The total antioxidant capacity of the diet is an independent predictor of plasma β-carotene

Abstract

Objective:

To investigate the contribution of the total antioxidant capacity (TAC) of the diet to plasma concentrations of β-carotene.

Design:

Cross-sectional study.

Setting:

Department of Public Health and Department of Internal Medicine and Biomedical Sciences, University of Parma.

Subjects:

A total of 247 apparently healthy adult men (n=140) and women (n=107).

Methods:

A medical history, a physical exam including height, weight, waist circumference and blood pressure measurements, a fasting blood draw, an oral glucose tolerance test and a 3-day food record.

Results:

We observe a negative trend across quartiles of plasma β-carotene for most biological variables clustering in the insulin resistance syndrome, as well as for traditional and new risk factors for type II diabetes and cardiovascular disease (CVD), including C-reactive protein and γ-glutamyltranspeptidase (P<0.05). Regarding dietary characteristics, energy-adjusted intake of fat, fiber, fruits, vegetables, β-carotene, vitamin C, vitamin E and dietary TAC significantly increased with increasing plasma β-carotene (P<0.05), whereas alcohol intake decreased (P=0.013). Adjusted geometric means (95% confidence interval) of plasma β-carotene significantly increased across quartiles of dietary TAC, even when single dietary antioxidants were considered in the model (QI=0.087 mg/dl (0.073–0.102); QII=0.087 mg/dl (0.075–0.103); QIII=0.114 mg/dl (0.098–0.132) and QIV=0.110 mg/dl (0.093–0.130); P for linear trend=0.026). When the population was divided on the basis of alcohol consumption, this trend was also observed in subjects drinking <20 g alcohol/day (P=0.034), but not in those with higher alcohol intake (P=0.448).

Conclusions:

Dietary TAC is an independent predictor of plasma β-carotene, especially in moderate alcohol drinkers. This may explain, at least in part, the inverse relationship observed between plasma β-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of β-carotene supplements alone in reducing such risk.

Sponsorship:

Supported by the European Community IST-2001–33204 ‘Healthy Market’, the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.

Introduction

Plasma concentrations of β-carotene have been reported to be reduced in insulin-resistant subjects compared to insulin-sensitive individuals (Facchini et al., 2000), and inversely correlate with the metabolic syndrome and glucose tolerance in large population studies (Ford et al., 2003; Ylonen et al., 2003; Coyne et al., 2005), but do not appear to predict incident type II diabetes independently of traditional risk factors (Reunanen et al., 1998), and a 12-year intervention with β-carotene supplements did not reduce the risk of type II diabetes in a cohort of over 22 000 healthy men (Liu et al., 1999). A similar pattern has been observed for cardiovascular disease (CVD) risk and death for all causes. With few exceptions, cohort studies show a higher incidence of atherosclerosis and CVD among subjects with low concentrations of plasma β-carotene and, to a lesser extent, with low dietary (or supplemental) intake of carotenoids (Kritchevsky et al., 1995; D'Odorico et al., 2000; Hak et al., 2003, 2004; Dwyer et al., 2004), but supplementation studies with β-carotene, either alone or in combination with other antioxidants, have demonstrated no effect in primary or secondary CVD prevention (Tornwall et al., 1999; Asplund, 2002; Vivekananthan et al., 2003). Finally, low-plasma β-carotene is associated with higher mortality for all causes, but β-carotene supplementation does not reduce the risk of death significantly (Greenberg et al., 1996).

This apparent lack of cause–effect relationship between intake of β-carotene and risk of chronic disease leads to hypothesize that plasma concentrations of β-carotene may act as marker of certain dietary patterns potentially useful for diabetes and atherosclerosis prevention that are not considered in supplementation studies (Gaziano et al., 1995; Montonen et al., 2004; Srinath Reddy and Katan, 2004). An additional, complementary explanation is that inflammation and oxidative stress that are usually associated with chronic disease could modulate plasma concentrations of β-carotene depending on the total antioxidant capacity (TAC) of the diet and not on the strict intake of carotenoids or single antioxidant vitamins.

The objective of this cross-sectional study was to investigate the contribution of the TAC of the diet to plasma concentrations of β-carotene in a cohort of adult, non-diabetic Italian subjects.

Subjects and methods

Subjects

Subjects were selected from a cohort of 299 apparently healthy workers and ex-workers of a food company participating on a follow-up survey on diabetes and CVD. Exclusion criteria included type II diabetes, recent cardiovascular events (<6 months), evidence of hepatitis B virus and/or hepatitis C virus infection, chronic liver diseases and/or nephropathies, autoimmune diseases, cancer and organ failure. All subjects gave their written informed consent at enrolment. The protocol was approved by the Ethics Committee for Human Research of the University of Parma.

Design

Subjects completed a medical history to retrieve information about health status, current medications including supplements of vitamins and minerals, alcohol drinking and smoking; a physical examination including height, weight, waist circumference and blood pressure measurements on two different occasions; a blood draw after 12-h fasting for biochemical analyses and an oral glucose tolerance test providing 75 g of glucose with blood draws up to 120 min for determination of glucose, insulin and exclusion of type II diabetes (Alberti and Zimmet, 1998). All volunteers completed a 3-day food record to obtain accurate information on short-term food intake.

Data collection

Anthropometric (height, weight and waist circumference) and dietary variables were collected as described previously (Brighenti et al., 2005). Blood pressure was measured on two different occasions in a standard manner (Brighenti et al., 2005), and hypertension was defined as active treatment with blood pressure-lowering medications or systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mm Hg in the two occasions in which blood pressure was measured.

Dietary data

A certified dietitian trained the subjects to fill in a 3-day food record, which included all foods, beverages and supplements consumed during two non-consecutive working days plus a weekend day, the week following the screening visit. The record was checked for completeness and portion sizes within 48 h from compilation using a book of photographs and standard household measures. Nutrient intake was assessed using a customized computer program linked to a database containing macro- and micronutrient composition of more than 700 Italian foods (Salvini, 1997). Data on TAC were included in the data bank on a number of foods directly analyzed in our laboratory and representative of the average Northern Italian diet (Pellegrini et al., 2003a; Pellegrini et al., 2006). Dietary TAC values used in this study have been obtained by applying the Trolox equivalents antioxidant capacity assay (Pellegrini et al., 2003b), expressed as TAC in mmol of Trolox/kg of fresh food, and reported as mmol of Trolox/day.

Alcohol intake was calculated from the 3-day records considering one serving of alcoholic beverage as a glass of wine (150 ml=12 g of ethanol), a can of beer (330 ml=13 g of ethanol) or a small glass of spirits (30 ml=13 g of ethanol).

Biochemical analyses

Serum insulin levels were measured by microparticle enzyme immunoassay (IMX; Abbott Laboratories, Abbott Park, IL, USA), with intra-assay and inter-assay coefficient of variations (CVs) of 3.0 and 5.3%, respectively. High-sensitivity C-reactive protein (hs-CRP) was measured using an ELISA kit (ICN Pharmaceuticals, Orangeburg, NY, USA), with a minimum detectable concentration of 0.004 mg/l. Intra-assay and inter-assay CVs were 2.3 and 2.5%, respectively. Plasma β-carotene was measured by high-performance liquid chromatography as described by Riso and Porrini (1997). Fasting plasma glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyltranspeptidase (GGT) were assessed by a central laboratory using standard methodologies.

Statistical analysis

Data are expressed as means±s.d.s for variables normally distributed and as medians (inter-quartile ranges) for variables with a markedly skewed distribution. All continuous variables were checked for normality using the Kolmogorov–Smirnoff test and non--normally distributed variables were log-transformed for correlation and regression analysis. Current smoker was defined as regular user of tobacco products in the last 6 months. Moderate alcohol consumption was defined as a daily intake below 20 g/day. The homeostasis model assessment was used as surrogate of insulin resistance (HOMA-IR) as suggested by Matthews et al., 1985. Dietary variables were adjusted for energy intake as described by Willett and Stampfer (1986). Linear P per trend across quartiles of β-carotene were calculated using analysis of variance for variables with a normal distribution and homogeneity of variances, the H of Kruskal–Wallis for variables non-normally distributed and the χ2 statistics for categorical variables. Adjusted geometric means (95% confidence interval) of β-carotene across quartiles of energy-adjusted dietary TAC were calculated using the general linear model (GLM) procedure in SPSS (version 12.0; SPSS Inc, Chicago, IL, USA). Covariates for GLMs adjustment were selected from clinical and dietary variables related to plasma concentrations of β-carotene in previous publications as well as in our sample, namely age, gender, body mass index (BMI), smoking, hypertension, HOMA-IR, plasma concentrations of HDL cholesterol, triglycerides, uric acid, GGT, C-reactive protein (CRP) and intake of fiber, alcohol, fat, vitamin C, vitamin E, β-carotene, fruits and vegetables (Carroll et al., 1999; Facchini et al., 2000; Kritchevsky et al., 2000; Ford et al., 2003; Brevik et al., 2004; Coyne et al., 2005). Independent predictors of plasma β-carotene were identified by stepwise multiple regression analysis. Differences of adjusted plasma β-carotene and TAC intake between moderate and high alcohol drinkers were assessed using t-test for independent samples. All tests were two-sided and a P-value <0.05 was considered significant.

Results

Table 1 summarizes the characteristics of volunteers at admission by gender. A total of 247 subjects were eligible for the study and had complete data for all variables considered. The sample included 132 subjects (53%) with hypertension, 93 of whom (71%) were on antihypertensive medications, and 17% were smokers. Further, 13 (5.3%) subjects were taking statins and 12 (11.2%) women were on hormone-replacement therapy. As shown in Table 1, men and women significantly differed in plasma concentrations of β-carotene, in most of the clinical variables related to the insulin resistance syndrome and in energy and alcohol intake. However, intake of fiber, of main dietary antioxidants and of dietary TAC were not significantly different between men and women after adjusting for energy intake.

Table 1 Demographic, clinical and dietary characteristics of the volunteersa

The clinical characteristics of subjects by quartiles of plasma β-carotene are shown in Table 2. Age, percent of males, BMI, waist circumference, prevalence of hypertension, HOMA-IR index and plasma concentrations of triglycerides, uric acid, GGT and hs-CRP significantly decreased and HDL cholesterol significantly increased across quartiles of plasma β-carotene, whereas nonsignificant differences were observed regarding prevalence of smokers, plasma concentrations of total cholesterol, AST or ALT.

Table 2 Clinical characteristics of subjects by quartiles of plasma β-carotene

Regarding dietary variables, intake of fat as % energy, and energy-adjusted intake of fiber, fruits, vegetables, oils and nuts, β-carotene, vitamin C, vitamin E and dietary TAC significantly increased, whereas alcohol intake significantly decreased across quartiles of plasma β-carotene (Table 3). Being alcohol intake a major contributor to total dietary TAC (Brighenti et al., 2005) but inversely related to plasma β-carotene, we further explored the contribution of different food groups to total dietary TAC by quartiles of plasma β-carotene (Table 3). Percent TAC deriving from intake of alcoholic beverages and cereals decreased and percent TAC from vegetables–pulses and nuts–oils increased, whereas the contribution of fruits and the coffee–tea–cocoa group and nuts–oils was not significantly different across quartiles of plasma β-carotene.

Table 3 Dietary characteristics of subjects by quartiles of plasma β-carotenea

Adjusted means of plasma β-carotene by quartiles of dietary TAC are shown in Table 4. Three sets of covariates were used for model adjustment: (1) a minimal model including only independent predictors of plasma β-carotene as identified by stepwise multiple regression analysis; (2) and (3) extended models using as covariates age, gender and BMI in addition to clinical variables in model 1. In model 2, intake of fruits, vegetables, oils and nuts were used as markers of antioxidant intake, whereas in model 3 single dietary antioxidants (namely vitamin C, tocopherols and carotenoids) were considered instead.

Table 4 Adjusted plasma concentrations of β-carotene by quartiles of energy-adjusted TAC of the diet

In all models, a significant positive linear trend for plasma concentrations of β-carotene across quartiles of energy-adjusted dietary TAC was observed (Table 4).

As alcohol intake was negatively correlated with plasma β-carotene but a major contributor to dietary TAC, we calculated plasma β-carotene concentrations by quartiles of dietary TAC in moderate (n=131) and heavy (n=116) alcohol drinkers. As seen in Figure 1, adjusted means of plasma β-carotene increased significantly across quartiles of TAC intake only among moderate alcohol drinkers, and were consistently higher in the latter than in heavy alcohol drinkers.

Figure 1
figure1

Adjusted mean plasma concentrations of β-carotene by quartiles of energy-adjusted TAC of the diet in moderate (n=131) and heavy (n=116) alcohol drinkers. Solid bars are geometric means and error bars are 95% confidence intervals. Plasma concentrations of β-carotene are adjusted by age, gender, BMI, HOMA-IR, hypertension, plasma triglycerides and intake of energy-adjusted fiber, fat, alcohol, vitamin C, vitamin E and β-carotene. P-per-trend for moderate drinkers=0.034; P-per-trend for heavy drinkers=0.488. *, **Significantly different from mild drinkers: *P=0.01, **P<0.001.

Discussion

Despite the epidemiological observation that intake of fruits and vegetables rich in carotenoids and plasma concentrations of β-carotene are both inversely related to the prevalence of type II diabetes (Coyne et al., 2005) and to the risk of future cardio- and cerebrovascular events (D'Odorico et al., 2000; Hak et al., 2003, 2004; Dwyer et al., 2004), intervention studies with β-carotene supplementation have failed to demonstrate a significant risk reduction in supplemented subjects (Liu et al., 1999; Tornwall et al., 1999; Asplund, 2002; Vivekananthan et al., 2003). This suggests that plasma β-carotene is a good marker of disease risk, but also that it may be modulated by other factors than its own intake. Actually, we observe a negative trend across quartiles of plasma β-carotene for most biological variables clustering in the insulin resistance syndrome, as well as for traditional and new risk factors for type II diabetes and CVD, including CRP and GGT (Best et al., 2005; Wannamethee et al., 2005). This is in agreement with recent investigations describing a negative association between serum β-carotene and GGT in young individuals, adults and alcohol drinkers with normal liver function (Lee et al., 2004; Lim et al., 2004; Sugiura et al., 2005), and between serum β-carotene and CRP in healthy subjects (Kritchevsky et al., 2000). However, β-carotene intake in the present study shows only a marginally significant relationship with plasma β-carotene, which appears to be intimately associated with many dietary factors. In fact, intake of the antioxidant vitamins C and E is strongly and positively related to plasma β-carotene. This is consistent with previous investigations (Carroll et al., 1999; El-Sohemy et al., 2002) and may reflect either a sharing of dietary sources (primarily vitamin C), a ‘protection’ of plasma β-carotene by antioxidant vitamins, or both. A similar reasoning may apply to the positive correlation observed between intake of fruits, vegetables–pulses, and fiber and plasma β-carotene. Fruits and vegetables are both rich in fiber and good sources of β-carotene, but also provide a consistent amount of other antioxidants (vitamins and non) that could theoretically ‘spare’ circulating β-carotene. On the other hand, intake of oils and nuts, which contain only marginal amounts of β-carotene, are important sources of vitamin E and are positively related to plasma β-carotene in our population as well as total dietary fat, probably because carotenoids are lipophilic compounds that are better absorbed when consumed in the context of a fatty meal. Thus, it appears that plasma concentrations of β-carotene are actually modulated by other factors than its own intake, and that the TAC of the diet may have an additional effect in preserving this negative marker of disease. This is supported by the positive trend of dietary TAC across quartiles of plasma β-carotene, and by the positive trend of plasma β-carotene across quartiles of dietary TAC even after adjusting by relevant clinical and dietary variables. Indeed, dietary TAC summarizes the capacity of scavenging preformed free radicals of all known and unknown antioxidant compounds present in foods, a concept that contains and exceeds single dietary antioxidants considered in most epidemiological research (Pellegrini et al., 2003a). As antioxidants with different activities and redox potentials synergistically network against oxidative stress and its consequences, including subclinical inflammation (Brighenti et al., 2005), the TAC-mediated effect of the usual diet on plasma β-carotene could explain, at least in part, why this carotenoid is associated with low risk of chronic disease (D'Odorico et al., 2000), but supplementation with β-carotene fails to reduce such risk (Liu et al., 1999; Tavani and La Vecchia, 1999).

A further comment merits the complex relationship emerging between dietary TAC, alcohol drinking and plasma β-carotene. Svilaas et al. (2004) reported a positive correlation between consumption of red wine and plasma β-carotene in a Norwegian cohort in which red wine contributed only 5% of total dietary TAC. In our population, 27% of dietary TAC was from alcohol and 75% of alcohol intake came from red wine, which is the most antioxidant alcoholic beverage and an important contributor to dietary TAC, but also a source of liver toxicity and oxidative stress when consumed in high amounts (Koch et al., 1991; Wheeler et al., 2001; Arteel, 2003). Indeed, alcohol consumption significantly decreased across quartiles of plasma β-carotene, and the positive trend of this carotenoid across quartiles of dietary TAC was noted only in moderate alcohol drinkers, who showed higher β-carotene concentrations as compared to heavy alcohol drinkers. This suggests a threshold level from which the capacity of ethanol to generate oxidative stress and liver damage may overcome the potential benefits of wine antioxidants in protecting plasma β-carotene by facing oxidative stress.

In conclusion, the TAC of the diet is an independent predictor of plasma β-carotene concentrations and may explain, at least in part, the inverse relationship observed between plasma β-carotene and risk of chronic diseases in which high levels of oxidative stress are present, namely type II diabetes, atherosclerosis and CVD, as well as the failure of β-carotene supplements alone in reducing disease risk. However, increasing dietary TAC by consuming excessive red wine may induce liver toxicity and increased oxidative stress, thus reducing the benefits that wine antioxidants may have in protecting plasma carotenoids.

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Acknowledgements

We thank Mrs Nadia Anelli from the Department of Public Health, University of Parma, for her skilful collection of dietary data. This study was supported by the European Community IST-2001-33204 ‘Healthy Market’, the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.

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Correspondence to S Valtueña.

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Guarantor: F Brighenti.

Contributors: SV participated in the study design and the collection of clinical data, performed the statistical analysis and was the primary writer of the paper, but received input from all the other authors. DDR contributed to the preparation of the paper, to laboratory analysis and to the study design. NP provided expert advice and was involved in paper editing and data interpretation. DA and LF participated in subjects' recruitment and management, in the collection and interpretation of clinical data and in the discussion of the paper. PMP and SS were involved in laboratory analysis and quality control. PR carried out the analysis of plasma β-carotene and provided expert advice on data interpretation. DDR, NP, SS and FB were responsible for the collection, completeness and interpretation of dietary data. IZ was responsible for ethical approval and subjects' recruitment. IZ and FB were responsible for the study concept and design and for securing the funding. None of the authors had any conflicts of interest in connection with this study.

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Valtueña, S., Del Rio, D., Pellegrini, N. et al. The total antioxidant capacity of the diet is an independent predictor of plasma β-carotene. Eur J Clin Nutr 61, 69–76 (2007). https://doi.org/10.1038/sj.ejcn.1602485

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Keywords

  • β-carotene
  • antioxidants
  • diet
  • oxidative stress
  • insulin resistance
  • alcohol drinking

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