induce oxidativestress, inflammation, SOCS3, TLR-4, oran increase in plasma LPS concentrations.

Acknowledgments— The study was sup-ported in part by a grant from the State ofFlorida, Department of Citrus. P.D. was alsosupported by the National Institutes of Health(R01-DK-069805 and R01-DK-075877) andthe American Diabetes Association (708CR13).The data were obtained from our laboratoryand were under our control, and the inter-pretations and conclusions are those of theinvestigators. Furthermore, the Principal In-vestigator (P.D.) takes the full responsibilityfor them.

No potential conflicts of interest relevant tothis article were reported.

References1. Ghanim H, Abuaysheh S, Sia CL, Korze-

niewski K, Chaudhuri A, Fernandez-RealJM, Dandona P. Increase in plasma endo-toxin concentrations and the expressionof Toll-like receptors and suppressor ofcytokine signaling-3 in mononuclear cellsfollowing a high-fat high-carbohydratemeal: implications for insulin resistance.Diabetes Care 2009;32:2281–2287

2. Rui L, Yuan M, Frantz D, Shoelson S,White MF. SOCS-1 and SOCS-3 block in-sulin signaling by ubiquitin-mediateddegradation of IRS1 and IRS2. J BiolChem 2002;277:42394–42398

3. Senn JJ, Klover PJ, Nowak IA, ZimmersTA, Koniaris LG, Furlanetto RW, MooneyRA. Suppressor of cytokine signaling-3(SOCS-3), a potential mediator of inter-leukin-6-dependent insulin resistance inhepatocytes. J Biol Chem 2003;278:13740–13746

4. Emanuelli B, Peraldi P, Filloux C, ChaveyC, Freidinger K, Hilton DJ, HotamisligilGS, Van Obberghen E. SOCS-3 inhibitsinsulin signaling and is up-regulated inresponse to tumor necrosis factor-alpha inthe adipose tissue of obese mice. J BiolChem 2001;276:47944–47949

5. Bjørbaek C, El-Haschimi K, Frantz JD,Flier JS. The role of SOCS-3 in leptin sig-naling and leptin resistance. J Biol Chem1999;274:30059–30065

6. Ghanim H, Aljada A, Daoud N, DeopurkarR, Chaudhuri A, Dandona P. Role of inflam-matory mediators in the suppression ofinsulin receptor phosphorylation in circu-

Figure 3—Change in NF!B binding activity in MNC (A) and plasma endotoxin concentrations(B) in normal subjects after a 300-calorie drink of cream (E), glucose (Œ), orange juice (OJ, ‚),or water (F). Data are means $ SEM. * and !, P % 0.05 with RMANOVA comparing changes inrelation to baseline after cream and glucose challenges; # and $, P % 0.05 with two-wayRMANOVA for comparisons of cream and glucose changes, respectively, to water (n & 12).

Macronutrients, oxidative stress, and inflammation

996 DIABETES CARE, VOLUME 33, NUMBER 5, MAY 2010 care.diabetesjournals.org

Nata

Sumo de Laranja

Glucose

Dieta Prudente - 1478 kcal:

¤ %CHO = 56 ¤ % Lípidos = 24

ARTICLE

Comparison of Low Fat and Low Carbohydrate Dietson Circulating Fatty Acid Composition and Markersof Inflammation

Cassandra E. Forsythe Æ Stephen D. Phinney Æ Maria Luz Fernandez ÆErin E. Quann Æ Richard J. Wood Æ Doug M. Bibus Æ William J. Kraemer ÆRichard D. Feinman Æ Jeff S. Volek

Received: 5 July 2007 / Revised: 24 October 2007 / Accepted: 25 October 2007 / Published online: 29 November 2007! AOCS 2007

Abstract Abnormal distribution of plasma fatty acids andincreased inflammation are prominent features of meta-

bolic syndrome. We tested whether these components of

metabolic syndrome, like dyslipidemia and glycemia, areresponsive to carbohydrate restriction. Overweight men

and women with atherogenic dyslipidemia consumed

ad libitum diets very low in carbohydrate (VLCKD)(1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat

(LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for

12 weeks. In comparison to the LFD, the VLCKD resultedin an increased proportion of serum total n-6 PUFA, mainly

attributed to a marked increase in arachidonate (20:4n-6),

while its biosynthetic metabolic intermediates weredecreased. The n-6/n-3 and arachidonic/eicosapentaenoic

acid ratio also increased sharply. Total saturated fatty acids

and 16:1n-7 were consistently decreased following theVLCKD. Both diets significantly decreased the concen-

tration of several serum inflammatory markers, but there

was an overall greater anti-inflammatory effect associatedwith the VLCKD, as evidenced by greater decreases in

TNF-a, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1.

Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 andn-6/n-3 are commonly viewed as pro-inflammatory, but

unexpectedly were consistently inversely associated with

responses in inflammatory proteins. In summary, a verylow carbohydrate diet resulted in profound alterations in

fatty acid composition and reduced inflammation compared

to a low fat diet.

Keywords Arachidonic acid ! Palmitoleic acid !Ketogenic diet ! Saturated fat ! Metabolic syndrome

AbbreviationsVLCKD Very low carbohydrate ketogenic diet

LFD Low fat diet

PL PhospholipidCE Cholesteryl ester

CVD Cardiovascular disease

RDA Recommended daily allowanceBMI Body mass index

IL Interleukin

TNF-a Tumor necrosis factor-aVEGF Vascular endothelial growth factor

IFN-c Interferon-cEGF Epidermal growth factorMCP-1 Monocyte chemotactic protein-1

ICAM-1 Intracellular cellular adhesion molecule-1

VCAM-I Vascular cellular adhesion molecule-INF-jB Nuclear factor-kappa B

C. E. Forsythe ! E. E. Quann ! W. J. Kraemer ! J. S. Volek (&)Department of Kinesiology, University of Connecticut,2095 Hillside Road, Unit 1110, Storrs, CT 06269-1110, USAe-mail: [email protected]

S. D. PhinneySchool of Medicine, University of California, Davis, CA, USA

M. L. Fernandez ! R. J. Wood ! J. S. VolekDepartment of Nutritional Science, University of Connecticut,Storrs, CT, USA

D. M. BibusUniversity of Minnesota and Lipid Technologies, LLC,Austin, MN, USA

R. D. FeinmanDepartment of Biochemistry, SUNY Downstate Medical Center,Brooklyn, NY, USA

123

Lipids (2008) 43:65–77

DOI 10.1007/s11745-007-3132-7

Dieta Very Low Carb - 1504 kcal:

¤ %CHO = 12 ¤ % Lípidos = 59

36,4 g de SAFA 11,7 g de SAFA

40 H e M c/ IMC> 25

RCT de 12 semanas:

0

2

4

6

8

10

12

14

14:O 16:O Total SAFA

Low Carb

Prudente

mg/dl

ÁCIDOS GORDOS NOS ÉSTERES DE COLESTEROL

See corresponding editorial on page 1541.

Intake of carbohydrates compared with intake of saturated fatty acidsand risk of myocardial infarction: importance of the glycemic index1–3

Marianne U Jakobsen, Claus Dethlefsen, Albert M Joensen, Jakob Stegger, Anne Tjønneland, Erik B Schmidt,and Kim Overvad

ABSTRACTBackground: Studies have suggested that replacing saturated fattyacids (SFAs) with carbohydrates is modestly associated with a high-er risk of ischemic heart disease, whereas replacing SFAs withpolyunsaturated fatty acids is associated with a lower risk of ische-mic heart disease. The effect of carbohydrates, however, may de-pend on the type consumed.Objectives: By using substitution models, we aimed to investigatethe risk of myocardial infarction (MI) associated with a higher en-ergy intake from carbohydrates and a concomitant lower energyintake from SFAs. Carbohydrates with different glycemic index(GI) values were also investigated.Design: Our prospective cohort study included 53,644 women andmen free of MI at baseline.Results: During a median of 12 y of follow-up, 1943 incident MIcases occurred. There was a nonsignificant inverse association be-tween substitution of carbohydrates with low-GI values for SFAsand risk of MI [hazard ratio (HR) for MI per 5% increment ofenergy intake from carbohydrates: 0.88; 95% CI: 0.72, 1.07). Incontrast, there was a statistically significant positive associationbetween substitution of carbohydrates with high-GI values for SFAsand risk of MI (HR: 1.33; 95% CI: 1.08, 1.64). There was noassociation for carbohydrates with medium-GI values (HR: 0.98;95% CI: 0.80, 1.21). No effect modification by sex was observed.Conclusion: This study suggests that replacing SFAs with carbohy-drates with low-GI values is associated with a lower risk of MI,whereas replacing SFAs with carbohydrates with high-GI values isassociated with a higher risk of MI. Am J Clin Nutr 2010;91:1764–8.

INTRODUCTION

Epidemiologic prospective cohort studies have suggested thatreplacing saturated fatty acids (SFAs) with carbohydrates ismodestly associated with a higher risk of ischemic heart disease(IHD), whereas replacing SFAs with polyunsaturated fatty acidsis associated with a lower risk of IHD (1). The effect of car-bohydrates, however, may depend on the type consumed.

Epidemiologic prospective cohort studies have shown a posi-tive association between dietary glycemic index (GI) and risk ofIHD (2). The dietary GI is an indicator of the average quality of thecarbohydrates consumed in terms of glycemic response. The GI,which was conceived to provide a classification of carbohydrate-containing foods on the basis of their ability to raise blood glu-cose, was introduced by Jenkins et al (3) in 1981. Blood glucose

concentration is tightly regulated by homeostatic regulatorysystems, but the rapid absorption of carbohydrates after con-sumption of a high-GI meal challenges these homeostaticmechanisms (4). A high-GI meal results in a high blood glucoseconcentration and a high insulin-to-glucagon ratio, followed byhypoglycemia, counterregulatory hormone secretion, and ele-vated plasma free fatty acid concentration (4). These events mayaffect the risk of IHD through promoting dyslipidemia, in-flammation, and endothelial dysfunction (4).

The aim of this study was to investigate the risk of myocardialinfarction (MI) with a higher energy intake from carbohydratesand a concomitant lower energy intake from SFAs. Carbohydrateswith different GI values were investigated. Furthermore, potentialeffect modification by sex was investigated because of differencesin the underlying biology such as hormonal differences.

SUBJECTS AND METHODS

Study population

Between December 1993 and May 1997, 160,725 women andmen were invited by mail to participate in the Danish prospectivecohort study Diet, Cancer, and Health. The criteria for invitationwere as follows: age between 50 and 64 y, born in Denmark, andno previous cancer diagnosis registered in the Danish CancerRegistry. All persons fulfilling these criteria and living in thegreater Copenhagen or Aarhus areas were invited. With the in-

1 From the Department of Clinical Epidemiology Aarhus University Hos-pital, Aalborg, Denmark (MUJ); the Department of Cardiology, Center forCardiovascular Research, Aalborg Hospital, Aarhus University Hospital,Aalborg, Denmark (MUJ, CD, AMJ, JS, EBS, and KO); the Danish CancerSociety, Institute of Cancer Epidemiology, Copenhagen, Denmark (AT); andthe Department of Epidemiology, School of Public Health, Aarhus Univer-sity, Aarhus, Denmark (KO).

2 This work is part of the project Hepatic and Adipose Tissue and Func-tions in the Metabolic Syndrome (HEPADIP; www.hepadip.org), which issupported by the European Commission as an Integrated Project under the6th Framework Programme (contract LSHM-CT-2005-018734), and part ofthe research program of the Danish Obesity Research Centre (DanORC;www.danorc.dk), which is supported by the Danish Council for StrategicResearch (contract 2101-06-0005).

3 Address correspondence to MU Jakobsen, Department of Clinical Epi-demiology, Aarhus University Hospital, Sdr. Skovvej 15, DK-9000 Aalborg,Denmark. E-mail: [email protected].

Received December 17, 2009. Accepted for publication March 16, 2010.First published online April 7, 2010; doi: 10.3945/ajcn.2009.29099.

1764 Am J Clin Nutr 2010;91:1764–8. Printed in USA. ! 2010 American Society for Nutrition

at Lund University Libraries on N

ovember 5, 2010

ww

w.ajcn.org

Dow

nloaded from

See corresponding editorial on page 1541.

Intake of carbohydrates compared with intake of saturated fatty acidsand risk of myocardial infarction: importance of the glycemic index1–3

Marianne U Jakobsen, Claus Dethlefsen, Albert M Joensen, Jakob Stegger, Anne Tjønneland, Erik B Schmidt,and Kim Overvad

ABSTRACTBackground: Studies have suggested that replacing saturated fattyacids (SFAs) with carbohydrates is modestly associated with a high-er risk of ischemic heart disease, whereas replacing SFAs withpolyunsaturated fatty acids is associated with a lower risk of ische-mic heart disease. The effect of carbohydrates, however, may de-pend on the type consumed.Objectives: By using substitution models, we aimed to investigatethe risk of myocardial infarction (MI) associated with a higher en-ergy intake from carbohydrates and a concomitant lower energyintake from SFAs. Carbohydrates with different glycemic index(GI) values were also investigated.Design: Our prospective cohort study included 53,644 women andmen free of MI at baseline.Results: During a median of 12 y of follow-up, 1943 incident MIcases occurred. There was a nonsignificant inverse association be-tween substitution of carbohydrates with low-GI values for SFAsand risk of MI [hazard ratio (HR) for MI per 5% increment ofenergy intake from carbohydrates: 0.88; 95% CI: 0.72, 1.07). Incontrast, there was a statistically significant positive associationbetween substitution of carbohydrates with high-GI values for SFAsand risk of MI (HR: 1.33; 95% CI: 1.08, 1.64). There was noassociation for carbohydrates with medium-GI values (HR: 0.98;95% CI: 0.80, 1.21). No effect modification by sex was observed.Conclusion: This study suggests that replacing SFAs with carbohy-drates with low-GI values is associated with a lower risk of MI,whereas replacing SFAs with carbohydrates with high-GI values isassociated with a higher risk of MI. Am J Clin Nutr 2010;91:1764–8.

INTRODUCTION

Epidemiologic prospective cohort studies have suggested thatreplacing saturated fatty acids (SFAs) with carbohydrates ismodestly associated with a higher risk of ischemic heart disease(IHD), whereas replacing SFAs with polyunsaturated fatty acidsis associated with a lower risk of IHD (1). The effect of car-bohydrates, however, may depend on the type consumed.

Epidemiologic prospective cohort studies have shown a posi-tive association between dietary glycemic index (GI) and risk ofIHD (2). The dietary GI is an indicator of the average quality of thecarbohydrates consumed in terms of glycemic response. The GI,which was conceived to provide a classification of carbohydrate-containing foods on the basis of their ability to raise blood glu-cose, was introduced by Jenkins et al (3) in 1981. Blood glucose

concentration is tightly regulated by homeostatic regulatorysystems, but the rapid absorption of carbohydrates after con-sumption of a high-GI meal challenges these homeostaticmechanisms (4). A high-GI meal results in a high blood glucoseconcentration and a high insulin-to-glucagon ratio, followed byhypoglycemia, counterregulatory hormone secretion, and ele-vated plasma free fatty acid concentration (4). These events mayaffect the risk of IHD through promoting dyslipidemia, in-flammation, and endothelial dysfunction (4).

The aim of this study was to investigate the risk of myocardialinfarction (MI) with a higher energy intake from carbohydratesand a concomitant lower energy intake from SFAs. Carbohydrateswith different GI values were investigated. Furthermore, potentialeffect modification by sex was investigated because of differencesin the underlying biology such as hormonal differences.

SUBJECTS AND METHODS

Study population

Between December 1993 and May 1997, 160,725 women andmen were invited by mail to participate in the Danish prospectivecohort study Diet, Cancer, and Health. The criteria for invitationwere as follows: age between 50 and 64 y, born in Denmark, andno previous cancer diagnosis registered in the Danish CancerRegistry. All persons fulfilling these criteria and living in thegreater Copenhagen or Aarhus areas were invited. With the in-

1 From the Department of Clinical Epidemiology Aarhus University Hos-pital, Aalborg, Denmark (MUJ); the Department of Cardiology, Center forCardiovascular Research, Aalborg Hospital, Aarhus University Hospital,Aalborg, Denmark (MUJ, CD, AMJ, JS, EBS, and KO); the Danish CancerSociety, Institute of Cancer Epidemiology, Copenhagen, Denmark (AT); andthe Department of Epidemiology, School of Public Health, Aarhus Univer-sity, Aarhus, Denmark (KO).

2 This work is part of the project Hepatic and Adipose Tissue and Func-tions in the Metabolic Syndrome (HEPADIP; www.hepadip.org), which issupported by the European Commission as an Integrated Project under the6th Framework Programme (contract LSHM-CT-2005-018734), and part ofthe research program of the Danish Obesity Research Centre (DanORC;www.danorc.dk), which is supported by the Danish Council for StrategicResearch (contract 2101-06-0005).

3 Address correspondence to MU Jakobsen, Department of Clinical Epi-demiology, Aarhus University Hospital, Sdr. Skovvej 15, DK-9000 Aalborg,Denmark. E-mail: [email protected].

Received December 17, 2009. Accepted for publication March 16, 2010.First published online April 7, 2010; doi: 10.3945/ajcn.2009.29099.

1764 Am J Clin Nutr 2010;91:1764–8. Printed in USA. ! 2010 American Society for Nutrition


ovember 5, 2010

ww

w.ajcn.org

Dow

nloaded from

first tertile of dietary GI: 0.88; 95% CI: 0.72, 1.07) and a sta-tistically significant positive association between substitution ofcarbohydrates with high-GI values for SFAs and risk of MI (HRin the third tertile of dietary GI: 1.33; 95% CI: 1.08, 1.64) (Table3). There was no association for carbohydrates with medium-GIvalues (HR in the second tertile of dietary GI: 0.98; 95% CI:0.80, 1.21) (Table 3). As assessed from the 95% CIs, themeasures of associations for extreme tertiles of GI were statis-tically significantly different. The P value for effect modificationby tertiles of dietary GI was 0.06 in women, 0.29 in men, and0.16 in all participants. The P value for effect modification bysex was 0.86.

DISCUSSION

The findings from this study suggest that the effect of sub-stitution of carbohydrates for SFAs varies depending on the type ofcarbohydrates. There was a nonsignificant inverse association

between substitution of carbohydrates with low-GI values for SFAsand risk of MI but a significant positive association betweensubstitution of carbohydrates with high-GI values for SFAs and riskof MI. In this study, dietary GI was used as an indicator of theaverage quality of carbohydrates consumed, but other classi-fications of carbohydrates may also be relevant, such as the extentof processing, which also reflects the intake of dietary fiber (16, 17).

Selection bias is unlikely to have affected the results. However,if censoring due to death from other causes is associated withintake of carbohydrates and risk of MI, then the true associationsbetween intake of carbohydrates and risk of MI may have beenunderestimated. Random measurement error cannot be excludedfrom having affected the results. A potential source of randommeasurement error arises from dietary self-reporting methods.Generally, random measurement error leads to underestimationof the true risk and to loss of statistical power. However, dietaryintake was determined by using a FFQ, which may reflect thehabitual eating pattern. Information bias is unlikely to have af-fected the results because cases were identified by record linkagewith central Danish registries and diagnoses were establishedindependently of the FFQs of the participants. We included car-bohydrates, proteins, monounsaturated fatty acids, and poly-unsaturated fatty acids expressed as percentages of the total energyintake and the total energy intake in the models because of po-tential confounding and extraneous variation. This also allowed usto estimate the difference in the risk for a higher energy intake fromcarbohydrates and a concomitant lower energy intake from SFAs.Relevant control for established risk factors for IHD did not changethe measures of associations, and thus residual confounding seemsunlikely. However, confounding from other IHD risk factors nottaken into account remains a possible explanation for the observedassociations.

Only 2 epidemiologic studies have investigated the sub-stitution of carbohydrates for SFAs (1, 18). In the prospectivecohort study by Hu et al (18), substitution of carbohydrates forSFAs was nonsignificantly associated with a lower risk of IHD,whereas in the prospective cohort study by Jakobsen et al (1), inwhich data from 11 American and European cohort studies werepooled, substitution of carbohydrates for SFAs was modestly

TABLE 2Hazard ratios for myocardial infarction per 5% increment of energy intakefrom carbohydrates and a concomitant lower energy intake from saturatedfatty acids1

All participants Women Men

Model 12 1.04 (0.93, 1.17) 1.09 (0.88, 1.36) 1.03 (0.90, 1.18)Model 23 1.04 (0.92, 1.17) 1.02 (0.82, 1.28) 1.05 (0.92, 1.21)

1 All values are hazard ratios; 95% CIs in parentheses. n = 53,644 forall participants, n = 28,495 for women, and n = 25,149 for men.

2 Model 1 included intake of glycemic carbohydrates, proteins, mono-unsaturated fatty acids, and polyunsaturated fatty acids expressed as percen-tages of total energy intake, total energy intake (kcal/d), an indicator variablefor alcohol consumption (0 and .0 g/d), and alcohol consumption (g/d).Hazard ratios with 95% CIs for the incidence of myocardial infarction werecalculated by using Cox proportional hazards regression with age as the timemetric. In analyses among all participants, sex was entered into the model.

3 Model 2 included variables in model 1 and BMI (in kg/m2; ,25, 25–29, and !30), education (,8, 8–10, and .10 y), smoking status (never,former, and currently smoking 1–14, 15–24, or !25 g tobacco/d), physicalactivity (,3.5 and !3.5 h/wk), and history of hypertension (yes, no, and donot know).

TABLE 3Hazard ratios (HRs) for myocardial infarction per 5% increment of energy intake from carbohydrates with low–glycemic index (low-GI), medium-GI, orhigh-GI values and a concomitant lower energy intake from saturated fatty acids1

All participants Women Men

Tertiles ofdietary GI2

Median dietary GI(80% central range) HR (95% CI)



Carbohydrates with low-GIvalues (first tertile)

82 (77, 85) 0.88 (0.72, 1.07) 80 (75, 82) 1.17 (0.80, 1.71) 84 (79, 86) 0.83 (0.65, 1.04)

Carbohydrates with medium-GIvalues (second tertile)

88 (86, 90) 0.98 (0.80, 1.21) 85 (84, 87) 0.80 (0.54, 1.18) 89 (87, 91) 1.08 (0.84, 1.38)

Carbohydrates with high-GIvalues (third tertile)

93 (91, 98) 1.33 (1.08, 1.64) 91 (88, 96) 1.10 (0.75, 1.63) 94 (92, 98) 1.34 (1.04, 1.71)

1 All models included intake of glycemic carbohydrates, proteins, monounsaturated fatty acids, and polyunsaturated fatty acids expressed as percentagesof total energy intake, total energy intake (kcal/d), an indicator variable for alcohol consumption (0 and .0 g/d), alcohol consumption (g/d), BMI (in kg/m2;,25, 25–29, and !30), education (,8, 8–10, and .10 y), smoking status (never, former, and currently smoking 1–14, 15–24, or !25 g tobacco/d), physicalactivity (,3.5 and !3.5 h/wk), and history of hypertension (yes, no, and do not know). HRs with 95% CIs for the incidence of myocardial infarction werecalculated by using Cox proportional hazards regression with age as the time metric. In analyses among all participants, sex was entered into the model.

2 Tertiles of dietary GI were based on the distribution of dietary GI among cases. n = 22,144, 17,000, and 14,400 for all participants in the first, second,and third tertiles of dietary GI, respectively; n = 9594, 10,202, and 8699 for women in the first, second, and third tertiles of dietary GI, respectively; and n =8941, 8127, and 8081 for men in the first, second, and third tertiles of dietary GI, respectively.

CARBOHYDRATES AND RISK OF MYOCARDIAL INFARCTION 1767


ovember 5, 2010

ww

w.ajcn.org

Dow

nloaded from

Glycemic index, glycemic load, and chronic disease risk—a meta-analysis of observational studies1,2

Alan W Barclay, Peter Petocz, Joanna McMillan-Price, Victoria M Flood, Tania Prvan,Paul Mitchell, and Jennie C Brand-Miller

ABSTRACTBackground: Inconsistent findings from observational studies haveprolonged the controversy over the effects of dietary glycemic index(GI) and glycemic load (GL) on the risk of certain chronic diseases.Objective: The objective was to evaluate the association betweenGI, GL, and chronic disease risk with the use of meta-analysis tech-niques.Design: A systematic review of published reports identified a totalof 37 prospective cohort studies of GI and GL and chronic diseaserisk. Studies were stratified further according to the validity of thetools used to assess dietary intake. Rate ratios (RRs) were estimatedin a Cox proportional hazards model and combined by using arandom-effects model.Results: From 4 to 20 y of follow-up across studies, a total of 40 129incident cases were identified. For the comparison between the high-est and lowest quantiles of GI and GL, significant positive associa-tions were found in fully adjusted models of validated studies fortype 2 diabetes (GI RR ! 1.40, 95% CI: 1.23, 1.59; GL RR ! 1.27,95% CI: 1.12, 1.45), coronary heart disease (GI RR ! 1.25, 95% CI:1.00, 1.56), gallbladder disease (GI RR ! 1.26, 95% CI: 1.13, 1.40;GL RR ! 1.41, 95% CI: 1.25, 1.60), breast cancer (GI RR ! 1.08,95% CI: 1.02, 1.16), and all diseases combined (GI RR ! 1.14, 95%CI: 1.09, 1.19; GL RR ! 1.09, 95% CI: 1.04, 1.15).Conclusions: Low-GI and/or low-GL diets are independently asso-ciated with a reduced risk of certain chronic diseases. In diabetes andheart disease, the protection is comparable with that seen for wholegrain and high fiber intakes. The findings support the hypothesis thathigher postprandial glycemia is a universal mechanism for diseaseprogression. Am J Clin Nutr 2008;87:627–37.

KEY WORDS Glycemic index, glycemic load, dietary carbo-hydrates, epidemiology

INTRODUCTION

Worldwide, chronic diseases such as diabetes, cardiovasculardisease, stroke, and cancer contribute to "60% of all deaths, andthe proportion is predicted to increase to 75% by the year 2020 (1,2). Habitual diet is the major modifiable risk factor, and theidentification of simple, cost-effective strategies for preventionand management is a matter of urgency.

Although changes in the quantity and quality of fat have re-ceived considerable attention, the role of carbohydrates is lessclear (2). Increases in refined sugar intake have been accompa-nied by more subtle changes in starchy foods, eg, processed

cereal products have replaced more traditionally processedgrains. Because carbohydrate is the main dietary componentaffecting insulin secretion and postprandial glycemia (3), it isimplicated in the etiology of many chronic diseases. Both theamount and type of carbohydrate consumed have an effect onboth insulin secretion and postprandial glycemia, with differ-ences not explained by glucose chain length (4). In 1981, theconcept of the glycemic index (GI) was introduced by Jenkins etal (5) to quantify the glycemic response to carbohydrates indifferent foods. Glycemic load (GL), the mathematical productof the GI of a food and its carbohydrate content, has been pro-posed as a global indicator of the glucose response and insulindemand induced by a serving of food (6).

The results of studies that investigated the association betweenoverall dietary GI, GL, and disease risk have been inconsistent.With respect to diabetes, a positive association was documentedin 6 large cohort studies (6–11), but no association was seen in 2others (12, 13). In cardiovascular disease, 2 studies reported apositive association (14, 15), whereas 1 found no relation (16).Most of the studies that have investigated cancer risk have re-ported no associations (11, 17–29), but there are notable excep-tions (30–37). Two studies that investigated the risk of gallblad-der disease showed positive associations (38, 39). Finally, 2studies (40, 41) reported an association with eye disease, whereasa third found no association (42).

Of concern, 5 (13%) (22, 25, 27, 31, 33) of the 37 prospectivestudies that investigated the relation between dietary carbohy-drates, GI, GL, and chronic disease risk did not validate carbo-hydrate intake, and an additional 5 (13%) (12, 13, 20, 36, 37)showed correlation coefficients for total carbohydrate of #0.5.Another 2 (5%) studies (29, 32) appear to have been validated,but the validation study has not been published, and 2 others (5%)

1 From the Human Nutrition Unit, University of Sydney, Sydney, Austra-lia (AWB, JM-P, VMF, and JCB-M); the Department of Statistics, Macqua-rie University, Sydney, Australia (PP and TP); the Department of Ophthal-mology, Centre for Vision Research, Westmead Millennium Institute,Westmead Hospital, University of Sydney, Sydney, Australia (VMF andPM); and the NSW Centre for Public Health Nutrition, Human NutritionUnit, University of Sydney, Sydney, Australia (VMF).

2 Address reprint requests and correspondence to JC Brand-Miller, HumanNutrition Unit, University of Sydney, Sydney, NSW, Australia 2006. E-mail:[email protected].

Received April 24, 2007.Accepted for publication September 24, 2007.

627Am J Clin Nutr 2008;87:627–37. Printed in USA. © 2008 American Society for Nutrition

by Custodio C

esar on Novem

ber 18, 2008 w

ww

.ajcn.orgD

ownloaded from





INTRODUCTION










by Custodio Cesar on November 18, 2008

www.ajcn.orgDownloaded from





INTRODUCTION










by Custodio C

esar on Novem

ber 18, 2008 w

ww

.ajcn.orgD

ownloaded from

foods in a nutrient database is to some extent subjective andmay be unreliable when extrapolating from one country toanother. It is likely in any case that any misclassification of GIor GL would lead to a bias toward the null hypothesis anddiminish the observed effect size. Despite comprehensivemeasurement and adjustment strategies, the uncontrolled orresidual confounding in observational studies of dietary in-take is always a concern. Healthy lifestyle effects associatedwith dietary intake cannot be completely adjusted for in ob-servational studies. Therefore, a meta-analysis of interventionstudies looking at “hard” clinical endpoints, not chronic-disease risk factors, may be warranted, when sufficient datahave accumulated.

Our findings support the hypothesis that postprandial hyper-glycemia, in individuals without diabetes, contributes to chronicdisease. Higher glucose concentrations are thought to play adirect pathogenic role in the disease process. The DECODEstudy, a meta-analysis of 13 studies involving 25 000 individu-als, found an almost 2-fold increased risk of all-cause mortalityin individuals with an elevated 2-h postchallenge blood glucose

(53). Similarly, a meta-analysis of 38 studies involving 194 000individuals found a progressive relation between hyperglycemiaand cardiovascular disease risk (54). Cancer risk is also elevatedin those with preexisting hyperglycemia. Larsson et al (55) re-ported a 30% increase in risk of colorectal cancer in a meta-analyses of persons with type 2 diabetes; similarly, Huxley et al(56) found an 82% increase in risk of pancreatic cancer.

There are plausible mechanisms linking the development ofcertain chronic diseases with high-GI diets. Specifically, 2 majorpathways have been proposed to explain the association withtype 2 diabetes risk (57). First, the same amount of carbohydratefrom high-GI foods produces higher blood glucose concentra-tions and a greater demand for insulin. The chronically increasedinsulin demand may eventually result in pancreatic ! cell failure,and, as a consequence, impaired glucose tolerance. Second, thereis evidence that high-GI diets may directly increase insulin re-sistance through their effect on glycemia, free fatty acids, andcounter-regulatory hormone secretion. High glucose and insulinconcentrations are associated with increased risk profiles forcardiovascular disease, including decreased concentrations of

TABLE 3 (Continued)

Chronic disease Glycemic index rate ratio1 P Glycemic load rate ratio1 P

Eye diseaseSchaumberg et al (41) 20046 1.11 (0.99, 1.25) 0.079 1.01 (0.83, 1.23) 0.921Schaumberg et al (41) 20047 0.95 (0.81, 1.11) 0.523 0.86 (0.65, 1.13) 0.285Chiu et al (42) 20058 1.09 (0.61, 1.94) 0.770 — —Chiu et al (42) 20059 1.15 (0.63, 2.10) 0.649 — —Chiu et al (40) 2006 2.71 (1.24, 5.93) 0.013 — —Overall 1.10 (0.91, 1.31) 0.323 0.96 (0.82, 1.12) 0.590All diseases (6–42)Overall 1.13 (1.08, 1.19) !0.0001 1.10 (1.06, 1.15) !0.0001

1 Final fully adjusted models only.2 White Americans.3 Black Americans.4 BMI ! 25 kg/m2.5 BMI " 25 kg/m2.6 Women.7 Men.8 Cortical opacity.9 Nuclear opacity.

TABLE 4Rate ratios (and 95% CIs) for the comparison of the highest with the lowest quantile for developing chronic disease because of increasing glycemic indexor glycemic load in 27 prospective cohort studies meeting a priori exclusion criteria (correlation between food-frequency questionnaire and weighed foodrecords/24-h dietary recall " 0.5 in representative subgroups)

Chronic diseaseGlycemic index rate

ratio1 PGlycemic load rate

ratio1 P

Type 2 diabetes (6–11) 1.40 (1.23, 1.59) !0.0001 1.27 (1.12, 1.45) !0.0001Heart disease (14, 16) 1.25 (1.00, 1.56) 0.050 1.57 (0.87, 2.84) 0.140Stroke (15) 1.02 (0.86, 1.21) 0.805 1.28 (0.83, 1.98) 0.270Breast cancer (17–19, 21, 30) 1.09 (1.02, 1.16) 0.015 0.99 (0.92, 1.06) 0.797Colorectal cancer (23, 29, 34, 35) 1.11 (0.99, 1.24) 0.059 1.11 (0.88, 1.40) 0.385Pancreatic cancer (11, 24) 0.98 (0.78, 1.25) 0.896 0.96 (0.75, 1.23) 0.733Endometrial cancer (26, 32) 1.13 (0.80, 1.60) 0.489 1.72 (0.75, 3.95) 0.204Gastric cancer (28) 0.77 (0.46, 1.29) 0.320 0.76 (0.46, 1.25) 0.282Gallbladder disease (38, 39) 1.26 (1.13, 1.40) !0.0001 1.41 (1.25, 1.60) !0.0001Eye disease (40–42) 1.10 (0.91, 1.31) 0.323 0.96 (0.82, 1.12) 0.590All diseases (6–11, 14–19, 21, 23, 24, 26, 28–30, 32, 34, 35,

38–42) 1.14 (1.09, 1.19) !0.0001 1.09 (1.04, 1.15) !0.00011 Final fully adjusted models only.

GLYCEMIC INDEX AND LOAD AND CHRONIC DISEASE RISK 633

by Custodio C

esar on Novem

ber 18, 2008 w

ww

.ajcn.orgD

ownloaded from

RECOMENDAÇÃO

• Ingerir diariamente 4 a 11 porções de cereais, derivados e tubérculos segundo as recomendações da Roda dos Alimentos. Estas porções devem ser distribuídas por 5 a 7 refeições.

O número de porções recomendado depende das necessidades energéticas individuais. As crianças de 1 a 3 anos devem guiar-se pelos limites inferiores

e os homens activos e os rapazes adolescentes pelos limites superiores; a restante população deve orientar-se pelos valores intermédios.

1 Porção de Cereais e derivados, tubérculos representa: 1 pão (50g)

1 fatia fina de broa (70g)

1 e ½ batata – tamanho médio (125g)

5 colheres de sopa de cereais de

pequeno-almoço (35g)

6 bolachas Maria/água e sal (35g)

2 colheres de sopa de arroz/massa crus (35g)

4 colheres de sopa de arroz/massa

cozinhados (110g)

Nota: pesar os alimentos poderá

ser uma boa forma de compreender as

porções.

RECOMENDAÇÃO

• Ingerir diariamente 4 a 11 porções de cereais, derivados e tubérculos segundo as recomendações da Roda dos Alimentos. Estas porções devem ser distribuídas por 5 a 7 refeições.

O número de porções recomendado depende das necessidades energéticas individuais. As crianças de 1 a 3 anos devem guiar-se pelos limites inferiores

e os homens activos e os rapazes adolescentes pelos limites superiores; a restante população deve orientar-se pelos valores intermédios.

1 Porção de Cereais e derivados, tubérculos representa: 1 pão (50g)

1 fatia fina de broa (70g)

1 e ½ batata – tamanho médio (125g)

5 colheres de sopa de cereais de

pequeno-almoço (35g)

6 bolachas Maria/água e sal (35g)

2 colheres de sopa de arroz/massa crus (35g)

4 colheres de sopa de arroz/massa

cozinhados (110g)

Nota: pesar os alimentos poderá

ser uma boa forma de compreender as

porções.

Alimento IG Dose Hidratos Carbono

CG

Pão branco 70 60 grs 30 grs 21 Baguete francesa 62 70 grs 42 grs 26 Pão centeio 50 60 grs 24 grs 12 Cheerios 74 30 grs 20 grs 15 Chocapic 84 30 grs 25 grs 21 CornFlakes 92 30 grs 26 grs 24 Golden Grahams 71 30 grs 25 grs 18 Special K 84 30 grs 24 grs 20 Bran Flakes 74 30 grs 16 grs 13 Cream Crackers 65 25 grs 17 grs 11 Alpen Muesli 55 30 grs 19 grs 10

ÍNDICE GLICÉMICO E CARGA GLICÉMICA

Foster-Powell K, Holt SH, Brand-Miller JC. Am J Clin Nutr. 2002 Jul;76(1):5-56.

Alimento IG Dose HC CG Arroz branco Uncle Ben’s 10 min 68 150 grs 37 grs 25 Arroz branco 56 150 grs 41 grs 23 Arroz branco Basmati 58 150 grs 38 grs 22 Arroz integral 55 150 grs 33 grs 18 Esparguete de milho 78 180 grs 42 grs 32 Fettucine com ovo 40 180 grs 46 grs 18 Gnocchi 68 180 grs 48 grs 33 Linguini 46 180 grs 48 grs 22 Macarroni 47 180 grs 48 grs 23 Ravioli 40 180 grs 42 grs 32 Spaghetti, cozido 5 min 38 180 grs 48 grs 18 Spaghetti, cozido 20 min 61 180 grs 44 grs 27 Esparguete integral 37 180 grs 42 grs 16

ÍNDICE GLICÉMICO E CARGA GLICÉMICA

Foster-Powell K, Holt SH, Brand-Miller JC. Am J Clin Nutr. 2002 Jul;76(1):5-56.

CEREAIS INTEGRAIS

studies,41 a substantial number of par-ticipants (11%, n=23) had antihyper-glycemic medication changes during thestudy. Only 6 participants had clear evi-dence of repeated hypoglycemic epi-sodes or low blood glucose levels, butall of these occurred in the low–glycemic index diet group. Further-more, retention of participants withmedication changes in the analysis didnot result in loss of significance in es-tablished treatment differences. Di-etary fiber intakes were not com-pletely balanced between treatmentswith an approximately 4.6 g/d higherfiber intake in the low–glycemic in-dex diet than in the high–cereal fiberdiet at week 24. Viscous fibers or diets

high in fiber from a variety of sourceshave been shown to improve blood lip-ids and markers of glycemic con-trol.24,42 However, with the exceptionof oat and barley fiber, cereal fibers arelargely without metabolic effect. In-creasing dietary intake of wheat fiber,even by as much as 20 g/d, has beenshown not to influence HbA1c or otherbiomarkers of chronic disease in pa-tients with type 2 diabetes.43 In addi-tion, controlling for fiber intake as a co-variate in the analysis of covarianceanalysis did not alter the significanceof the results. Similarly, controlling forfiber in the partial regression analysisdid not alter the significance of the as-sociation of the change in glycemic in-

dex with change in HbA1c. A further po-tential weakness was that our study wasa single-site study, which may be seenas a limitation to its generalizability.

Study strengths include the indepen-dence of the effect of glycemic index onHbA1c from the fiber or carbohydrate in-take and the similarity of the observedHbA1c effect with the magnitude of re-duction in glycated proteins observed inameta-analysis.11 Another strengthofourstudy was the comparison of the low–glycemic index diet with a high–cerealfiber diet representing another treat-ment rather than simply a control.Increased cereal fiber intakes havebeen associated with reduced incidenceof diabetes and CHD in the longer

Figure 3. Mean Study Measurements in Participants With Type 2 Diabetes Completing Either a High–Cereal Fiber Diet or a Low–GlycemicIndex Diet

High–cereal fiber diet (n = 75) Low–glycemic index diet (n = 80)

90

82

84

86

88

80

Time, wk

kg

Body weight

0 4 8 12 16 20 24

7.30

6.50

6.70

6.90

7.10

6.30

Time, wk

%

HbA1c

0 4 8 12 16 20 24

146

122

130

138

114

Time, wk

mg/

dL

Fasting glucose

0 4 8 12 16 20 24

46.0

40.0

42.0

44.0

38.0

Time, wk

mg/

dL

HDL-C

0 4 8 12 16 20 24

140

110

120

130

100

Time, wk

mg/

dL

Triglycerides

0 4 8 12 16 20 24

4.5

3.9

4.1

4.3

3.7

Time, wk

Rat

io

Total cholesterol : HDL-C

0 4 8 12 16 20 24

2.7

2.3

2.5

2.1

Time, wk

Rat

io

LDL-C : HDL-C

0 4 8 12 16 20 24

128

130

120

122

124

126

118

Time, wk

mm

Hg

Systolic BP

0 4 8 12 16 20 24

76

70

72

74

68

Time, wk

mm

Hg

Diastolic BP

0 4 8 12 16 20 24

P <.001 P = .04

P = .01 P = .90 P = .12

P = .09 P = .39 P = .43

P = .052

HbA1c indicates glycated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BP, blood pressure. Error bars indi-cate SEM. The P value at the lower left of each panel indicates the comparison between high–cereal fiber diet vs a low–glycemic index diet as change from week 0 toweek 24 for each measurement by intention-to-treat analysis using an analysis of covariance model.

LOW–GLYCEMIC INDEX OR HIGH–CEREAL FIBER DIET AND TYPE 2 DIABETES

©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, December 17, 2008—Vol 300, No. 23 2751

at LUNDS UNIVERSITAET on May 4, 2011jama.ama-assn.orgDownloaded from


Effect of a Low–Glycemic Indexor a High–Cereal Fiber Diet on Type 2 DiabetesA Randomized TrialDavid J. A. Jenkins, MDCyril W. C. Kendall, PhDGail McKeown-Eyssen, PhDRobert G. Josse, MB, BSJay Silverberg, MDGillian L. Booth, MDEdward Vidgen, BScAndrea R. Josse, MScTri H. Nguyen, MScSorcha Corrigan, BScMonica S. Banach, BScSophie Ares, MA, RD, CDESandy Mitchell, BASc, RDAzadeh Emam, MScLivia S. A. Augustin, MScTina L. Parker, BASc, RDLawrence A. Leiter, MD

THE NEED FOR IMPLEMENTA-tion of effective dietary strate-gies in diabetes prevention andmanagement has been empha-

sized by the success of diet and life-style changes in preventing diabetes inhigh-risk patients.1 There is also con-cern that use of antihyperglycemicmedications to improve glycemic con-trol in type 2 diabetes may not alwayssignificantly improve cardiovascularoutcomes.2-7

One dietary strategy aimed at im-proving both diabetes control and car-diovascular risk factors is the use oflow–glycemic index diets.8-10 These dietshave been reported to benefit the

control of diabetes11; increase high-density lipoprotein cholesterol(HDL-C)12,13; lower serum triglycer-ide, plasminogen activator inhibitor 1,and high-sensitivity C-reactive pro-tein (CRP) concentrations14-16; and re-duce diabetes incidence8,9 and overallcardiovascular events.10 Use of the !-

glucosidase carbohydrate absorption in-hibitor acarbose, which effectivelycreates a low–glycemic index diet by

Author Affiliations are listed at the end of this article.Corresponding Author: David J. A. Jenkins, MD, De-partment of Nutritional Sciences, Faculty of Medi-cine, University of Toronto, 150 College St, Toronto,ON, M5S 3E2, Canada ([email protected]).

Context Clinical trials using antihyperglycemic medications to improve glycemic con-trol have not demonstrated the anticipated cardiovascular benefits. Low–glycemic in-dex diets may improve both glycemic control and cardiovascular risk factors for pa-tients with type 2 diabetes but debate over their effectiveness continues due to triallimitations.

Objective To test the effects of low–glycemic index diets on glycemic control andcardiovascular risk factors in patients with type 2 diabetes.

Design, Setting, and Participants A randomized, parallel study design at a Ca-nadian university hospital research center of 210 participants with type 2 diabetes treatedwith antihyperglycemic medications who were recruited by newspaper advertisementand randomly assigned to receive 1 of 2 diet treatments each for 6 months betweenSeptember 16, 2004, and May 22, 2007.

Intervention High–cereal fiber or low–glycemic index dietary advice.

Main Outcome Measures Absolute change in glycated hemoglobin A1c (HbA1c), withfasting blood glucose and cardiovascular disease risk factors as secondary measures.

Results In the intention-to-treat analysis, HbA1c decreased by !0.18% absolute HbA1c

units (95% confidence interval [CI], !0.29% to !0.07%) in the high–cereal fiber dietcompared with !0.50% absolute HbA1c units (95% CI, !0.61% to !0.39%) in thelow–glycemic index diet (P" .001). There was also an increase of high-density lipo-protein cholesterol in the low–glycemic index diet by 1.7 mg/dL (95% CI, 0.8-2.6 mg/dL) compared with a decrease of high-density lipoprotein cholesterol by !0.2 mg/dL(95% CI, !0.9 to 0.5 mg/dL) in the high–cereal fiber diet (P=.005). The reduction indietary glycemic index related positively to the reduction in HbA1c concentration (r=0.35,P" .001) and negatively to the increase in high-density lipoprotein cholesterol (r=!0.19,P=.009).

Conclusion In patients with type 2 diabetes, 6-month treatment with a low–glycemic index diet resulted in moderately lower HbA1c levels compared with a high–cereal fiber diet.

Trial Registration clinicaltrials.gov identifier: NCT00438698JAMA. 2008;300(23):2742-2753 www.jama.com

2742 JAMA, December 17, 2008—Vol 300, No. 23 (Reprinted) ©2008 American Medical Association. All rights reserved.








90

82

84

86

88

80

Time, wk

kg

Body weight

0 4 8 12 16 20 24

7.30

6.50

6.70

6.90

7.10

6.30

Time, wk

%

HbA1c

0 4 8 12 16 20 24

146

122

130

138

114

Time, wk

mg/

dL

Fasting glucose

0 4 8 12 16 20 24

46.0

40.0

42.0

44.0

38.0

Time, wk

mg/

dL

HDL-C

0 4 8 12 16 20 24

140

110

120

130

100

Time, wk

mg/

dL

Triglycerides

0 4 8 12 16 20 24

4.5

3.9

4.1

4.3

3.7

Time, wk

Rat

io


0 4 8 12 16 20 24

2.7

2.3

2.5

2.1

Time, wk

Rat

io

LDL-C : HDL-C

0 4 8 12 16 20 24

128

130

120

122

124

126

118

Time, wk

mm

Hg

Systolic BP

0 4 8 12 16 20 24

76

70

72

74

68

Time, wk

mm

Hg

Diastolic BP

0 4 8 12 16 20 24

P <.001 P = .04

P = .01 P = .90 P = .12

P = .09 P = .39 P = .43

P = .052

















































90

82

84

86

88

80

Time, wk

kg

Body weight

0 4 8 12 16 20 24

7.30

6.50

6.70

6.90

7.10

6.30

Time, wk

%

HbA1c

0 4 8 12 16 20 24

146

122

130

138

114

Time, wk

mg/

dL

Fasting glucose

0 4 8 12 16 20 24

46.0

40.0

42.0

44.0

38.0

Time, wk

mg/

dL

HDL-C

0 4 8 12 16 20 24

140

110

120

130

100

Time, wk

mg/

dL

Triglycerides

0 4 8 12 16 20 24

4.5

3.9

4.1

4.3

3.7

Time, wk

Rat

io


0 4 8 12 16 20 24

2.7

2.3

2.5

2.1

Time, wk

Rat

io

LDL-C : HDL-C

0 4 8 12 16 20 24

128

130

120

122

124

126

118

Time, wk

mm

Hg

Systolic BP

0 4 8 12 16 20 24

76

70

72

74

68

Time, wkm

m H

g

Diastolic BP

0 4 8 12 16 20 24

P <.001 P = .04

P = .01 P = .90 P = .12

P = .09 P = .39 P = .43

P = .052











90

82

84

86

88

80

Time, wk

kg

Body weight

0 4 8 12 16 20 24

7.30

6.50

6.70

6.90

7.10

6.30

Time, wk%

HbA1c

0 4 8 12 16 20 24

146

122

130

138

114

Time, wk

mg/

dL

Fasting glucose

0 4 8 12 16 20 24

46.0

40.0

42.0

44.0

38.0

Time, wk

mg/

dL

HDL-C

0 4 8 12 16 20 24

140

110

120

130

100

Time, wk

mg/

dL

Triglycerides

0 4 8 12 16 20 24

4.5

3.9

4.1

4.3

3.7

Time, wk

Rat

io


0 4 8 12 16 20 24

2.7

2.3

2.5

2.1

Time, wk

Rat

io

LDL-C : HDL-C

0 4 8 12 16 20 24

128

130

120

122

124

126

118

Time, wk

mm

Hg

Systolic BP

0 4 8 12 16 20 24

76

70

72

74

68

Time, wk

mm

Hg

Diastolic BP

0 4 8 12 16 20 24

P <.001 P = .04

P = .01 P = .90 P = .12

P = .09 P = .39 P = .43

P = .052
























The Journal of Nutrition

Nutrition and Disease

Whole-Grain Foods Do Not Affect InsulinSensitivity or Markers of Lipid Peroxidationand Inflammation in Healthy, ModeratelyOverweight Subjects1,2

Agneta Andersson,3* Siv Tengblad,3 Brita Karlstrom,3 Afaf Kamal-Eldin,4 Rikard Landberg,4 Samar Basu,3

Per Aman,4 and Bengt Vessby3

3Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, 751 85 Uppsala, Swedenand 4Department of Food Science, the Swedish University of Agriculture Sciences (SLU), 750 07 Uppsala, Sweden

Abstract

High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes, but

themechanisms remain unclear. Our study aimed to evaluate the effects of a diet rich in whole grains comparedwith a diet

containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and inflammation. In a

randomized crossover study, 22 women and 8 men (BMI 28 6 2) were given either whole-grain or refined-grain products

(3 bread slices, 2 crisp bread slices, 1 portion muesli, and 1 portion pasta) to include in their habitual daily diet for two 6-wk

periods. Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic clamp tests. 8-Iso-prostaglandin F2a

(8-iso PGF2a), an F2-isoprostane, wasmeasured in the urine as amarker of lipid peroxidation, and highly sensitive C-reactive

protein and IL-6 were analyzed in plasma as markers of inflammation. Peripheral insulin sensitivity [mg glucose ! kg body

wt21 !min21 per unit plasma insulin (mU/L)3 100] did not improvewhen subjects consumedwhole-grain products (6.86 3.0

at baseline and6.562.7 after 6wk) or refinedproducts (6.462.9 and6.963.2, respectively) and therewereno differences

between the 2 periods. Whole-grain consumption also did not affect 8-iso-PGF2a in urine, IL-6 and C-reactive protein in

plasma, blood pressure, or serum lipid concentrations. In conclusion, substitution of whole grains (mainly based on milled

wheat) for refined-grain products in the habitual daily diet of healthy moderately overweight adults for 6-wk did not affect

insulin sensitivity or markers of lipid peroxidation and inflammation. J. Nutr. 137: 1401–1407, 2007.

Introduction

Whole-grain products are reported to have several positive effectson human health (1). An inverse, relatively strong correlationbetween the intake of whole grain foods (2–6) and fiber fromgrains (7–10), based mainly on FFQ and the incidence of coro-nary heart disease, is consistently shown in epidemiological studiesof both men and women. In addition, recent studies have linkedcereal fiber and whole-grain foods to a reduced risk of type 2diabetes (11–16) and of the metabolic syndrome (6,17). Theserelations seem to be most striking among overweight subjects(11,18,19). The scientific evidence is considered sufficient to permithealth claims regarding the cardio-protective effect of whole-

grain products in many countries including the U.S., the U.K.,and Sweden. The claims must, however, be set within the contextof other lifestyle factors such as exercise and healthy eating habitsin general (1).

Despite indications that whole grain foods may beneficiallyinfluence glucose and lipid metabolism, knowledge of howbiological mechanisms contribute to the health effects of wholegrain remain weak. Several bioactive components, such as die-tary fiber, vitamins, minerals, antioxidants, and other phyto-protectants in whole grain may act synergistically to lower therisk of chronic diseases (20,21). Insulin resistance and oxidativestress are both important factors in the pathogenesis of type 2diabetes and cardiovascular diseases (22–25) and may poten-tially be affected by whole-grain intake. Induction of lipid per-oxidation in humans has been associated with impairment ofinsulin sensitivity along with a proportional increase in specificmarkers of lipid peroxidation and inflammation (26). In a studyof patientswith coronary heart disease, the consumption of whole-grain products, in combination with other plant products, re-ducedmarkers of lipid peroxidation (27). A healthy dietary patternthat includes whole grain products lowers serum insulin concen-trations (28), and improved glycemic tolerance was found in

1 Supported by grants from the Swedish Governmental Agency for InnovationSystems (VINNOVA), the Swedish Research Council for Environment,Agricultural Sciences and Spatial Planning (FORMAS), the Swedish ResearchCouncil, and the Swedish Diabetes Association. Supported by food productsfrom Lantmannen Food R&D AB, Wasa Brod AB and ICA AB.2 Author disclosures: A. Andersson, S. Tengblad, B. Karlstrom, A. Kamal-Eldin,R. Landberg, S. Basu, P. Aman, and B. Vessby, no conflicts of interest.* To whom correspondence should be addressed. E-mail: [email protected].

0022-3166/07 $8.00 ª 2007 American Society for Nutrition. 1401Manuscript received 31 January 2007. Initial review completed 8 February 2007. Revision accepted 10 March 2007.

by guest on February 9, 2011jn.nutrition.org

Dow

nloaded from

The Journal of Nutrition

Nutrition and Disease

Whole-Grain Foods Do Not Affect InsulinSensitivity or Markers of Lipid Peroxidationand Inflammation in Healthy, ModeratelyOverweight Subjects1,2

Agneta Andersson,3* Siv Tengblad,3 Brita Karlstrom,3 Afaf Kamal-Eldin,4 Rikard Landberg,4 Samar Basu,3

Per Aman,4 and Bengt Vessby3

3Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, 751 85 Uppsala, Swedenand 4Department of Food Science, the Swedish University of Agriculture Sciences (SLU), 750 07 Uppsala, Sweden

Abstract

High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes, but

themechanisms remain unclear. Our study aimed to evaluate the effects of a diet rich in whole grains comparedwith a diet

containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and inflammation. In a

randomized crossover study, 22 women and 8 men (BMI 28 6 2) were given either whole-grain or refined-grain products

(3 bread slices, 2 crisp bread slices, 1 portion muesli, and 1 portion pasta) to include in their habitual daily diet for two 6-wk

periods. Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic clamp tests. 8-Iso-prostaglandin F2a

(8-iso PGF2a), an F2-isoprostane, wasmeasured in the urine as amarker of lipid peroxidation, and highly sensitive C-reactive

protein and IL-6 were analyzed in plasma as markers of inflammation. Peripheral insulin sensitivity [mg glucose ! kg body

wt21 !min21 per unit plasma insulin (mU/L)3 100] did not improvewhen subjects consumedwhole-grain products (6.86 3.0

at baseline and6.562.7 after 6wk) or refinedproducts (6.462.9 and6.963.2, respectively) and therewereno differences

between the 2 periods. Whole-grain consumption also did not affect 8-iso-PGF2a in urine, IL-6 and C-reactive protein in

plasma, blood pressure, or serum lipid concentrations. In conclusion, substitution of whole grains (mainly based on milled

wheat) for refined-grain products in the habitual daily diet of healthy moderately overweight adults for 6-wk did not affect

insulin sensitivity or markers of lipid peroxidation and inflammation. J. Nutr. 137: 1401–1407, 2007.

Introduction

Whole-grain products are reported to have several positive effectson human health (1). An inverse, relatively strong correlationbetween the intake of whole grain foods (2–6) and fiber fromgrains (7–10), based mainly on FFQ and the incidence of coro-nary heart disease, is consistently shown in epidemiological studiesof both men and women. In addition, recent studies have linkedcereal fiber and whole-grain foods to a reduced risk of type 2diabetes (11–16) and of the metabolic syndrome (6,17). Theserelations seem to be most striking among overweight subjects(11,18,19). The scientific evidence is considered sufficient to permithealth claims regarding the cardio-protective effect of whole-

grain products in many countries including the U.S., the U.K.,and Sweden. The claims must, however, be set within the contextof other lifestyle factors such as exercise and healthy eating habitsin general (1).

Despite indications that whole grain foods may beneficiallyinfluence glucose and lipid metabolism, knowledge of howbiological mechanisms contribute to the health effects of wholegrain remain weak. Several bioactive components, such as die-tary fiber, vitamins, minerals, antioxidants, and other phyto-protectants in whole grain may act synergistically to lower therisk of chronic diseases (20,21). Insulin resistance and oxidativestress are both important factors in the pathogenesis of type 2diabetes and cardiovascular diseases (22–25) and may poten-tially be affected by whole-grain intake. Induction of lipid per-oxidation in humans has been associated with impairment ofinsulin sensitivity along with a proportional increase in specificmarkers of lipid peroxidation and inflammation (26). In a studyof patientswith coronary heart disease, the consumption of whole-grain products, in combination with other plant products, re-ducedmarkers of lipid peroxidation (27). A healthy dietary patternthat includes whole grain products lowers serum insulin concen-trations (28), and improved glycemic tolerance was found in

1 Supported by grants from the Swedish Governmental Agency for InnovationSystems (VINNOVA), the Swedish Research Council for Environment,Agricultural Sciences and Spatial Planning (FORMAS), the Swedish ResearchCouncil, and the Swedish Diabetes Association. Supported by food productsfrom Lantmannen Food R&D AB, Wasa Brod AB and ICA AB.2 Author disclosures: A. Andersson, S. Tengblad, B. Karlstrom, A. Kamal-Eldin,R. Landberg, S. Basu, P. Aman, and B. Vessby, no conflicts of interest.* To whom correspondence should be addressed. E-mail: [email protected].

0022-3166/07 $8.00 ª 2007 American Society for Nutrition. 1401Manuscript received 31 January 2007. Initial review completed 8 February 2007. Revision accepted 10 March 2007.


Downloaded from

inflammation are presumed to be central factors involved in theetiology of coronary heart disease and type 2 diabetes (22–25)and are suggested to contribute to the beneficial effects by wholegrain. However, we did not find a significant effect of whole-grain intake on insulin sensitivity, lipid peroxidation, inflamma-tory markers, or on any of the metabolic variables studied.

In the present study, 30 participants were included to allowan 80% power to detect a 10% change in insulin sensitivity. Thispermitted the possibility of detecting a clinically important effectof whole grain on insulin sensitivity and gave a low risk for type2 error. However, there were no indications of any improvementafter subjects consumed a diet enriched with whole-grain foods,suggesting that an effect on insulin sensitivity would be small,if any. An intervention of 6 wk might be too short to achievesignificant effects on insulin sensitivity. However, one earlierdietary intervention study with a similar fiber intake and includ-ing 11 subjects with similar BMI as in the present study, indi-cated improved insulin sensitivity after 6-wk of consuming awhole-grain diet. Their fasting insulin concentrations were low-ered by 10% during the whole-grain diet period and the glucoseinfusion rate increased during the final 30 min of a clamp test(32). Those subjects were hyperinsulinemic, with fasting insulinlevels;3 times that of the present study. Dietary effects are morelikely to occur in individuals with a poor habitual diet and morepronounced metabolic abnormalities.

The whole-grain products in the present study were mostlybased onmilled flour with small particle size in the form of breadand pasta.Wheat, rye, oats, and rice were all included, but wheatclearly dominated. Improved blood glucose and insulin metab-olism following a higher fiber intake was particularly evident forsoluble fiber (29–31). The domination of wheat indicated in the

present study may reduce the effects on glucose and insulinbecause wheat contains less soluble andmore insoluble fiber thanrye, oats, or barley. However, two other intervention studiesshowed no effect of high-fiber cereals (even when high in solublefiber; rye and oats) on insulin sensitivity measured indirectly byintravenous-glucose tolerance test (44,45). Paradoxically, a stron-ger inverse relationship with the intake of insoluble fiber thansoluble fiber on the risk of diabetes is suggested (16).

Other aspects of the cereal products may be of importance.The postprandial insulin response to grain products has beendetermined more by the form of food and botanic structure thanby the amount of fiber or type of cereal (31,46).Whole-grain breadwith a more intact structure has been shown to improve post-prandial glycemic and insulinemic responses than whole-wheatbread made from milled flour (47).

Based on epidemiological studies, positive health effects canbe expected at a level of 3 servings of whole-grain foods per day(48). Our study included 7 servings per day, which is comparableto the dietary intervention by Pereira et al. (32). In that study, allof the food consumed was provided to the subjects on a 6 dmenurotation. In our study, only cereal products were provided as apart of each individual’s habitual diet. The products eaten werecarefully noted in the diaries. The reported nutrient intakes dur-ing both diet periods were similar, except for a higher intake ofseveral minerals, fiber, a-tocopherol, and linoleic acid, 18:2 (n-6)during the whole-grain period, as expected. Diet adherence wastherefore considered good in the present study.

Another study suggested that whole-grain intake, in combi-nation with other plant products, reduced markers of lipid per-oxidation (27). The intervention period in that study was 16 wk.The whole grain was supplied in the form of coarse powder, and

TABLE 5 BMI, blood pressure, and blood chemistry of all participants before and after 6 wk consumingwhole-grain or refined-grain diets1

Whole-grain period Refined-grain period

Before After Before After P-value treatment effect2

n 30 30 30 30BMI, kg/m2 28.5 6 2.4 28.8 6 2.5a 28.4 6 2.1 28.6 6 2.1 0.046Fasting blood glucose, mmol/L 5.2 6 0.8 5.3 6 0.8 5.2 6 0.9 5.2 6 0.8 0.28Fasting insulin, pmol/L 56.2 6 22.9 57.6 6 24.3 60.4 6 30.6 57.6 6 25.7 0.47Insulin sensitivity,3 M 5.9 6 2.1 5.5 6 1.7 5.7 6 1.9 6.0 6 2.0 0.24

M/I 6.8 6 3.0 6.5 6 2.7 6.4 6 2.9 6.9 6 3.2 0.79Total cholesterol, mmol/L 5.5 6 0.7 5.5 6 0.7 5.5 6 0.8 5.5 6 0.7 0.76HDL cholesterol, mmol/L 1.3 6 0.3 1.2 6 0.3 1.2 6 0.2 1.2 6 0.3 0.15LDL cholesterol, mmol/L 3.7 6 0.8 3.7 6 0.7 3.7 6 0.8 3.6 6 0.7 0.40TG cholesterol, mmol/L 1.4 6 0.8 1.5 6 0.8 1.3 6 0.6 1.6 6 1.0c 0.19Free fatty acid, mmol/L 0.56 6 0.19 0.61 6 0.18 0.63 6 0.17 0.62 6 0.18 0.99Systolic blood pressure, mm Hg 130 6 17 129 6 15 130 6 16 130 6 15 0.35*Diastolic blood pressure, mm Hg 81 6 9 81 6 8 80 6 10 81 6 9 0.608-iso-PGF2a, nmol/mmol creatinine 0.43 6 0.14 0.43 6 0.14 0.42 6 0.15 0.44 6 0.21 0.48a-tocopherol, mmol/mmol lipid 4.68 6 0.72 4.78 6 0.61 4.38 6 1.07 4.64 6 0.61 0.08g-tocopherol, mmol/mmol lipid 0.26 6 0.12 0.24 6 0.07 0.26 6 0.10 0.26 6 0.10 0.10CRP, mg/L 2.03 6 1.62 2.38 6 2.29 2.86 6 2.96 2.34 6 1.57 0.55IL-6, ng/L 14.8 6 32.2 15.2 6 33.2 15.9 6 32.4 15.8 6 30.9 0.79PAI-1 activity, kU/L 24.7 6 15.8 26.9 6 20.3 24.8 6 19.9 22.1 6 19.5 0.26

1 Data are means 6 SD.2 P-values (treatment effect) for differences between the whole-grain and refined-grain diet adjusted for changes in BMI. Differences within

groups when compared to baseline: aP , 0.001; bP , 0.01; cP , 0.05. *Parallel group design, only from 1st diet period (because carryover

effect was found).3 M, glucose disposal during clamp in mg glucose ! kg body wt21 ! min21. M/I, glucose disposal rate during clamp in mg glucose ! kg body

wt21 ! min21 per unit plasma insulin ( mU/L ) 3 100. To convert glucose from mg to mmol, divide by 180. To convert insulin from mU/L to

pmol/L, multiply by 6.945.

Whole-grain foods and insulin sensitivity 1405


Dow

nloaded from

J. Nutr. 137: 1401–1407, 2007.

Sem diferenças entre os grupos

Effect of Wheat Bran on Glycemic Controland Risk Factors for CardiovascularDisease in Type 2 DiabetesDAVID J. A. JENKINS, MD

1,2,3,4

CYRIL W. C. KENDALL, PHD1,3

LIVIA S. A. AUGUSTIN, MSC1,3

MARGARET C. MARTINI, PHD5

METTE AXELSEN, PHD6

DOROTHEA FAULKNER, RD1

EDWARD VIDGEN, BSC1,3

TINA PARKER, RD1

HERB LAU, MD7,8

PHILIP W. CONNELLY, PHD2,9,10

JEROME TEITEL, MD7,8

WILLIAM SINGER, MD2

ARTHUR C. VANDENBROUCKE, PHD7,10

LAWRENCE A. LEITER, MD1,2,3,4

ROBERT G. JOSSE, MD1,2,3,4

OBJECTIVE — Cohort studies indicate that cereal fiber reduces the risk of diabetes andcoronary heart disease (CHD). Therefore, we assessed the effect of wheat bran on glycemiccontrol and CHD risk factors in type 2 diabetes.

RESEARCH DESIGN AND METHODS — A total of 23 subjects with type 2 diabetes(16 men and 7 postmenopausal women) completed two 3-month phases of a randomizedcrossover study. In the test phase, bread and breakfast cereals were provided as products high incereal fiber (19 g/day additional cereal fiber). In the control phase, supplements were low in fiber(4 g/day additional cereal fiber).

RESULTS — Between the test and control treatments, no differences were seen in bodyweight, fasting blood glucose, HbA1c, serum lipids, apolipoproteins, blood pressure, serum uricacid, clotting factors, homocysteine, C-reactive protein, magnesium, calcium, iron, or ferritin.LDL oxidation in the test phase was higher than that seen in the control phase (12.1 ! 5.4%, P "0.034). Of the subjects originally recruited, more dropped out of the study for health and foodpreference reasons from the control phase (16 subjects) than the test phase (11 subjects).

CONCLUSIONS — High-fiber cereal foods did not improve conventional markers of glyce-mic control or risk factors for CHD in type 2 diabetes over 3 months. Possibly longer studies arerequired to demonstrate the benefits of cereal fiber. Alternatively, cereal fiber in the diet may bea marker for another component of whole grains that imparts health advantages or a healthylifestyle.

Diabetes Care 25:1522–1528, 2002

There is much interest in the possiblehealth benefits of fiber-containingcereals (1–3). The exact component

or facet of fiber that is responsible has notbeen clearly defined, and there are indi-cations that the whole grain confers met-abolic benefits (4) and reduces the risk ofchronic disease (1,5,6). The results oflarge cohort studies have suggested thatwheat fiber protects against the develop-ment of diabetes (1–3). Many diabetes as-sociations advise increased fiber intake,either to improve glycemic control (7) orto confer general health benefits (8). In-creases in fiber from a variety of dietarysources have been shown to improve gly-cemic control in type 2 diabetes (9). Earlystudies suggested that cereal fiber im-proved both glycemic control in diabetes(10) and glucose tolerance in nondiabeticsubjects (11). The reason for the benefi-cial effects of nonviscous cereal fiber is notclear. Cereal fibers do not reduce the rateof gastric emptying and small intestinalabsorption or flatten the postprandial gly-cemic response to a high-carbohydratetest meal (12). In contrast, viscous fiberssuch as guar and pectin have been shownto reduce the rate of gastric emptying (13)and small intestinal absorption (14),thereby providing a mechanism for po-tential benefits. These fibers have beenshown to reduce postprandial glycemiawhen added to test meals. They also de-crease 24-h urinary glucose losses whenadded to the diets of subjects with type 2diabetes (15).

Furthermore, it is wheat fiber, ratherthan viscous fiber, that for more than twodecades has been shown consistently incohort studies to be associated with a re-duced risk of heart disease (5,6,16,17).These effects are seen despite the fact thatviscous fibers from oats, barley, psyllium,pectins, and guar gum have been shownto lower serum cholesterol and improvethe blood lipid profile, whereas the insol-uble fibers were largely without effect(18,19).

In view of the apparent benefits of ce-real fiber in preventing diabetes and car-diovascular disease and the lack of an

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

From the 1Clinical Nutrition and Risk Factor Modification Center, St. Michael’s Hospital, Toronto, Ontario,Canada; the 2Department of Medicine, Division of Endocrinology and Metabolism, St. Michael’s Hospital,Toronto, Ontario, Canada; the 3Department of Nutritional Sciences, Faculty of Medicine, University ofToronto, Toronto, Ontario, Canada; the 4Department of Medicine, Faculty of Medicine, University ofToronto, Toronto, Ontario, Canada; 5Kraft Foods, Glenview, Illinois; the 6Lundberg Laboratory for DiabeticResearch, Department of Internal Medicine, Sahlgrenska University Hospital, Goteborg, Sweden; the 7De-partment of Laboratory Medicine, Division of Clinical Biochemistry, St. Michael’s Hospital, Toronto, On-tario, Canada; the 8Department of Hematology, St. Michael’s Hospital, Toronto, Ontario, Canada; the9Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; andthe 10Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto,Toronto, Ontario, Canada.

Address correspondence and reprint requests to David J. A. Jenkins, Clinical Nutrition and Risk FactorModification Center, St. Michael’s Hospital, 61 Queen St. East, Toronto, Ontario, Canada, M5C 2T2. E-mail:[email protected].

Received for publication 12 April 2002 and accepted in revised form 28 May 2002.Abbreviations: CHD, coronary heart disease; NCEP, National Cholesterol Education Program.A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion

factors for many substances.See accompanying editorial on p. 1652.

C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o nO R I G I N A L A R T I C L E

1522 DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002


1,2,3,4




METTE AXELSEN, PHD6



TINA PARKER, RD1

HERB LAU, MD7,8



WILLIAM SINGER, MD2








Diabetes Care 25:1522–1528, 2002





! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !








1,2,3,4




METTE AXELSEN, PHD6



TINA PARKER, RD1

HERB LAU, MD7,8



WILLIAM SINGER, MD2








Diabetes Care 25:1522–1528, 2002





! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !








1,2,3,4




METTE AXELSEN, PHD6



TINA PARKER, RD1

HERB LAU, MD7,8



WILLIAM SINGER, MD2








Diabetes Care 25:1522–1528, 2002





! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !







Jenkins D, et al. Diabetes Care 25:1522–1528, 2002

AUMENTO DA INGESTÃO DE FIBRA A PARTIR DE CEREAIS INTEGRAIS DE 9 PARA 17 GRAMAS

AUMENTO NÃO SIGNIFICATIVO DO RISCO RELATIVO EM 18%


52

MUFAS

Mensink RP, Zock PL, Kester AD, Katan MB. Am J Clin Nutr. 2003 May;77(5):1146-‐55

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

original article

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

Ramón Estruch, M.D., Ph.D., Emilio Ros, M.D., Ph.D., Jordi Salas-Salvadó, M.D., Ph.D., Maria-Isabel Covas, D.Pharm., Ph.D., Dolores Corella, D.Pharm., Ph.D.,

Fernando Arós, M.D., Ph.D., Enrique Gómez-Gracia, M.D., Ph.D., Valentina Ruiz-Gutiérrez, Ph.D., Miquel Fiol, M.D., Ph.D., José Lapetra, M.D., Ph.D., Rosa Maria Lamuela-Raventos, D.Pharm., Ph.D., Lluís Serra-Majem, M.D., Ph.D., Xavier Pintó, M.D., Ph.D., Josep Basora, M.D., Ph.D., Miguel Angel Muñoz, M.D., Ph.D.,

José V. Sorlí, M.D., Ph.D., José Alfredo Martínez, D.Pharm, M.D., Ph.D., and Miguel Angel Martínez-González, M.D., Ph.D., for the PREDIMED Study Investigators*

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Estruch at the Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain, or at [email protected], or to Dr. Martínez-González at the Department of Preventive Medi-cine and Public Health, Facultad de Me-dicina–Clínica Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain, or at [email protected].

* The PREDIMED (Prevención con Dieta Mediterránea) study investigators are listed in the Supplementary Appendix, available at NEJM.org.

Drs. Estruch and Martínez-González con-tributed equally to this article.

This article was published on February 25, 2013, at NEJM.org.

N Engl J Med 2013.DOI: 10.1056/NEJMoa1200303Copyright © 2013 Massachusetts Medical Society.

A bs tr ac t

BackgroundObservational cohort studies and a secondary prevention trial have shown an in-verse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary preven-tion of cardiovascular events.

MethodsIn a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Medi-terranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational ses-sions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.

ResultsA total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, ac-cording to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, ver-sus the control group (109 events). No diet-related adverse effects were reported.

ConclusionsAmong persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government’s Instituto de Salud Carlos III and oth-ers; Controlled-Trials.com number, ISRCTN35739639.)

The New England Journal of Medicine Downloaded from nejm.org on February 27, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

N Engl J Med 2013.



original article

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

Ramón Estruch, M.D., Ph.D., Emilio Ros, M.D., Ph.D., Jordi Salas-Salvadó, M.D., Ph.D., Maria-Isabel Covas, D.Pharm., Ph.D., Dolores Corella, D.Pharm., Ph.D.,

Fernando Arós, M.D., Ph.D., Enrique Gómez-Gracia, M.D., Ph.D., Valentina Ruiz-Gutiérrez, Ph.D., Miquel Fiol, M.D., Ph.D., José Lapetra, M.D., Ph.D., Rosa Maria Lamuela-Raventos, D.Pharm., Ph.D., Lluís Serra-Majem, M.D., Ph.D., Xavier Pintó, M.D., Ph.D., Josep Basora, M.D., Ph.D., Miguel Angel Muñoz, M.D., Ph.D.,

José V. Sorlí, M.D., Ph.D., José Alfredo Martínez, D.Pharm, M.D., Ph.D., and Miguel Angel Martínez-González, M.D., Ph.D., for the PREDIMED Study Investigators*

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Estruch at the Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain, or at [email protected], or to Dr. Martínez-González at the Department of Preventive Medi-cine and Public Health, Facultad de Me-dicina–Clínica Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain, or at [email protected].

* The PREDIMED (Prevención con Dieta Mediterránea) study investigators are listed in the Supplementary Appendix, available at NEJM.org.

Drs. Estruch and Martínez-González con-tributed equally to this article.

This article was published on February 25, 2013, at NEJM.org.

N Engl J Med 2013.DOI: 10.1056/NEJMoa1200303Copyright © 2013 Massachusetts Medical Society.

A bs tr ac t

BackgroundObservational cohort studies and a secondary prevention trial have shown an in-verse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary preven-tion of cardiovascular events.

MethodsIn a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Medi-terranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational ses-sions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.

ResultsA total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, ac-cording to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, ver-sus the control group (109 events). No diet-related adverse effects were reported.

ConclusionsAmong persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government’s Instituto de Salud Carlos III and oth-ers; Controlled-Trials.com number, ISRCTN35739639.)



ü  7447 Pacientes H (55-80 años) y M (60-80 años) sem DCV, mas com risco cardiovascular aumentado (Diabetes T2 ou 3 dos siguintes factores: tabaco, HTA, LDL-C aumentado, HDL-C baixo, excesso de peso, história familiar de doença cardíaca coronária prematura)

ü  3 dietas:

1)  Dieta c/ restrição de gordura 2)  Dieta Med c/ 1L de azeite /semana 3)  Dieta Med c/ 30g de frutos secos/día (15g de nozes+7,5g de avelãs +

7,5g de amêndoas)

N Engl J Med 2013.

N Engl J Med 2013.


n engl j med nejm.org8

for the Mediterranean-diet groups (both groups merged vs. the control group) before and after this date. Adjusted hazard ratios were 0.77 (95% CI, 0.59 to 1.00) for participants recruited before October 2006 and 0.49 (95% CI, 0.26 to 0.92) for those recruited thereafter (P = 0.21 for interaction).

Discussion

In this trial, an energy-unrestricted Mediterra-nean diet supplemented with either extra-virgin olive oil or nuts resulted in an absolute risk re-duction of approximately 3 major cardiovascular

Inci

denc

e of

Com

posi

te C

ardi

ovas

cula

rEn

d Po

int

1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5

Years

0.06

0.04

0.02

0.00

0.05

0.03

0.01

0 1 2 3 4 5

B Total Mortality

A Primary End Point (acute myocardial infarction, stroke, or death from cardiovascular causes)

Med diet, EVOO: hazard ratio, 0.70 (95% CI, 0.53–0.91); P=0.009

Med diet, nuts: hazard ratio, 0.70 (95% CI, 0.53–0.94); P=0.02

No. at RiskControl dietMed diet, EVOOMed diet, nuts

245025432454

226824862343

202023202093

158319871657

126816871389

94613101031

Tota

l Mor

talit

y

1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5

Years

0.06

0.04

0.02

0.00

0.05

0.07

0.03

0.01

0 1 2 3 4 5

Med diet, EVOO: hazard ratio, 0.81 (95% CI, 0.63–1.05); P=0.11

Med diet, nuts: hazard ratio, 0.95 (95% CI, 0.73–1.23); P=0.68

No. at RiskControl dietMed diet, EVOOMed diet, nuts

245025432454

226824852345

202623222097

158519881662

127216901395

94813081037

Control diet

Control diet

Med diet, nuts

Med diet, nuts

Med diet, EVOO

Med diet, EVOO

Figure 1. Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population.

Panel A shows the incidence of the primary end point (a composite of acute myocardial infarction, stroke, and death from cardiovascular causes), and Panel B shows total mortality. Hazard ratios were stratified according to center (Cox model with robust variance estimators). CI denotes confidence interval, EVOO extra-virgin olive oil, and Med Mediterranean.



30%

Mediterr anean Diet and Cardiovascular Events


the use of a separate 9-item dietary screener (Table S3 in the Supplementary Appendix).

A general medical questionnaire, a 137-item validated food-frequency questionnaire,15 and the Minnesota Leisure-Time Physical Activity Questionnaire were administered on a yearly basis.10 Information from the food-frequency questionnaire was used to calculate intake of energy and nutrients. Weight, height, and waist circumference were directly measured.16 Bio-markers of compliance, including urinary hy-droxytyrosol levels (to confirm compliance in the group receiving extra-virgin olive oil) and plasma alpha-linolenic acid levels (to confirm compliance in the group receiving mixed nuts), were measured in random subsamples of par-ticipants at 1, 3, and 5 years (see the Supplemen-tary Appendix).

End PointsThe primary end point was a composite of myo-cardial infarction, stroke, and death from cardio-vascular causes. Secondary end points were stroke, myocardial infarction, death from cardio-vascular causes, and death from any cause. We used four sources of information to identify end points: repeated contacts with participants, con-tacts with family physicians, a yearly review of medical records, and consultation of the Nation-al Death Index. All medical records related to end points were examined by the end-point adju-dication committee, whose members were un-aware of the study-group assignments. Only end points that were confirmed by the adjudication committee and that occurred between October 1, 2003, and December 1, 2010, were included in the analyses. The criteria for adjudicating pri-mary and secondary end points are detailed in the Supplementary Appendix.

Statistical AnalysisWe initially estimated that a sample of 9000 par-ticipants would be required to provide statistical power of 80% to detect a relative risk reduction of 20% in each Mediterranean-diet group versus the control-diet group during a 4-year follow-up period, assuming an event rate of 12% in the control group.10,17 In April 2008, on the advice of the data and safety monitoring board and on the basis of lower-than-expected rates of end-point events, the sample size was recalculated as 7400 participants, with the assumption of a 6-year follow-up period and underlying event rates of

Table 1. Summary of Dietary Recommendations to Participants in the Mediterranean-Diet Groups and the Control-Diet Group.

Food Goal

Mediterranean diet

Recommended

Olive oil* !4 tbsp/day

Tree nuts and peanuts† !3 servings/wk

Fresh fruits !3 servings/day

Vegetables !2 servings/day

Fish (especially fatty fish), seafood !3 servings/wk

Legumes !3 servings/wk

Sofrito‡ !2 servings/wk

White meat Instead of red meat

Wine with meals (optionally, only for habitual drinkers)

!7 glasses/wk

Discouraged

Soda drinks <1 drink/day

Commercial bakery goods, sweets, and pastries§ <3 servings/wk

Spread fats <1 serving/day

Red and processed meats <1 serving/day

Low-fat diet (control)

Recommended

Low-fat dairy products !3 servings/day

Bread, potatoes, pasta, rice !3 servings/day

Fresh fruits !3 servings/day

Vegetables !2 servings/wk

Lean fish and seafood !3 servings/wk

Discouraged

Vegetable oils (including olive oil) "2 tbsp/day

Commercial bakery goods, sweets, and pastries§ "1 serving/wk

Nuts and fried snacks "1 serving /wk

Red and processed fatty meats "1 serving/wk

Visible fat in meats and soups¶ Always remove

Fatty fish, seafood canned in oil "1 serving/wk

Spread fats "1 serving/wk

Sofrito‡ "2 servings/wk

* The amount of olive oil includes oil used for cooking and salads and oil con-sumed in meals eaten outside the home. In the group assigned to the Medi-terranean diet with extra-virgin olive oil, the goal was to consume 50 g (ap-proximately 4 tbsp) or more per day of the polyphenol-rich olive oil supplied, instead of the ordinary refined variety, which is low in polyphenols.

† For participants assigned to the Mediterranean diet with nuts, the recommend-ed consumption was one daily serving (30 g, composed of 15 g of walnuts, 7.5 g of almonds, and 7.5 g of hazelnuts).

‡ Sofrito is a sauce made with tomato and onion, often including garlic and aro-matic herbs, and slowly simmered with olive oil.

§ Commercial bakery goods, sweets, and pastries (not homemade) included cakes, cookies, biscuits, and custard.

¶ Participants were advised to remove the visible fat (or the skin) of chicken, duck, pork, lamb, or veal before cooking and the fat of soups, broths, and cooked meat dishes before consumption.



N Engl J Med 2013.

58

0

0,5

1

1,5

2

2,5

1 2 3 4 5

CRP LDL

INFLAMAÇÃO E DCV!

Quintis de Risco Relativo para todos os Acidentes Cardiovasculares!

Ridker PM et al. N Engl J Med 2002;347:1557-65.

bowel disease. Chronic overproduction of TNF-! and IL-1 cancause adipose tissue and muscle wasting and loss of bone massand may account for alterations in body composition and tissueloss seen in inflammatory diseases and in cancer cachexia. Aswell as its clear and obvious association with classic inflamma-tory diseases, inflammation is now recognized to play an impor-tant role in the pathology of other diseases, such as cardiovas-cular disease and neurodegenerative diseases of aging.Additionally, the realization that adipose tissue is a source ofinflammatory cytokines has given rise to the notion that obesity,the metabolic syndrome, and type 2 diabetes have an inflamma-tory component.

ARACHIDONIC ACID–DERIVED EICOSANOIDS ANDINFLAMMATION

The key link between polyunsaturated fatty acids (PUFAs)and inflammation is that eicosanoids, which are among the me-diators and regulators of inflammation, are generated from 20-carbon PUFAs. Because inflammatory cells typically contain ahigh proportion of the n!6 PUFA arachidonic acid (20:4n!6)and low proportions of other 20-carbon PUFAs, arachidonic acidis usually the major substrate for eicosanoid synthesis. Eico-sanoids, which include PGs, thromboxanes, leukotrienes (LTs),and other oxidized derivatives, are generated from arachidonicacid by the metabolic processes summarized in Figure 3. Eico-sanoids are involved in modulating the intensity and duration ofinflammatory responses (see references 2 and 3 for reviews),have cell- and stimulus-specific sources, and frequently haveopposing effects (Table 1). Thus, the overall physiologic (orpathophysiologic) outcome will depend on the cells present, thenature of the stimulus, the timing of eicosanoid generation, theconcentrations of different eicosanoids generated, and the sen-sitivity of the target cells and tissues to the eicosanoids generated.Recent studies have shown that PGE2 induces cyclooxygenase 2(COX-2) in fibroblasts cells and so up-regulates its own produc-tion (5), induces the production of IL-6 by macrophages (5),inhibits 5-lipoxygenase (5-LOX) and so decreases production ofthe 4-series LTs (6), and induces 15-LOX and so promotes theformation of lipoxins (6, 7), which have been found to haveantiinflammatory effects (8, 9). Thus, PGE2 possesses both pro-and antiinflammatory actions (Table 1).

FIGURE 1. The role of inflammatory cells and mediators in regulating the whole-body metabolic and immunologic responses to infection and injury.Modified from reference 1 with permission from the American Oil Chemists’ Society.

FIGURE 2. Diagrammatic representation of the movement of leukocytesthrough the endothelium and the subsequent generation of inflammatorymediators.

1506S CALDER


ww

w.ajcn.org

Dow

nloaded from

Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S)

De Caterina R. N Engl J Med 2011

EPA/DHA E AA

Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S.

7

EPA e DHA

Į-Linolênico

Time course relativo à incorporação de EPA e DHAem fosfolipídios de membrana de células mononucleares

Indivíduos saudáveis: 2,1 g EPA + 1,1 g DHA/dia/12 semanas

0 4 8 12 200

1

2

3

4

Time (weeks)

EP

A i

n m

on

on

ucle

ar

cell P

L (

%)

0 4 8 12 201

2

3

4

Time (weeks)

DH

A i

n m

on

on

ucle

ar

cell P

L (

%)

Eur. J. Clin. Invest. 30, 260-274, 2000 Mozaffarian et al. (2006) JAMA 296, 1885-1899Eur. J. Clin. Invest. 30, 260-‐274, 2000

INCORPORAÇÃO DE EPA E DHA NOS FOSFOLÍPIDOS DE CÉLULAS MONONUCLEARES

Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S)

DHA

De Caterina R. N Engl J Med 2011

67 Gilroy DW. 2010

Serhan, CN. Annu. Rev. Immunol. 2007. 25:101–37

EPA & DHA

Calder PC. Biochimie. 2009 Feb 3. [Epub ahead of print]

tures, and modest intake of such foodsis not associated with CHD risk.85

Total Mortality. n-3 PUFAs moststrongly affect CHD death5,9,14-16,18 andare unlikely to affect appreciably othercauses of mortality. Effects on total mor-tality in a population would thereforedepend on the proportion of deaths dueto CHD, ranging from one quarter ofdeaths in middle-age populations86 toone half of deaths in populations withestablished CHD.9 Thus, given a !36%reduction in CHD death (Figure 2), in-take of fish or fish oil would reduce totalmortality by between !9% (36% re-duction!25% CHD deaths) to !18%(36% reduction!50% CHD deaths), oran average of !14% in mixed popula-tions. This is consistent with a meta-analysis of randomized trials through20033,9,51,56,57,87-93 that found a nonsig-nificant 14% reduction in total mortal-ity with n-3 PUFAs (pooled relative risk,0.86; 95% CI, 0.70 to 1.04).94 When weadded additional placebo-controlled,double-blind, randomized trials60-62 per-formed since 2003, marine n-3 PUFAsreduced total mortality by 17% (pooledrelative risk, 0.83; 95% CI, 0.68 to 1.00;P=.046) (FIGURE 4). This can be com-pared to effects of statins on total mor-tality—a 15% reduction—in a meta-analysis of randomized trials (pooledrelative risk, 0.85; 95% CI, 0.79 to0.92).95

Neurologic Development. DHA ispreferentially incorporated into the rap-idly developing brain during gestationand the first 2 years of infancy, concen-trating in gray matter and retinal mem-branes.26 Infants can convert shorter-chain n-3 fatty acids to DHA,96 but itis unknown whether such conversionis adequate for the developing brain inthe absence of maternal intake ofDHA.22,25

Effects of maternal DHA consump-tion on neurodevelopment have been in-vestigated in observational studies andrandomized trials, with heterogeneity inassessed outcomes (visual acuity, globalcognition, specific neurologic do-mains) and timing of DHA intake (ges-tational vs nursing). In a meta-analysisof 14 trials, DHA supplementation

Table 1. Summary of Evidence for Effects of Consumption of Fish or Fish Oilon Cardiovascular Outcomes

OutcomeClinicalEffect

Strengthof Evidence Comment

CHD mortalityCHD deathSudden death

! 35% decrease! 50% decrease

StrongStrong

Probable threshold of effect—most risk reduction occurswith modest intake(! 250 mg/d EPA " DHA),with little additional benefitwith higher intakes2-4,6-17,45-51*

Ischemic stroke ! 30% decrease Moderate Strong evidence from prospectivecohort studies53,54; no RCTs

Nonfatal CHDNonfatal MI Modest benefit? Equivocal Possible benefits at very high intakes

(! 2 g/d n-3 PUFAs)17,50

Progression ofatherosclerosis

Modest benefit? Equivocal Mixed results in cohort studies55

and RCTs56-58

Postangioplastyrestenosis

Modest benefit? Equivocal Possible benefits in a meta-analysisof RCTs59

Recurrent ventriculartachyarrhythmias

Modest benefit? Equivocal Mixed results in 3 RCTs60-62

Atrial fibrillation ! 30%" decrease Limited Mixed results in 2 cohort studies63,64;benefit in 1 RCT65

Congestive heart failure ! 30% decrease Limited Benefit in 1 prospective cohort study66

Abbreviations: CHD, coronary heart disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;MI, myocardial infraction; n-3 PUFA, n-3 polyunsaturated fatty acid; RCT, randomized clinical trial.

*See Figure 1.

Figure 3. Schema of Potential Dose Responses and Time Courses for Altering Clinical Eventsof Physiologic Effects of Fish or Fish Oil Intake

Rel

ativ

e S

tren

gth

of E

ffect

0 500 1500 25002000 1000

EPA + DHA Intake, mg/d

TYPICAL SUPPLEMENTALDOSES

Antiarrhythmia Weeks

Clinical Effect Time Course ToAlter Clinical Events

Triglyceride-Lowering Months to YearsHeart Rate–Lowering MonthsBP–Lowering Months to Years

Antithrombosis Weeks

TYPICAL DIETARYDOSES

The relative strength of effect is estimated from effects of eicosapentaenoic acid (EPA)"docosahexaenoic acid(DHA) on each risk factor and on the corresponding impact on cardiovascular risk.70-72,79-84 For example, doseresponse for antiarrhythmic effects is initially steep with a subsequent plateau, and clinical benefits may occurwithin weeks, while dose response for triglyceride effects is more gradual and monotonic, and clinical benefitsmay require years of intake. At typical Western levels of intake (eg, #750 mg/d EPA"DHA), the physiologiceffects most likely to account for clinical cardiovascular benefits include (1) modulation of myocardial sodiumand calcium ion channels, reducing susceptibility to ischemia-induced arrhythmia;18,19 and (2) reduced left ven-tricular workload and improved myocardial efficiency as a result of reduced heart rate, lower systemic vascularresistance, and improved diastolic filling.67-72,80 At higher levels of intake seen with fish oil supplementation orin Japanese populations49,50 ($750 mg/d EPA"DHA), maximum antiarrythmic effects have been achievedand clinically relevant effects occur on levels of serum triglycerides79 and possibly, at very high doses, throm-bosis.75 Potentially important effects on endothelial,73 autonomic,74 and inflammatory43 responses are not shownbecause dose responses and time courses of such effects on clinical risk are not well established. Effects are notnecessarily exclusive: eg, antiarrythmic effects may be partly mediated by effects on blood pressure (BP) orheart rate.

FISH INTAKE, CONTAMINANTS, AND HUMAN HEALTH

1888 JAMA, October 18, 2006—Vol 296, No. 15 (Reprinted) ©2006 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ on 03/06/2013

Mozaffarian D, Rimm EB. JAMA. 2006 Oct 18;296(15):1885-‐99.

71

ÍNDICE Ω3

von Schacky C, Harris WS. Cardiovasc Res. 2007 Jan 15;73(2):310-5.

≥ 8% vs ≤ 4%

Risco de morte por ECV 90% <

ACTIVIDADE LIMITADA

ACTIVIDADE LIMITADA

BETA-OXIDAÇÃO

EPA & DHA POR CADA 100G PEIXE

Fede lacko. n−3 PUFAs—From dietary supplenents to medicines. Pathophysiology 14 (2007) 127–132

ÓLEOS VEGETAIS RICOS EM ÓMEGA-6 DIMINUEM O RISCO DE DCV

Blasbalg TL, et al. Am J Clin Nutr. 2011

impairment of the conversion of 24:5n23–24:6n23 by com-peting for the active site of D6-desaturase in the endoplasmicreticulum (34, 35), which inhibits the production of DHA(22:6n23); and 3) the impairment of the incorporation of EPA,DPA n23, DHA, and n26 AA into tissue membranes bycompeting for esterification into the sn-2 position of phospho-lipids (36). The competition of LA with n23 and n26 HUFAsfor phospholipid incorporation may account for the significantinverse correlation of LAwith EPA (r =20.46, P, 0.01), DHA(r = 20.49, P , 0.01), and AA (r = 20.60, P , 0.01) shown inerythrocyte phosphatidylcholine of pregnant Canadians as re-ported by Friesen and Innis (36). In the Los Angeles VeteransStudy, a very high–LA diet (15% of energy) reduced AA con-centrations by 40% (P , 0.05) in coronary atheroma phospho-

lipids (37), presumably via the same mechanism. Thus, highdietary intakes of LA may displace AA in tissues, which mayaccount for the potential benefits of LA at very high intakes.However, because LA may also displace EPA and DHA, neteffects may be nonlinear and difficult to predict.

A randomized trial that compared the effects of infant formulaswith high LA (6.7% of energy) compared with low LA (1.7% of

FIGURE 8. Omega-3 tissue highly unsaturated fatty acid (HUFA)predictions over the 20th century. Solid arrows indicate the percentage ofn23 in HUFA (36.8%) and the estimated omega-3 index (8.3) calculatedfrom available nutrient intakes for 1909 traditional foods (1909-T).

TABLE 11Sources of docosapentaenoic acid1

Food category

Percentage contributionPercentagedifference1909 1999

Poultry 10.59 63.65 501Legumes 4.29 3.99 27Beef 3.02 1.84 239Finfish 28.97 15.38 247Shellfish 53.13 13.92 274Game 0 0.26 NAOils 0 0.94 NASpice 0 0.03 NATotal 100 100 —

1 NA, not applicable.

TABLE 12Sources of docosahexaenoic acid1

Food category

Percentage contributionPercentagedifference1909 1999

Poultry 6.64 25.42 283Shellfish 8.12 12.49 54Eggs 14.75 11.78 220Finfish 59.99 43.39 228Beef 10.49 6.84 235Game 0 0.10 NATotal 100 100 —

1 NA, not applicable.

FIGURE 9. Time-series determination of the dependence of thepercentage of n23 in highly unsaturated fatty acids (HUFA) on linoleicacid (LA) (A) compared with on a-linolenic acid (ALA) (B). Slopes ofsuggested regression lines between contrived series plots (dashed lines)and original functions (bold lines) were similar in direction and magnitudefor LA. For ALA, slopes of regression lines were opposite in direction andlower in magnitude than the original prediction plot. Therefore, the tissuepercentage of n23 in HUFAwas dependent on changes in dietary LA ratherthan in ALA.

10 of 13 BLASBALG ET AL

population (38). However, errors in dietary reporting, which ofteninclude underreporting in dietary records but a tendency foroverreporting in FFQs, are well known (54), but these would biasresults to weaker associations between dietary intakes andmeasures of blood lipid fatty acids and are not likely to have led toinflated associations among RBC membrane fatty acids. We didnot consider potential modifying effects of other nutrients orgenetic variables, such as polymorphisms in FADS2 and FADS1(55, 56). Fish, and thus EPA and DHA intakes, are relatively lowin our population, which limited the ability to identify effects ofhigher EPA and DHA intakes on n26 fatty acids. Regardless, thepresent study highlights that DHA, EPA, and ARA incorporationinto membrane lipids is complex. Interactions among fattyacids may include inhibition of DHA and EPA synthesis fromALA, but may also reflect effects of LA in reducing the con-centrations of n23 fatty acids through competition for acylation,

which is shifted to favor higher EPA and DHA by increasingthe dietary intake of preformed EPA and DHA. Finally, ourresults show that DHA intakes are skewed, with elevated RBCEPG concentrations of n26 fatty acids with 22 carbon chainsamong women with low DHA intakes, which suggests thatDHA status may be low among some pregnant women in ourcommunity.

We particularly thank Janette D King for providing laboratory analysis andShalu Duggal for subject enrollment and collection of the dietary and socio-demographic data.

The authors’ responsibilities were as follows—SMI (principal investiga-tor): conceived, designed, and implemented the study; RWF: undertookthe dietary and data analysis as part of the requirements for an MSc degree;and SMI and RWF: wrote the manuscript. Neither of the authors had any po-tential conflicts of interest.

FIGURE 4. Scatter plots of the inverse relation between concentrations of linoleic acid (LA) and docosahexaenoic acid (DHA), eicosapentaenoic acid(EPA), and arachidonic acid (ARA) in red blood cell (RBC) phosphatidylcholine (PC) and ethanolamine phosphoglyceride (EPG). n = 105 Canadian women at36 wk of gestation. The results were analyzed by using Pearson correlation analysis.

DIET AND RED BLOOD CELL n–6 AND n–3 FATTY ACIDS 29

at Lund University Libraries on April 6, 2011

ww

w.ajcn.org

Dow

nloaded from

LA diminui DHA na membrana dos eritrócitos

LA diminui EPA na membrana dos

eritrócitos

Friesen RW, Innis SM. Am J Clin Nutr. 2010 Jan;91(1):23-31.

N= 105 Mulheres (Canadá) Grávidas

(36 semanas)

Mensink RP, Zock PL, Kester AD, Katan MB. Am J Clin Nutr. 2003 May;77(5):1146-‐55

non-‐fatal myocardial infarc\on (MI) + CHD death.

n-6 specific PUFA trials non significantly increased the risk of

non-fatal MI + CHD death by 13% (risk ratio (RR) 1·13; 95% CI 0·84, 1·53; P=0·427)

83

LYON HEART STUDY

Okuyama H, Ichikawa Y, Sun Y, Hamazaki T, Lands WE. World Rev Nutr Diet. 2007;96:83-103.

84

RÁCIO N-6 / N-3 DE ALGUNS ALIMENTOS

Alimento ratio Ω6 / Ω3

Ovo convencional 19,4

Ovo de Creta 1,3

Carne (músculo) bovina alimentada com cereais

5,19

Carne (músculo) bovina de pasto 2,2

Cordain L et al. European Journal of Clinical Nutrition 2002; 56:181 – 191.

Simopoulos AP. J Nutr. 2001 Nov;131(11 Suppl):3065S-73S

[email protected]

www.nutriscience.pt

Obrigado

dieta e prevenção cvd versão slideshare

Documents