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Selenium: Supplementation and Type 2 Diabetes Mellitus
By Mary Hardy, MD
Source: Stranges S, et al: Effects of long-term selenium supplementation on the incidence of type 2 diabetes. Ann Intern Med. 2007;147:217-223.
Goal: to assess the effect of long-term selenium supplementation on the incidence of new onset type 2 diabetes mellitus (DM).
Study Design: Secondary analysis of a randomized, double-blind, placebo-controlled trial (part of the Nutritional Prevention of Cancer, or NPC, trial) during its blinded phase.
Subjects: People with a history of nonmelanoma skin cancer in the year prior to randomization, but without DM at baseline, seen in dermatology clinics in locales where selenium consumption is low (average daily dietary intake = 90 µ; analysis on n = 1,202 with a valid selenium value obtained within 4 days of date of randomization, n = 600 receiving selenium).
Methods: Subjects were randomized to receive either a placebo tablet containing yeast or 200 m selenium from high-selenium baker's yeast tablets. Baseline evaluation included collection of demographic information, anthropometric data and behavioral characteristics. Biannual evaluations were subsequently held during which changes in clinical status were documented and blood samples were obtained. Individual medical records were reviewed periodically. An initial report of DM came from 3 possible sources: self-report during the clinical interview, reported use of drugs for DM, and medical records. For analytical purposes, plasma selenium levels were divided at tertiles and at the median level.
Results: Over an average follow-up of 7.7 years, a total of 97 new cases of Type 2 DM were diagnosed, with a higher cumulative incidence in the selenium group (n =58, hazard ratio = 1.55). The risk for type 2 DM was consistently higher across all subgroups for those taking selenium, except in the highest tertile of body mass index, where no difference between groups was identified. A significantly increased risk for Type 2 DM was found for those subjects whose baseline selenium levels were higher than the median value (hazard ratio = 2.50). An exposure-response gradient was found across all tertiles of baseline plasma selenium level, with a significantly increased risk for Type 2 DM in the top tertile (hazard ratio = 2.70). When results were stratified according to behavioral and anthropometric covariates, lack of benefit with selenium supplementation persisted.
Conclusion: Long-term selenium supplementation at a dose of 200 µ/d does not prevent Type 2 DM, but may instead adversely affect glucose metabolism, and increase risk for the disease.
Study strengths: Sample size; no participants lost to follow-up; selenium content of each batch of pills was determined in laboratories; review of diagnostic documentation.
Study weaknesses: Diabetes was a secondary outcome of the original trial, and conclusions were based on exploratory analyses; self-reported diagnosis of DM; lack of generalizability (most participants were older Caucasian men — non-whites were excluded); as the authors note, lack of detailed information on unmeasured risk factors (eg, family history).
Of note: The goal of the NPC trial was primarily to determine whether selenium supplementation offered benefits with respect to cancer prevention; insulin resistance, impaired glucose tolerance, and Type 2 DM are all linked to oxidative stress, and observational data suggest that dietary or plasma antioxidants protect against development of Type 2 DM; however, the few clinical trials of antioxidant supplementation to help prevent Type 2 DM or its complications have produced negative results; the data assessed in this paper are at least 16 years old; for inclusion, participants had to have a life expectancy of least five years and no history of internal cancer over the prior five years; non-white persons were excluded because the trial focused on the effects of selenium on nonmelanoma skin cancer, theoretically controlling for the effects of skin pigmentation on cancer recurrence risk; the incidence of DM in this trial mirrors that found in other studies of mainly white subjects; some data suggest that selenium may help prevent non-skin cancers, but recent research does not support a significant role for selenium with respect to cardioprotection.
We knew that: The majority of multivitamin and mineral supplement products contain 30-200 µ of selenium; findings from animal models suggest that low-dose selenium supplementation improves glucose metabolism, while the effects of high-dose selenium supplementation remain unclear; both in vivo and in vitro studies suggest that selenium mediates many insulin-like actions, thereby enhancing insulin sensitivity; some data suggest that people with DM are relatively deficient in selenium, and that selenium may help prevent vascular complications in people with DM; the SU.VI. MAX study showed no benefit on fasting blood glucose levels from antioxidant supplementation that included selenium (100 µ) over 7.5 years of follow-up, however longitudinal analysis of the relationship between baseline plasma selenium antioxidants and fasting blood glucose revealed a statistically significant association.
Comments: Selenium's importance in human health continues to be explored and debated. It plays a role in maintaining immunity and proper thyroid function, and there have been high hopes for selenium supplementation as a cancer chemopreventive agent, and as an aid in other endocrinologic realms, most notably DM. As regards to the latter, animal data provided reason for optimism, but other research contradicts positive experiments. The current study brings up concerns of selenium actually increasing the risk of DM.
Unless a person suffers from significant gastrointestinal disease or requires total parenteral nutrition, most people in the United States have adequate, though perhaps not optimal, selenium levels. Trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) will help clarify matters regarding selenium supplementation, but results are not expected until 2013.
The conclusions of this study raise real concerns, but methodological limitations severely limit generalizability. It is far too early in this story to start lobbying for the removal of selenium supplements from store shelves, and benefits may yet be identified. Until more is known, no action need be taken, but consideration could be given to lessening supplemental selenium for those at high risk of developing DM.
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