ANTIOXIDANTS AND DIABETES MELLITUS
P. Knekt and A. Reunanen. National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland.
1 INTRODUCTION Autoimmune destruction of pancreatic beta cells leads to insulin dependent diabetes mellitus (IDDM). Oxygen-derived free radicals play an important role in the destruction process.' Nitroso compounds have been shown to be toxic to beta cells in animals2 Accordingly, vitamin E, which is a free radical scavenger and blocker of nitrosamine formation, may provide protection against IDDM. Pharmacological doses of vitamin E have been shown to reduce insulin re~istance,~ which plays a leading role in the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM). The hypothesis that vitamin E status predicts the occurrencc of IDDM and NIDDM was studied in a prospective population study. 2 POPULATIONS AND METHODS
Both the IDDM study and the NIDDM study5 were carried out as case-control studies nested within a cohort of individuals with no previous history of diabetes mellitus at the baseline examination. Under the Sickness Insurance Act, all diabetics needing drug therapy are entitled to reimbursement of drug costs, eligibility for which requires a detailed medical certificate from an attending physician. A central register of all patients receiving drug reimbursement is kept by the Social Insurance Institution. Individuals in the study populations of the present study were linked to that register using the unique social security code assigned to each Finnish citizen. The IDDM study was based on a cohort of 7526 men aged 15-99 years and free from diabetes. During follow-up, from the baseline examination in 1973-1976 to the end of 1994, 19 diabetes cases occurred. The mean age of the diabetes patients was 26 years (range 21-46). Three controls per case were selected by individual matching for sex, age and municipality; thus a total of 57 controls were chosen. The NIDDM study was based on 1427 men and women from 25 communities, 1599 years old and free from diabetes. The population was monitored for occurrence of NIDDM from the baseline in 1968-1972 to the end of 1986. During this period NIDDM occurred in 55 men and 5 1 women. For each diabetes patient two controls were individually matched for sex, age, and municipality. A total of 201 controls were chosen. Serum levels of selenium, a-tocopherol and D-carotene were determined for the cases and controls based on serum samples stored at -20 "C at the baseline examination. Serum levels of a-tocopherol and D-carotene were determined using high performance
Oxidative Stress and Antioxidants in Type II Diabetes
liquid chromatography, and of serum selenium using the direct graphite furnace atomic absorption spectrometric method. The statistical analyses were based on the conditional logistic model. 3 RESULTS High levels of serum a-tocopherol were associated with decreased risk of insulin dependent diabetes mellitus. The mean level in cases was 5.3 mg/l and in controls 6.4 mg/l (p for difference=0.07). The cholesterol-adjusted relative risk of the disease between the highest and lowest tertiles of the a-tocopherol distribution was 0.12 (95 % confidence interval (CI) =0.02-0.85). No association was observed for serum selenium status; the mean levels in cases and controls were 55.4 pg/l and 55.8 @1, respectively. An inverse association was observed between serum a-tocopherol and serum Rcarotene and incidence of non-insulin dependent diabetes mellitus. The relative risks between the highest and lowest tertiles were 0.61 (CI = 0.32-1.15) and 0.45 (CI= 0.22-0.92), respectively. Adjustment for serum cholesterol, body mass index, and smoking abolished the associations, however. The adjusted relative risks were 1.24 (CI=O.54-2.83)for serum atocopherol and 0.98 (CI=O.41-2.36)for pcarotene. Serum selenium was not associated with occurrence ofNIDDM; the mean level for cases was 64.8 @I and for controls 63.6 ~ g / l . 4 CONCLUSIONS The findings corroborated the hypothesis that high vitamin E status provides protection against IDDM. On the basis of this small observational study it is, however, impossible to say whether the association is causal or related to other as yet undefined factors, and thus further epidemiologic studies on this topic are suggested. Our finding of a lower risk of NIDDM in individuals w t h higher levels of serum antioxidants, particularly those with higher levels of serum alpha-tocopherol, is in agreement with an earlier finding.6 However, the significance of the reduction disappeared after adjustment for cardiovascular risk factors. Our results therefore do not support the hypothesis that low levels of dietary antioxidants cause NIDDM, but rather suggest that the association is mediated through factors more closely connected with the pathogenesis of NIDDM. References 1. L. W. Oberley, Free Radi. Biol. Med. 1988, 5 , 113. 2. E. Wilander and R. Gunnarsson, Acta Path. Microbiol. Scand. Sect. A . 1975, 83,206. 3. G. Paolisso, A. D’Amore, D. Giugliano, A. Ceriello, M. Varricchio and F. D’Onofrio, Am. J. Clin. Nutr. 1993, 57,650. 4. P. Knekt, A. Reunanen, J. Marniemi, A. Leino and A. Aromaa. J. Int. Med. 1998, 244, (in press). 5. A. Reunanen, P. Knekt, R-K. Aaran and A. Aromaa, Eur. J. Clin. Nutr. 1998,52, 89. 6. J. T. Salonen, K. Nyyssonen,T-P. Tuomainen, P. H. Maenpaa, H. Korpela, G. A. Kaplan, J. L. Lynch, S. P. Helmrich and R. Salonen, Br. J. Med. 1995,311, 1124.