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* Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Department of Epidemiology, Harvard School of Public Health, Boston, MA; and ** Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA
2 To whom correspondence should be addressed. E-mail: luwang{at}rics.bwh.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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45 y and free from self-reported cardiovascular disease, cancer, and DM at baseline. Intakes of lycopene and total and individual tomato-based food products were assessed by a 131-item–validated semiquantitative food-frequency questionnaire. During a median follow-up of 10.2 y, 1544 cases of incident type 2 DM were documented. After adjusting for age, total energy intake, randomized treatment assignment, body mass index, and other known DM risk factors, the multivariate-adjusted relative risks and 95% CI of type 2 DM across increasing quintiles of dietary lycopene, were 1.00 (baseline), 1.10 (0.94–1.29), 1.10 (0.94–1.29), and 1.07 (0.91–1.26) (P linear trend = 0.56). Compared with women who consumed <1.5 servings/wk total tomato-based food products, women who consumed 1.5 to <4, 4 to <7, 7 to <10, and 10 servings/wk had multivariate relative risks (95% CI) of 1.03 (0.88–1.20), 1.02 (0.87–1.20), 1.09 (0.89–1.33), and 1.04 (0.80–1.36), respectively (P linear trend = 0.54). The associations for individual tomato-based food products were similar to the results for the combination of all tomato products. Our study found little evidence for an association between dietary intake of lycopene or lycopene-containing foods and the risk of type 2 DM.
KEY WORDS: • lycopene • tomato products • intake • diabetes mellitus • epidemiology
Oxidative stress is implicated in the pathogenesis of type 2 diabetes mellitus (DM)3 by inducing insulin resistance in the peripheral tissues and impairing insulin secretion from pancreatic ß-cells (1–3). The abundant conjugated double bonds of carotenoids can scavenge peroxyl radicals, making them powerful antioxidants that may provide protection against the development of type 2 DM. Lycopene, a carotenoid without provitamin A activity, is one of the major carotenoids detected in human tissues. Compared with other carotenoids, lycopene in vitro has been shown to have more potent antioxidant properties (4). Dietary intake of lycopene predominantly comes from the consumption of tomatoes or tomato products such as tomato juice, tomato sauce, and ketchup (5).
Epidemiologic studies that assess the role of lycopene in the primary prevention of type 2 DM are limited. There is indirect evidence for a protective effect that has been indicated in previous cross-sectional studies (6–12). However, the only known prospective study on dietary lycopene and the risk of type 2 DM did not find significant associations in a Finnish cohort of men and women (13). We therefore sought to examine the association between baseline dietary intake of lycopene and subsequent development of type 2 DM in a large cohort of middle-aged and older women from the United States. We also investigated whether the dietary intakes of combined or individual lycopene-containing foods were associated with the risk of type 2 DM.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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45 y, 94% Caucasian, and free from self-reported CVD and cancer (except nonmelanoma skin cancer), were randomized into the WHS. Among them, 39,310 women provided detailed dietary information at baseline by completing a 131-item validated semiquantitative food frequency questionnaire (SFFQ) (16). Of the 39,310 women, 829 were excluded from the present analysis due to insufficient completion of the questionnaire (>70 items left blank) or an implausible mean energy intake of either <600 or 3500 kcal/d (1 kcal = 4.1888 kJ). Women with incomplete data on consumption of tomato-based food products (n = 1784), prevalence of DM (n = 1160), or prerandomization CVD or cancer (n = 37) were also excluded. A final sample of 35,783 women remained for analysis. The study protocol was approved by Brigham and Women's Hospital Institutional Review Board. Lycopene, lycopene food sources, and other baseline covariates. For each food item, a commonly used unit or portion size was specified on the SFFQ. Participants were asked how often they had consumed that amount, on average, during the previous year. Nine possible responses ranging from "never or less than once per month" to "6+ per day" were recorded. The average daily intakes for the individual food items were calculated by multiplying the intake frequency by the portion size. Four tomato-based food products specifically included on the SFFQ (tomatoes, tomato juice, tomato sauce, and pizza) were considered major lycopene food sources. The total intake of tomato-based foods was computed by adding the intakes of the 4 tomato-based food products. Nutrient intakes were computed by multiplying the intake frequency of each unit of food by the nutrient content of the specified portion size according to food composition tables from the Harvard School of Public Health (17). Each nutrient reported was adjusted for total energy intake using the residual method (18). The SFFQ used in the WHS has demonstrated reasonable validity as a measurement for long-term average dietary intakes in populations of health professionals (19). Previous validation studies have reported high correlations between the SFFQ and dietary records for lycopene food sources (r > 0.70) (20,21).
On the baseline questionnaire, women provided self-reports of age (y), weight and height (calculated as BMI, kg/m2), smoking status (never, former, and current), alcohol use (rarely/never, 1–3 drinks/mo, 1–6 drinks/wk, and 1 drink/d), vigorous exercise (rarely/never, <1, 1–3, and 4 times/wk), family history of DM in a first-degree relative (no, yes), menopausal status (no, yes, and uncertain), postmenopausal hormone use (never, former, and current), and multivitamin use (never, former, and current). Also included were physician-diagnosed hypertension (no, yes), self-reported systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or any past or current treatment for high blood pressure. Measures for cholesterol included physician-diagnosed hypercholesterolemia (no, yes), self-reported cholesterol level 240 mg/dL (6.21 mmol/L), and any past or current treatment for high cholesterol.
Ascertaining type 2 DM. During annual follow-ups, participants were asked whether and when they had been diagnosed with DM since completing the last questionnaire. As described previously (22), two complementary approaches were used to confirm self-reported type 2 DM in the WHS. First, we attempted to contact 473 women with self-reported DM who provided a blood sample. Using the American Diabetes Association's diagnostic criteria (23), the self-reported diagnosis for type 2 DM was confirmed in 406 (91%) of 446 women who responded by telephone interview. Second, a random sample of 147 women with self-reported DM were sent a supplemental diabetes questionnaire. Among 136 respondents, 124 women (91%) were classified as having type 2 DM by the supplemental questionnaire. In addition, 113 of the 124 women gave us permission to contact their primary care physician. Of 113 physicians, 97 responded, and 90 of those provided adequate information for the American Diabetes Association's diagnostic criteria. Out of these 90 women, 89 (99%) were confirmed to have type 2 DM on the basis of combined information from the supplemental questionnaire and information from the physicians. This concluded our criteria for affirming the validity of self-reported type 2 DM in the WHS.
Statistical analyses.
Statistical analysis was performed using SAS software, version 8 (SAS Institute). Univariate distributions were presented as means ± SD for continuous variables and as proportional percentages for categorical variables. DM risk factors were first compared according to quintiles of lycopene intake. After testing the proportional hazard assumption, Cox regression models were used to estimate the relative risk (RR) and 95% CI of developing type 2 DM across lycopene quintiles with the lowest quintile as the baseline category. Models were adjusted for age, total energy intake, and randomized treatment assignment, and then by lifestyle factors, including smoking, alcohol use, exercise, menopausal status, postmenopausal hormone use, multivitamin use, and family history of DM. They were also adjusted for clinical factors, including BMI, history of hypertension, and hypercholesterolemia; and finally, they were adjusted for other nutrient intake, including total fat, fiber, and dietary glycemic load. Major food sources of lycopene were categorized a priori. The intake of tomatoes (1 tomato = 1 serving) included 4 categories (none, 1–3 servings/mo, 1–4 servings/wk, and 5 servings/wk). The intake of tomato juice (small glass = 1 serving), tomato sauce (1/2 cup or 118 mL = 1 serving), and pizza (2 slices = 1 serving) were also divided into 4 categories (none, 1–3 servings/mo, 1 serving/wk, and 2 servings/wk). The total tomato-based food-product intake was divided into < 1.5, 1.5 to <4, 4 to <7, 7 to <10, and 10 servings/wk as done in a previous study (24). Linear trends were tested using the median value of each intake category as an ordinal variable. We also tested curvilinear trends by modeling intake as a continuous variable with a quadratic term. Because the effect of lycopene on the risk of type 2 DM may be modified by existing insulin insensitivity, we also stratified the analysis by using surrogate markers of insulin sensitivity such as BMI (< or 30 kg/m2), history of hypertension, and hypercholesterolemia (with or without). Interactions were tested using the Wald chi-square test, with P < 0.05 considered statistically significant.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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20,482 µg/d, had a multivariate RR (95% CI) of 1.03 (0.78–1.35) vs. those in the lowest quintile after controlling for lifestyle and clinical factors.
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10 servings/wk, respectively (P linear trend = 0.54, P curvilinear trend = 0.01). The results for more specific lycopene food sources were similar to the results for the total-tomato products. Women consuming intermediate amounts of tomatoes, tomato sauce, and pizza seemed to have a moderately lower risk of type 2 DM in the age-, energy-, and treatment-adjusted model, but these inverse associations were not statistically significant in the multivariate-adjusted models.
The analysis was then stratified by BMI (<30, 30 kg/m2), history of hypertension (no, yes), and history of hypercholesterolemia (no, yes). Subgroup results were similar to the overall results (data not shown), and the associations were not modified by BMI or history of hypertension or hypercholesterolemia (for all interactions P > 0.05).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Protection against oxidative damage is theorized to be the biological link between lycopene and the metabolism of glucose. Increased free radical activities impair insulin action and glucose disposal in the peripheral tissues (2,3,25,26). Free radical-mediated tissue damage also contributes to ß-cell dysfunction (1,3,26–28). Furthermore, evidence is accumulating that oxidative stress may be actively involved in the pathogenesis of chronic inflammation, a possible common pathway underlying insulin resistance, type 2 DM, and CVD (3). An in vitro study demonstrated that lycopene has the strongest single oxygen-quenching capacity among the major antioxidant carotenoids (4), which may play a protective role in preventing diseases associated with free radical attack, including type 2 DM. Several human intervention studies have shown improvements in LDL oxidation by lycopene-containing foods or lycopene supplementation (29–31). However, direct evidence regarding the beneficial effect of lycopene on insulin action and glucose tolerance is still lacking. One animal study found that feeding a natural tomato extract containing 5% lycopene had no significant effect on plasma glucose levels in diabetic rats (32). Similarly, a randomized trial of 57 patients with well-controlled type 2 DM reported that short-term dietary supplementation with tomato juice, 250 mL twice daily for 4 wk, increased plasma lycopene and LDL resistance to oxidation, but did not change plasma glucose (33). Our prospective study of middle-aged and older women did not provide additional support for the potential benefits of long-term high lycopene intake in preventing the development of type 2 DM.
Previous epidemiologic studies on the relation between lycopene intake and risk of type 2 DM are scarce. In a cross-sectional study (7), food records suggested that a greater dietary lycopene intake was associated with reduced fasting plasma glucose concentration in nondiabetic male, but not female, relatives of patients with type 2 DM. Plasma concentrations of lycopene have been shown to have an inverse association with type 2 DM, fasting blood glucose, glucose tolerance, or glycosylated hemoglobin in population-based surveys (6,8) and cross-sectional analyses (9–12). However, these cross-sectional observations cannot directly infer any cause-effect relation. The low concentration of serum lycopene observed in patients with DM or impaired glucose metabolism may reflect a depleted antioxidant system due to DM or a change in diet after diagnosis. To our knowledge, there is only 1 published study that examines the prospective association between dietary lycopene and incidence of type 2 DM (13). In this Finnish cohort of 2285 men and 2019 women, aged 40–69 y and free of type 2 DM and heart disease at baseline, no associations were found between baseline lycopene intake (estimated using a dietary history interview) and the risk of type 2 DM during 23-y of follow-up. The results of our study of middle-aged and older U.S. women corroborate this earlier finding. Our study also shows no association between the combined or individual lycopene-containing foods and the risk of type 2 DM.
The correlation between dietary and plasma lycopene in a subsample of 483 women in WHS was statistically significant but weak (age-adjusted Spearman rank correlation coefficient r = 0.14) (24). This may reflect a large interindividual variation in blood lycopene in response to dietary intake. Heating, processing, and the simultaneous ingestion of fat have been seen to improve the bioavailability of lycopene, but the specific biological mechanisms underlying lycopene absorption and in vivo metabolism remain poorly understood (34).
The prospective design, long period of follow-up, validated diet assessment, and documentation of a large number of incident type 2 DM cases are the unique strengths of our study. Yet several methodological issues must be considered as potential limitations. First, the single measurement of dietary intake at baseline and lack of cohort-wide screening in identifying undiagnosed DM may induce nondifferential misclassification and therefore bias the association toward null. Second, high lycopene intake may simply coincide with other lifestyle or dietary patterns that may be associated with glucose metabolism. Although we comprehensively adjusted for multiple DM risk factors in our analysis, residual confounding may remain. Third, these findings might be restricted to middle-aged and older, mostly nonhispanic, white women who were generally healthy and willing to participate in a clinical trial. Lycopene intake in our study was comparable to other published large U.S. cohort studies; however, further research is necessary to consider lycopene intake in a variety of populations and conditions and to assess its association with the risk of type 2 DM.
In conclusion, our study found little evidence for an association between dietary intake of lycopene or lycopene-containing foods and the risk of type 2 DM. More research is needed to further elucidate the biological mechanisms of lycopene absorption and metabolism and to determine the specific role of lycopene in the development of type 2 DM.
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FOOTNOTES |
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3 Abbreviations used: CVD, cardiovascular disease; DM, diabetes mellitus; RR, relative risk; SFFQ, semiquantitative food frequency questionnaire; WHS, Women's Health Study.
Manuscript received 12 September 2005. Initial review completed 16 November 2005. Revision accepted 12 December 2005.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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