Relations of Serum Ascorbic Acid and
-Tocopherol to Diabetic Retinopathy in the Third National Health and Nutrition Examination Survey
Amy E. Millen1,
Michael Gruber1,
Ron Klein1,
Barbara E. K. Klein1,
Mari Palta2 and
Julie A. Mares1
1 Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI.
2 Department of Preventive Medicine, University of Wisconsin Medical School, Madison, WI.
Received for publication February 13, 2002; accepted for publication January 17, 2003.
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ABSTRACT
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The protective relation of ascorbic acid and
-tocopherol to the development of diabetic retinopathy has not been thoroughly evaluated in epidemiologic studies. The association of prevalent diabetic retinopathy with serum ascorbic acid and
-tocopherol was studied among participants with type 2 diabetes (
40 years) (n = 998) in the Third National Health and Nutrition Examination Survey (19881994); 20% of the sample (n = 199) had prevalent retinopathy. The overall odds ratio for retinopathy among participants in quartile 4 compared with quartile 1 for serum ascorbic acid was 1.3 (95% confidence interval: 0.8, 2.3), with a p for trend = 0.60 after adjustment for the confounders of smoking, race, waist/hip ratio, hypertension, and duration of diabetes. The overall odds ratio for retinopathy among participants in quartile 4 compared with quartile 1 for serum
-tocopherol was 2.7 (95% confidence interval: 1.6, 4.6), with a p for trend = 0.14 after adjustment for confounders. After removal of supplement users of vitamin C (n = 307) or vitamin E (n = 298), the odds ratio changed direction or was attenuated: adjusted odds ratios for retinopathy among participants in quartile 4 compared with quartile 1 for serum ascorbic acid and
-tocopherol = 0.7 (95% confidence interval: 0.3, 1.4) and 1.6 (95% confidence interval: 0.9, 2.9), respectively. In summary, no significant associations were observed between serum levels of major dietary antioxidants and retinopathy. Recent use of supplements for treatment of complications of diabetes may explain the direct associations.
ascorbic acid; diabetic retinopathy; nutrition surveys; vitamin E
Abbreviations:
Abbreviation: NHANES III, Third National Health and Nutrition Examination Survey.
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INTRODUCTION
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Persons with diabetes suffer from micro- and macrovascular disease such as diabetic retinopathy, a disease of the retinal microvasculature. Retinopathy occurs in just over 2.5 percent of the population aged 18 years or more (1). Ascorbic acid and
-tocopherol are nutrients hypothesized to prevent retinopathy by affecting presumed pathogenic factors: protein glycosylation, insulin sensitivity, retinal blood flow, and oxidative stress (224). Not all studies, however, support these hypotheses (2530). The majority of research investigating the potential protective effect of ascorbic acid and
-tocopherol has been conducted in diabetic animal models and short-term supplementation trials. Only one population-based study has investigated the relation between the risk of severity of diabetic retinopathy and these antioxidant nutrients, using dietary intake from one 24-hour recall (31). This previous study showed an increased risk of diabetic retinopathy with increasing intake of vitamins C and E (31). Additional research is needed to assess the association between these micronutrients and retinopathy in the general population of persons with diabetes.
The Third National Health and Nutrition Examination Survey (NHANES III) provides the opportunity to investigate the association between biomarkers of ascorbic acid and
-tocopherol intakes and the odds of prevalent diabetic retinopathy in a large sample of free-living persons (32). The purpose of this research was to investigate the association between serum ascorbic acid and
-tocopherol concentrations and prevalent retinopathy using data from NHANES III. We hypothesized that participants in the highest, compared with the lowest, quartile of serum ascorbic acid and
-tocopherol would have less retinopathy.
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MATERIALS AND METHODS
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Study design
NHANES III was conducted by the Centers for Disease Control and Prevention between 1988 and 1994 using a nationally representative probability sample of the US noninstitutionalized civilian population. A multistage probability sample design was used with oversampling of certain subgroups to allow more precise estimates, including non-Hispanic Blacks, Mexican Americans, and adults over 60 years of age. All eligible participants were invited to complete a household interview to obtain information on demographic and socioeconomic characteristics, health history, and dietary behavior. All interviewed persons were invited to participate in a medical examination that was conducted at a mobile examination center. The examination included body measurements, fundus photography, urine collection, a 24-hour dietary recall interview, and phlebotomy to measure a number of hematologic factors.
Sample selection
Persons with type 2 diabetes were identified from a total of 14,464 persons 40 years of age or more who were invited to participate in NHANES III. Of the 14,464 persons aged 40 or more years who were eligible for the survey, 11,448 persons were interviewed and 9,737 were examined in the mobile examination center. These analyses were restricted to non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans. Persons of other races or ethnicities were excluded (n = 371), because the sample sizes were too small to allow statistically reliable estimates.
A total of 1,434 persons were classified as having type 2 diabetes. Participants who reported being diagnosed with diabetes by their physician and who recalled being diagnosed at age 30 or more years were considered to have type 2 diabetes (n = 1,137). If a participant fasted for 10 or more hours, completed an oral glucose tolerance test, and had a plasma glucose level equal to or greater than 200 mg/dl, he/she was also considered to have type 2 diabetes (n = 297) (33).
Persons with missing or ungradable fundus photographs for retinopathy were excluded (n = 256). Persons were also excluded if they had missing serum ascorbic acid or
-tocopherol values (n = 75), missing food frequency data (n = 1), or missing data for potential confounders or other significant covariates (n = 104). Thus, a total of 998 participants with type 2 diabetes were eligible for inclusion in these analyses, and 20 percent (n = 199) had retinopathy. Overall, the sample used in these analyses was 70 percent of all non-Hispanic White, non-Hispanic Black, or Mexican-American persons 40 years of age or more classified with type 2 diabetes in NHANES III (n = 1,434).
To understand the differences between the sample we selected for our study (n = 998) and those persons who were excluded (n = 436) from the original sample of non-Hispanic White, non-Hispanic Black, and Mexican-American persons with type 2 diabetes for missing data, we compared the demographic, physical, lifestyle, dietary, and medical characteristics of these two samples. The persons with type 2 diabetes who were excluded from this study were older (65 vs. 62 years, p < 0.0001), more likely to be Mexican American and non-Hispanic Black than non-Hispanic White (Mexican American: 6.3 percent vs. 5.2 percent; non-Hispanic Black: 14 percent vs. 13 percent, p = 0.008), had a longer duration of diabetes (8.2 vs. 6.9 years, p = 0.003), were less likely to be anemic (hemoglobin of <15 g/dl: 93 percent vs. 89 percent, p = 0.009), and were more likely to have had higher plasma cholesterol concentrations (6.0 vs. 5.9 mg/dl, p = 0.009). These two groups did not differ with respect to sex, glycosylated hemoglobin, body mass index, dietary intake, hypertension, smoking, prevalent retinopathy, cardiovascular disease, or supplement use.
Serum data
Serum samples were analyzed for
-tocopherol and ascorbic acid levels using reversed phase high-performance liquid chromatography with multiwavelength detection at the National Health and Nutrition Examination Survey laboratory located at the Centers for Disease Control and Prevention. Detailed descriptions of laboratory analyses are described elsewhere (34).
Serum
-tocopherol values were log transformed because of the skewness of the data. Because
-tocopherol levels are directly associated with serum cholesterol levels (35) (Pearsons correlation coefficient = 0.33), log-transformed serum
-tocopherol values were regressed on serum cholesterol to compute residuals. The residuals were used in analyses to remove the effect of interindividual lipid level variation on serum
-tocopherol measurements.
Dietary and supplement data
The dietary and supplement data collected included a 24-hour recall, query for supplement use including questions regarding dose and duration, and a 60-item food frequency questionnaire (36). The food frequency questionnaire was designed to estimate dietary intake over a 1-month period of time prior to the interview (36). The nutrient composition databases used to create the nutrient estimates were developed using foods reported in the NHANES III 24-hour recalls as described previously (37).
The food frequency questionnaire was not quantitative or comprehensive for energy-yielding foods. Additionally, the food frequency questionnaire data could not be used to adequately represent the intake of dietary vitamin E, of which
-tocopherol is one isomer, because the food frequency questionnaire queried for intakes of fats and oils but did not differentiate between animal and vegetable fats. Only vegetable fats are rich sources of vitamin E. Additionally, the use of added fats and oils in cooking, a large source of vitamin E in the diet, was not assessed in the NHANES III food frequency questionnaire. For these reasons, analyses of the association between dietary sources of vitamins C and E are not presented in this paper.
Fundus photography and grading
Retinopathy was assessed by nonmydriatic fundus photographs of one randomly chosen eye for all participants aged 40 years or more. Photographic fields were graded, in a masked fashion, by trained graders at the Ocular Epidemiology Grading Center, University of Wisconsin Medical School. The presence and severity of retinopathy, as well as the presence of specific diabetic lesions, were classified using the Modified Airlie House Classification scheme and the Early Treatment for Diabetic Retinopathy Study severity scale (38). Participants were classified as having no retinopathy, mild nonproliferative retinopathy, moderate nonproliferative retinopathy, or proliferative retinopathy. The outcome variable was binary: any retinopathy (mild, moderate, or proliferative) versus no retinopathy.
Statistical analyses
Odds ratios and 95 percent confidence intervals for retinopathy were calculated using logistic regression for each quartile of serum ascorbic acid and
-tocopherol, with those in the lowest quartile as the reference category. The Wald test for trend was performed on continuous serum ascorbic acid or
-tocopherol concentrations.
The variables tested as potential confounders were race, duration of diabetes, treatment group (a categorical variable defined as dietary treatment only, oral hypoglycemic agent use, or insulin use), insulin use, oral hypoglycemic agent use, body mass index, waist/hip ratio, hypertension, smoking status, and hemoglobin concentrations, as a marker for anemia, as shown in table 1. If treatment type was determined to be a confounder, then neither insulin use nor oral hypoglycemic agent use was added to the final model to avoid the effects of multicollinearity. Potential confounders were entered singly into the logistic regression model. If the factor changed the beta coefficient 10 percent or more, it was determined to be a confounder. If an inverse association was found between either ascorbic acid or
-tocopherol, then glycosylated hemoglobin, a monitor of longitudinal blood glucose control, was added to the final model to investigate to what degree glycosylated hemoglobin might explain the protective effect of these nutrients on retinopathy.
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TABLE 1. Characteristics of participants aged 40 or more years with type 2 diabetes (n = 998) by quartile of serum ascorbic acid and -tocopherol, Third National Health and Nutrition Examination Survey, 19881994
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The relations of these serum nutrients to retinopathy were evaluated for interactions. The consistency of relations of serum ascorbic acid and
-tocopherol to retinopathy was evaluated after stratification of the overall analyses by potential effect modifiers (i.e., race, blood glucose control, duration of diabetes, and the treatment type used to control blood glucose levels). Analyses were stratified by the median cutpoint for duration of diabetes (10 years) in this population. The sample was also stratified by glycosylated hemoglobin levels above and below the American Diabetes Association recommended cutoffs for poor and good glycemic control using glycosylated hemoglobin (39). The likelihood ratio test, comparing the logistic regression models with and without interaction terms, was used with an alpha level of 0.10 or less to determine significance.
Further exploratory analyses were conducted after removal of supplement users. We categorized supplement users of vitamin C or vitamin E to be participants who consumed the nutrient in supplement form at the level of at least one recommended daily allowance per week. Otherwise participants were considered nonusers. Serum nutrient levels may reflect recent use of supplements and not long-term supplement use or dietary status. Recent use of supplements might also have occurred as a result of diabetes severity or complications.
Total interview or examination sample final weights were applied to all estimates to account for differential probability of selection and for nonresponse (40). For each regression analysis, the jackknife replication method was used to obtain appropriate variance estimates (41).
All analyses were conducted using SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina).
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RESULTS
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Serum ascorbic acid and diabetic retinopathy
Distributions of risk factors by level of serum ascorbic acid
Differences in potential risk factors of retinopathy between high and low quartile ranges of serum ascorbic acid concentrations are shown in table 1. Participants at the highest level of serum ascorbic acid were older and more likely to be female, non-Hispanic White, users of hypoglycemic agents, leaner, persons with smaller waist/hip ratios, and less hypertensive. Participants at the highest level of serum ascorbic acid were also more likely to be past smokers and supplement users than those individuals in quartile 1. Persons in quartile 4 of serum ascorbic acid also had higher serum
-tocopherol concentrations, higher intake of dietary vitamin C, carbohydrates, and dietary fiber, but lower dietary intake of total, saturated, and monounsaturated fat compared with persons in quartile 1 of serum ascorbic acid.
Relations of serum ascorbic acid to retinopathy
The odds of retinopathy did not differ between persons in the high versus the low serum ascorbic acid quartile (odds ratio = 1.4, 95 percent confidence interval: 0.8, 2.3). Adjustment for confounders did not alter this association (table 2). After supplement users of vitamin C were removed from the overall analyses (n = 301), serum ascorbic acid was no longer directly associated with retinopathy (table 2).
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TABLE 2. Odds ratios and 95% confidence intervals for prevalent diabetic retinopathy among participants aged 40 or more years with type 2 diabetes in quartiles 24 compared with quartile 1 of serum ascorbic acid, Third National Health and Nutrition Examination Survey, 19881994*
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Analyses were conducted in separate strata for potential effect modifiers. Associations were not consistent across race or treatment groups. There was a borderline significant interaction by race (p for interaction = 0.09) and treatment group (p for interaction = 0.02). For non-Hispanic Blacks and Mexican Americans, the risk of retinopathy was lower in quartile 4 compared with quartile 1, but the association was statistically significant only among Mexican Americans (table 2). Additionally, the association between serum ascorbic acid and retinopathy was inverse, albeit not statistically significant, among persons who used oral hypoglycemics or insulin for glycemic control (table 2 ).
Serum
-tocopherol and diabetic retinopathy
Distributions of risk factors by level of serum
-tocoph-erol
Participants in quartile 4 for serum
-tocopherol were more likely be non-Hispanic White, past smokers, and supplement users compared with participants in quartile 1 for serum
-tocopherol (table 1). Participants in quartile 4 for serum
-tocopherol were also more likely to have greater serum ascorbic acid, triglyceride, and cholesterol concentrations and greater intake of dietary fiber than participants in quartile 1 for serum
-tocopherol (table 1).
Relations of serum
-tocopherol to retinopathy
The crude overall odds ratio for retinopathy among persons in high versus low serum
-tocopherol quartile ranges was direct (odds ratio = 2.2, 95 percent confidence interval: 1.4, 3.6). Adjustment for confounders did not change the direction but slightly increased the magnitude of this association (table 3). After removal of supplement users of vitamin E (n = 298), the adjusted relation was attenuated (table 3).
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TABLE 3. Odds ratios and 95% confidence intervals for prevalent diabetic retinopathy among participants aged 40 years or older with type 2 diabetes in quartiles 24 compared with quartile 1 of serum -tocopherol, Third National Health and Nutrition Examination Survey, 19881994*
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There was a statistically significant interaction of the relation of serum
-tocopherol to retinopathy by treatment type (p for interaction = 0.009) and also by level of glycosylated hemoglobin (p for interaction = 0.003). The odds ratios were slightly attenuated in persons using insulin or oral hypoglycemic agents to control their blood sugar (table 3). Stratification by glycosylated hemoglobin resulted in attenuation of the odds ratio in the direction of the null in persons with poor glycemic control (glycosylated hemoglobin,
7 percent) and strengthening of the association in persons with good glycemic control (glycosylated hemoglobin, <7 percent) (table 3).
Supplements of vitamins C and E and diabetic retinopathy
The relation between the odds of prevalent retinopathy and duration of supplement use containing vitamin C or E was investigated (table 4). There was no relation between reti-nopathy and supplement use of either nutrient for a period from 1 to less than 5 years. The relation between supplement use of vitamins C and E for at least 5 years was directly related to the risk of diabetic retinopathy, but it was not statistically significant.
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TABLE 4. Adjusted odds ratios and 95% confidence intervals for prevalent diabetic retinopathy among participants aged 40 years or older with type 2 diabetes (n = 930) by duration of use of supplements containing vitamin C or E, Third National Health and Nutrition Examination Survey, 19881994*
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DISCUSSION
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Although we hypothesized that those participants in the highest, compared with the lowest, quartile of serum ascorbic acid would have less prevalent retinopathy, we found no such overall association. We may have failed to find a protective effect of ascorbic acid on retinopathy because people at a higher risk for retinopathy may have begun to use supplements subsequent to the development of retinopathy. This could have masked a potential inverse association. In support of this, the overall association was reversed after supplement users of vitamin C were excluded from analyses, and use of supplements containing vitamin C for longer than 5 years was directly related to retinopathy (albeit not significantly).
Serum measurements reflect recent dietary intake (within the last few weeks) and not a persons exposure over the course of a year or many years. This may contribute to random measurement error of ascorbic acid exposure, reducing the ability to observe a statistically significant protective relation of serum ascorbic acid. Perhaps, the primary window of exposure for the development of retinopathy occurs earlier then what was detected by our studys measurements. If a person had made dietary changes as a result of diabetic complications prior to 1988, this would not have been reflected in the single measurements of serum ascorbic acid collected in NHANES III. Conclusions from other studies of diet and age-related eye disease have shown that assessment of past dietary intake, or intake prior to incident disease, may be more influential then recent dietary intake on eye disease development (42, 43).
Data from supplementation trials, in vitro studies, and animal models suggest that ascorbic acid may protect against retinopathy (27, 1417, 21, 22). Despite direct associations with serum ascorbic acid and retinopathy, further analyses indicated that this association did not persist within subgroups of this sample. There was no association between serum ascorbic acid and retinopathy among non-Hispanic Whites, and the odds ratios for retinopathy were less than 1.0 among non-Hispanic Blacks and Mexican Americans. When the NHANES III sample weights were applied to the analyses, the non-Hispanic White subgroup, which was not oversampled in NHANES III, was given a greater amount of weight in the overall weighted analyses. This may have resulted in the overall direct association, although not statistically significant relation, observed between serum ascorbic acid and diabetic retinopathy.
Contrary to our hypothesis, we observed a direct overall association between serum
-tocopherol and retinopathy. Similar to the results of the serum ascorbic acid analyses, the direct association found between serum
-tocopherol and retinopathy was attenuated after exclusion of supplement users of vitamin E. The recent use of vitamin E supplements for treatment of complications of diabetes may have resulted in the positive association reported. At the same time, long-term supplement use of vitamin E was directly, although not significantly, associated with retinopathy. Thus, the direct association with vitamin E may reflect the earlier presence of diabetic complications or other characteristics of persons using vitamin E supplements.
The statistically significant, direct relation between serum
-tocopherol and retinopathy was not consistent across treatment groups. This interaction was probably driven by the direct relation between serum
-tocopherol and retinopathy in the dietary treatment group, which had too few cases to report a stable risk estimate. There was no statistically significant relation between serum
-tocopherol and retinopathy in persons who used insulin or oral hypoglycemic agents.
Some studies have found diet to be protective against retinopathy in only those persons with poor glycemic control (44) (A. E. Millen, University of Wisconsin-Madison, unpublished manuscript). For this reason, we stratified our analyses by glycemic control. We did not observe an inverse association in those persons with poor blood glycemic control (glycosylated hemoglobin,
7 percent), but the direct relation between
-tocopherol and retinopathy was attenuated in this subgroup. We observed a direct association in those persons with good blood glycemic control (glycosylated hemoglobin, <7 percent), but the small number of cases in this subgroup may have prevented us from determining a stable estimate of the relation of
-tocopherol to retinopathy.
To date, this is only the second epidemiologic study investigating the relations between diabetic retinopathy and antioxidant nutrients. The San Luis Valley Diabetes Study investigated the relation between antioxidant intake and the risk of severity of retinopathy among participants with type 2 diabetes (31). Mayer-Davis et al. found a statistically significant risk for increased severity of retinopathy with increasing levels of ascorbic acid intake over time and an increased risk of retinopathy with increasing intake of vitamin E in participants not using insulin. The San Luis Valley Study was unable to explain the observed direct associations between antioxidant intake and retinopathy; however, they used only a 24-hour recall, which is not reflective of long-term dietary intake. Clearly, both the present study and the San Luis Valley Study are limited by their cross-sectional design that can be problematic when analyzing relations of conditions that develop over the long term.
Our analyses may have been biased by the exclusion of those persons with missing data who were identified to have type 2 diabetes. These persons were older with a longer duration of diabetes and were therefore at a greater risk of retinopathy. Their exclusion may have diminished our ability to detect an association if one exists. Additionally, our sample size would have been larger if persons from the afternoon or evening sample of NHANES III had been more accurately diagnosed with diabetes (45). Overall, this study was limited by statistical power (e.g., power to detect an odds ratio of 0.60 in quartile 4 for retinopathy = 80 percent), with power diminishing in stratified analyses.
In summary, we observed no relation between serum ascorbic acid or
-tocopherol and retinopathy in NHANES III. The large body of evidence that indicates a potential for protection in animal studies and short-term supplementation trials is inconsistent with the sparse epidemiologic data to date. Inconsistent results across population subgroups in this study, as well as insufficient statistical power to evaluate relations in subgroups, indicate the need to further evaluate these associations in large prospective studies.
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ACKNOWLEDGMENTS
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This research is supported by National Institutes of Health grant EY11722 (J. Mares) and, in part, by the Research to Prevent Blindness.
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NOTES
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Reprint requests to Dr. Julie A. Mares, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 405 WARF, Madison, WI 53705-2397 (e-mail: jmarespe{at}facstaff.wisc.edu). 
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