Vitamin C Supplement Survey Question Articles & Resources

At the baseline survey between 1993 and 1998, men and women 45-74 years of age were identified from general practice patient lists and were invited to participate in the study Subjects who volunteered completed a detailed health and lifestyle questionnaire. They were asked about personal illness with the question "Has the doctor ever told you that you have any of the following?" Options included hypertension requiring treatment with drugs, hyperlipidemia, myocardial infarction, stroke, diabetes (excluding gestational diabetes), and cancer. Family history of diabetes was ascertained by a positive response to the diabetes option of the question "Have any of your immediate family had any of the following conditions?" Subjects recorded the approximate age at which diabetes first occurred in their mothers, fathers, and/or siblings.

Smoking history was derived from yes/no responses to the questions "Have you ever smoked as much as 1 cigarette a day for as long as a year?" and "Do you smoke cigarettes now?" The question "Did you have any further education at college or university after you left school?" identified those who had tertiary education.

Subjects were classified as vegetarians if they gave a positive response to the vegetarian option of the question "Do you follow any particular diets?" and as supplement takers if they answered "yes" to the question "Have you taken any vitamin, minerals, or other food supplements regularly during the past year (such as vitamin C, vitamin D, iron, calcium, fish oils, primrose oil, beta carotene, etc.)?" Data on dietary intake of saturated fat, vitamin E, and fiber and on alcohol consumption were obtained from food frequency questionnaires [8,9].

Subjects were asked to choose among four options to describe the type and amount of physical activity involved in their work. These options were sedentary (mostly sitting), standing (mostly standing or walking but no intense physical activity), physical work (handling heavy objects and use of tools), or heavy manual work (very vigorous physical activity). A validation study showed that this question was a valid measure of usual energy expenditure [10]. Subjects also recorded the hours spent each week on leisure-time physical activity during the summer and winter, and the average was calculated [11]

For the purpose of identifying subjects who may have consciously altered their lifestyles, we defined subjects with "known diabetes" as those who reported themselves as either being told by a physician that they have diabetes or who responded positively to the diabetes option of the question "Have you modified your diet in the past year (give reasons)?"

After completing the questionnaire, the subjects were invited to attend the general practice surgery where research nurses performed a health check. Height and weight were measured with subjects in light clothing and with their shoes removed. Height was measured to the nearest cm using a stadiometer. Weight was measured to the nearest 100 g using Salter scales. These were used to calculate the BMI as weight in kilograms divided by height in meters squared. Waist circumference was measured at the smallest circumference between the ribs and iliac crest to the nearest cm, and hip circumference was measured as the maximum circumference between the iliac crest and the crotch to the nearest cm. These measurements were used to calculate the waist-to-hip ratio (WHR).

Consent to have blood taken was obtained from 95% of subjects who had blood taken after the health check. Plasma vitamin C levels were measured from blood drawn into citrate bottles. The blood was stored overnight in a dark box in a refrigerator at 4-7[degrees]C and then spun at 2,100g for 15 min at 4[degrees]C. Plasma was stabilized in a standardized volume of metaphosphoric acid and then stored at - 70[degrees]C. The plasma vitamin C level was estimated using a fluorometric assay within 1 week of sampling [12]. The coefficient of variation was % at the lower end of the range (mean [mu]mol/1) and % at the upper end of the range (mean [mu]mol/1).

Beginning in November 1995, a sample of EDTA-anticoagulated blood was taken for [.1C] measurement. The blood was stored in a refrigerator at 4-7[degrees]C until it was transported at an ambient temperature within a week of sampling to be assayed. The [.1c] assays were carried out using high-performance liquid chromatography (HPLC) on a Bio-Rad Diamat (Richmond, CA) [13]. The coefficient of variation was % at the lower end of the range (mean %) and % at the upper end of the range (mean %).

Statistical analysis

Subjects who had completed the health and lifestyle questionnaire and health check, had given blood for [.1C] determinations and vitamin C measurement, and had complete data entry by July 1998 formed the study population. Of the 10,242 subjects recruited after November 1995, 6,596 met these criteria. This population was divided into 3 groups: self-reported diabetes (physician diagnosis or dietary modification because of diabetes), prevalent previously undiagnosed hyperglycemia ([.1c] [geq]7% and no treatment for diabetes), and others (classified as having normal glucose tolerance [.1c] [less than]7% and no history of diabetes]). A cutoff point of 7% was chosen because only 4% of individuals would be misclassified as having normal glucose tolerance above this level [14]. Comparisons were made separately for the sexes among the 3 groups for plasma vitamin C, [.1C], and possible confounding factors. The subjects were then divided into quintiles based on plasma vitamin C level after ex cluding those with self-reported diabetes. Comparisons were made separately for men and women using common quintiles.

Statistical analysis was performed using SAS Version (SAS Institute, Cary, NC). Significance testing was done using analysis of variance (ANOVA) with a post-ANOVA test comparison for means and the [[chi].] test for proportions. A value of P [less than] was used for statistical significance. The risk of prevalent undiagnosed hyperglycemia was analyzed using logistical regression. Adjustment for possible con-founders of the association between plasma vitamin C and [.1C] was performed using linear regression.

RESULTS -- We present data on all 2,898 men and 3,560 women who comprised 98% of the subjects who were recruited to the EPIC-Norfolk study between 1995 and 1997 and had complete data available by July 1998. Data on [.1C] measurement were missing in 138 (2%) subjects. No differences were evident regarding age, BMI, and plasma vitamin C level between the population defined for this analysis and the entire EPIC-Norfolk cohort (P [greater than] for each variable).

The distribution of variables by glycemic status is shown in Table 1. Of the 176 individuals classified as having self-reported diabetes, 137 reported having a physician's diagnosis, and 39 indicated that they had modified their diets as a result of diabetes without reporting a physician's diagnosis of diabetes. Of these 39 individuals, 28 reported that they were taking medication for diabetes or had an [.1C] level [geq] 7%. Subjects with self-reported diabetes or an [.1C] level [geq] 7% were significantly older and heavier than their counterparts who were classified as normoglycemic. Mean plasma vitamin C levels were significantly higher in men and women with an [.1C] level 7% than in subjects with self-reported diabetes or an [.1C] level [geq] 7% (P [less than] ). Among women, vitamin C levels were similar in subjects with self-reported diabetes compared with subjects with undiagnosed hyperglycemia. In men with undiagnosed hyperglycemia, vitamin C levels were lower than in men with self-reported diabetes, but this difference was not statistically significant (P = ). After adjusting for covariates (Table 1) in men and women, the difference in mean plasma vitamin C concentrations between normoglycemic and hyperglycemic subjects remained significant (P = men, P [less than] women).

Women with an [.1C] level [less than] 7% were significantly more likely to take supplements than women with hyperglycemia (P = ). No significant differences were noted in men (P = ). Men and women with self-reported diabetes were less likely to be current smokers, but the differences were not statistically significant (P = men, P = women). Women with self-reported diabetes were more likely to be sedentary than women with an [.1C] level [less than]7% (P = ).

When the subjects with an [.1C] level [less than]7% were divided into quintiles of [.1C] distribution, a gradient was found in mean plasma vitamin C levels in both men and women. Subjects in the lowest quintile of [.1c] level had the highest mean plasma vitamin C levels, and subjects in the highest quintile of [.1c] level had the lowest mean plasma vitamin C levels. The means were significantly different across quintiles in both sexes (P = ) (Fig. 1).

The relationship between [.1c] and plasma vitamin C levels with possible confounding factors is shown in Tables 2 and 3 for men and women, respectively. The distribution of these factors across the quintiles of plasma vitamin C concentration was similar in both sexes. Subjects in the lowest quintile of plasma vitamin C level had the highest mean [.1c] level but were also older and heavier than subjects in the highest quintiles. Subjects in the lowest quintile were the most likely to be current smokers and the least likely to take supplements.

Prevalent undiagnosed hyperglycemia (n = 74) was the dependent variable in logistical regression, and subjects with self-reported diabetes were excluded from the analysis. An increase of 20 [mu]mol/l (or 1 SD) in plasma vitamin C level (approximately equivalent to 1 orange daily) was associated with a reduction in the risk of having prevalent undiagnosed hyperglycemia. The odds ratio (95% CI) was (.95) and was independent of sex, age, BMI, supplement taking, smoking history, a vegetarian diet, physical activity, alcohol consumption, dietary vitamin E, dietary fiber, and dietary saturated fat.

The association between [.1c] and plasma vitamin C was further investigated with linear regression. An inverse relationship was found in both men and women and was demonstrated in all subgroups analyzed. The unadjusted change in [.1c] per 20-[mu]mol/1 increase in vitamin C was % ( to ) in men and % ( to ) in women. After adjusting for the possible confounders, these values were % ( to ) in men and % ( to ) in women.

CONCLUSIONS -- Our findings in this study confirm the observation that subjects with diabetes have lower plasma vitamin C levels than subjects without diabetes. We also demonstrated reduced plasma vitamin C levels in subjects who were likely to have undiagnosed diabetes. These results are not likely because of chance and support the hypothesis that the association between diabetes and vitamin C is not because of behavioral or dietary change resulting from the diagnosis. In addition, we demonstrated an inverse relationship between plasma vitamin C and [.1c] levels in both men and women. This association was independent of age, BMI, WHR, educational status, supplement taking, smoking history, alcohol consumption, physical activity, dietary vitamin E, dietary fiber, dietary saturated fat, and self-reported vegetarianism.

We chose a sensitive definition of diabetes to exclude individuals who may have changed their behavior and diet as a result of having diabetes. Although no validation of the diagnoses was done, subjects were recruited through general practices, and therefore a report of physician-diagnosed diabetes is likely to be correct. Of the subjects who reported only modifying their diet because of diabetes, 72% were also taking diabetic medication or had an [.1c] measurement [greater than]7%.

The EPIC-Norfolk study was designed as a prospective cohort study and was not primarily intended to give reliable population prevalence estimates. The planned analysis aimed to examine comparisons within the cohort cross-sectionally and over time [8]. Nevertheless, the distributions of BMI and blood pressure are similar to those from nationally representative samples [8,15]. The within-population associations are not likely to be because of selection bias.

Seasonality could be a possible confounder because seasonal trends have been described with various measures of glucose tolerance [16,17]. However, we found no seasonal trend in [.1c] in our study. Dietary intake of vitamin C may be one of the mediators of the social class gradient sometimes observed for diabetes [18-21]. Consequently social class may be causally related to plasma vitamin C and therefore not a true confounder. Physical activity was not found to be an important confounder in this study However, we cannot exclude the possibility of residual confounding resulting from measurement error in the assessment of this variable and in the assessment of dietary variables.

Another possibility is that the relationship results from interference by vitamin C on the assay of [.1c] [22]. Weykamp et al. [23] investigated the effect of vitamin C supplementation for 12 weeks on the assay of glycosylated hemoglobin using 4 methods: HPLC, electrophoresis, affinity chromatography, and immunoassay. They concluded that no interference occurred in the assay and that vitamin C did not affect in vivo glycosylation of hemoglobin.

Some researchers have postulated that diabetes may result in decreased plasma vitamin C [4] through several mechanisms, including loss of vitamin C in the urine [24,25] and increased oxidative stress [26,27]. However, in this study we found a gradient of mean plasma vitamin C levels across quintiles of subjects who are not likely to have diabetes with no apparent threshold. The relationship therefore seems to exist even in nondiabetic individuals. This suggests that vitamin C may protect against impaired glucose regulation. Support for this hypothesis comes from a study by Feskens et al. [28] in which past dietary intake of vitamin C was inversely related to 2-h plasma glucose levels at 20-year follow-up in Finnish and Dutch men. Frequent consumption of salad vegetables (a source of dietary vitamin C) was found to decrease risk of type 2 diabetes in another population-based study [29].

Will et al. [30] found that serum vitamin C concentrations were lower in subjects with newly diagnosed diabetes than in subjects without diabetes. After adjusting for covariates including dietary intake of vitamin C, the difference was no longer significant. An important difference between the groups was that subjects who did not develop diabetes had a much higher mean intake of supplemental vitamin C than subjects who developed diabetes. This result is consistent with a protective role of vitamin C intake on the risk of diabetes.

Dietary vitamin C is a determinant of serum vitamin C concentration. Serum or plasma vitamin C reflects short-term vitamin C intake but also is positively correlated with the habitual intake of fresh fruit and vegetables [31]. When Will et al. [30] adjusted for dietary vitamin C in their study they may have attenuated the relationship between serum vitamin C and diabetes because dietary vitamin C and serum vitamin C are causally related.

Vitamin C may act as a marker of some other dietary or lifestyle factors that are protective against diabetes [31]. Nevertheless, oxidative stress is known to impair insulin action [32,33], and vitamin C may play a role in ameliorating insulin resistance because of its antioxidant function [34]. A population-based study did not find an association between dietary intake of vitamin C and vitamin E as assessed by food frequency questionnaire and insulin sensitivity [35]. This maybe because of the measurement error in the assessment of dietary intake thus attenuating the true effect [9]. In contrast, Salonen et al. [36] found that low plasma vitamin F levels were associated with an increased risk of type 2 diabetes after 4 years of follow-up in a prospective study of Finnish men.

Reducing free radical damage to [beta]-cells (37,38) may be another mechanism by which vitamin C protects against diabetes. Vitamin C was found in to be important for insulin secretion in animal studies [39,40], and further research may uncover a similar role in humans. In the presence of diabetes, vitamin C is potentially important in reducing complications mediated through free radical damage from auto-oxidation of glucose and glycosylation of structural proteins [41].

Microvascular complications of diabetes are associated with the concentration of glycosylated hemoglobin (42,43). If vitamin C is indeed protective (and this will require confirmation by longitudinal studies and randomized controlled trials), then it is of considerable clinical and public health importance. We found that an increase in plasma vitamin C levels of 20 [mu]mol/l was associated with a reduction in the risk of undiagnosed hyperglycemia by almost one-third. This increase in plasma vitamin C is achievable by dietary means and would be another benefit of increased regular intake of fresh fruit and vegetables (44-47). Such an intervention could be an effective prevention strategy in individuals at high risk for developing diabetes.

Acknowledgments -- The cohort of EPIC-Norfolk is supported by grant funding from the Cancer Research Campaign, the Medical Research Council, the Stroke Association, the British Heart Foundation, the Department of Health, the Europe Against Cancer Programme Commission of the European Union, and the Ministry of Agriculture, Fisheries and Food. .W. is an Medical Research Council Clinician Scientist Fellow.

We thank the staff members of EPIC for their invaluable contributions and Terry Elsey and colleagues of the University of Cambridge Department of Clinical Biochemistry who performed blood assays. We are indebted to the general practitioners who allowed us to approach the patients on their lists and to the people of Norfolk who took part in this study.

From the Department of Community Medicine (.S., .W., ., .D., .L., ., ., .K.), University of Cambridge, Institute of Public Health; and the Medical Research Council Dunn Human Nutrition Unit (.),. Cambridge, .

Address correspondence and reprint requests to Lincoln A. Sargeant, DM, EPIC-Norfolk, University of Cambridge, Institute of Public Health, Strangeways Research Laboratory Wort's Causeway, Cambridge CB1 8RN, . E-mail: ..

Received for publication 4 August 1999 and accepted in revised form 15 February 2000.

Abbreviations: ANOVA, analysis of variance; EPIC-Norfolk, European Prospective Investigation Into Cancer--Norfolk; HPLC, high-performance liquid chromatography; WHR, waist-to-hip ratio.

A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion factors for many substances.

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