In this representative cross-sectional study of the U.S. population conducted in 2003–2004, high serum selenium concentrations were associated with a higher prevalence of diabetes, as well as with higher fasting plasma glucose and glycosylated hemoglobin levels. These data are consistent with the previous observation of an increased risk of diabetes with high selenium concentrations in NHANES III, conducted in 1988–1994 (Bleys et al. 2007
). From 1988–1994 to 2003–2004, however, serum selenium concentrations among U.S. subjects ≥ 40 years of age increased from 125.8 μg/L (95% CI, 124.1–127.6 μg/L) in NHANES III (n
= 9,085) to 136.6 μg/L (134.4–138.7 μg/L) in NHANES 2003–2004 (n
= 2,903). This increasing trend in serum selenium levels highlights the importance of understanding the association between serum selenium levels and diabetes. Moreover, the NPC trial—a randomized, double-blind clinical trial to evaluate the efficacy of selenium supplementation (200 μg/day) for the prevention of cancer—showed an increased risk of diabetes after 7.7 years of follow-up (hazard ratio, 1.50; 95% CI, 1.03–2.33) comparing selenium supplementation with placebo (Stranges et al. 2007
). Interestingly, the excess risk of diabetes with selenium supplementation in the NPC trial was restricted to participants in the highest tertile of plasma selenium at baseline (> 121.6 μg/L). More recently, SELECT, a large randomized clinical trial to evaluate the efficacy of selenium supplements (200 μg/day) on prostate cancer prevention, found more cases of diabetes in the group taking only selenium compared with placebo (relative risk, 1.07; 99% CI, 0.94–1.22; p
= 0.16) but not in the selenium plus vitamin E group (relative risk, 0.97; 99% CI, 0.85–1.11; p
= 0.62) (Lippman et al. 2009
The high soil content of selenium in several areas of the United States and the use of supplements (Rayman 2008
) explain the high mean selenium concentration in our sample (137 μg/L). This level is high compared with selenium needs for optimizing selenoprotein synthesis and activity (Institute of Medicine and Panel on Dietary Antioxidants and Related Compounds 2000
) and relative to selenium levels in other populations (Rayman 2008
). Glutathione peroxidases synthesis plateaus above serum selenium levels of 70–90 μg/L (Combs 2001
). Above this threshold, serum selenium levels do not correlate with glutathione peroxidase activity or with mRNA synthesis for a variety of selenoproteins, but reflect variation in selenomethionine that is incorporated nonspecifically in serum proteins, mainly in albumin (Institute of Medicine and Panel on Dietary Antioxidants and Related Compounds 2000
), with unknown physiologic activity. Because only one participant in our sample had serum selenium levels < 90 μg/L, variability in serum selenium levels is unlikely to reflect underlying variation in selenoprotein levels.
Many other countries, including most of Europe, have substantially lower serum selenium levels (mean values < 100 μg/L) (Rayman 2000
), mainly due to poorer soil content, so our findings may not extrapolate to them. In an observational analysis of the Supplementation with Antioxidant Vitamins and Minerals trial (SU.VI.MAX) conducted in France, plasma selenium concentration at baseline (mean, 87 μg/L) was positively associated with fasting plasma glucose at baseline and after 7.5 years of follow-up (Czernichow et al. 2006
). However, no differences in fasting glucose levels were found in the randomized component of the trial, comparing a multivitamin supplement that included 100 μg/day of selenium versus placebo over the follow-up (Czernichow et al. 2006
). In a cross-sectional analysis of the French Etude du Viellissement Artérial (EVA), Coudray et al. (1997)
found no statistically significant correlations between plasma selenium (mean, 87 μg/L) and fasting plasma glucose or diabetes prevalence. Finally, a small cross-sectional study of Asian persons residing in Singapore also found similar mean serum selenium levels among participants with and without diabetes (Hughes et al. 1998
An excess of reactive oxygen species may increase insulin resistance and affect pancreatic β-cell function (Houstis et al. 2006
), and some selenium compounds such as selenite and methylselenol (a metabolite of selenomethionine) (Rayman 2005
) can induce oxidative stress (Drake 2006
; Spallholz 1994
; Spallholz et al. 2004
). However, whereas substantial attention has been paid to explain the mechanisms for a potential benefit of increasing serum selenium in low-selenium intake populations, the mechanistic explanation for the effects of selenium above the levels required to maximize glutathione peroxidase activity is largely unexplored. Further experimental and epidemiologic research is needed to explain the mechanisms underlying the observed associations between high selenium exposure and cardiometabolic risk factors.
Higher selenium concentrations were associated with some diabetes risk factors such as increasing age. In contrast, selenium concentrations decreased with higher BMI, which is one of the stronger diabetes risk factors. The associations of selenium and diabetes reported were adjusted for these risk factors, reducing the possibility that the association between selenium and diabetes is driven by differences in established diabetes risk factors across selenium levels.
The strengths of our study come from the rigorous sampling design, the quality of the study measurements, and the representativeness of the NHANES sample. Among its limitations, the cross-sectional design restricts our ability to evaluate the temporality of the observed association. It is possible that high serum selenium levels are related to body weight. Nevertheless, the observed association persisted after adjusting for BMI as well as for use of multivitamin/mineral supplements. The use of a single measurement of serum selenium may not reflect completely the known high within-person variability (Longnecker et al. 1993
) and does not provide information on selenium metabolism. A cross-sectional analysis of a subsample of the Health Professionals Follow-up Study found an inverse association between toenail selenium levels and the prevalence of diabetes (Rajpathak et al. 2005
). Serum and toenail selenium are both biomarkers of selenium intake but are likely to reflect different selenium compartments. Toenail selenium could represent a longer trend of selenium intake than serum selenium, but there are no data supporting the grounds of their differences. More detailed analysis of different selenoproteins and related activities are needed to better understand the association of selenium with diabetes.