Epidemiology of selenium and type 2 diabetes: Can we make sense of it?

Highlights

• There is a clear link between certain selenoproteins and glucose metabolism.

• In vivo and in vitro studies have shown antidiabetic effects of inorganic selenium.

• In observational studies, high selenium exposure is associated with type 2 diabetes.

• Results of randomized controlled trials from posthoc analyses have been inconsistent.

• The relationship between selenium and type 2 diabetes is undoubtedly complex.

Abstract

The potential of some selenoproteins to protect against oxidative stress led to the expectation that selenium would be protective against type 2 diabetes, and indeed in early in vivo and in vitro studies, selenium (as selenate) was shown to have antidiabetic and insulin-mimetic effects. However, more recently, findings from observational cross-sectional studies have raised concern that high selenium exposure may be associated with type 2 diabetes or insulin resistance, at least in well-nourished populations, though trial results have been inconsistent. Moreover, the largest trials that investigated the effects of selenium supplementation on diabetes endpoints have had cancer prevention as their primary outcome, casting doubt on the interpretation of posthoc analyses. Factors affecting serum/plasma selenium are not just location and level of disease-associated inflammation but the fact that higher concentrations of plasma selenoprotein P yet lower concentrations of glutathione peroxidase are found in type 2 diabetic patients than in normal subjects. From a public health perspective, selenium is marketed as a dietary supplement and is commonly added to multivitamin/mineral preparations that are consumed in many Western countries. Based on current evidence, however, the indiscriminate use of selenium supplements in individuals and populations with adequate-to-high selenium status cannot be justified and may increase risk. In conclusion, although there is a clear link between certain selenoproteins and glucose metabolism or insulin resistance, the relationship between selenium and type 2 diabetes is undoubtedly complex. It is possible that the relationship is U-shaped, with possible harm occurring both below and above the physiological range for optimal activity of some or all selenoproteins.

Introduction

The trace mineral selenium is essential for human health [1]. As selenocysteine, it is the key component of a number of selenoproteins with essential enzymatic functions that include redox homeostasis, thyroid hormone metabolism, and protection from oxidative stress and inflammation [2].

We know that selenoproteins play a role in certain health conditions because single-nucleotide polymorphisms (SNPs) in a number of selenoprotein genes affect the risk of those conditions. Relevant to the current topic, polymorphisms in selenoproteins have been associated with inflammation and diabetes-related conditions [2], [3]: SNPs in cytosolic glutathione peroxidase (GPx1) have been associated with the risks of metabolic syndrome and macrovascular disease [4], [5]; SNPs in selenoprotein S (SEPS1) have been associated with waist-to-hip ratio, body-mass index, and inflammation [6]; and a SNP in type II iodothyronine deiodinase has been associated with the prevalence of type 2 diabetes and insulin resistance [7], [8], [9].

However, not all selenium in the body is present as selenoproteins; a proportion is present as selenomethionine in body proteins, e.g., in albumin in plasma [1]. Selenomethionine is the main form of selenium in foods, particularly in bread and cereals, and the body incorporates it as if it were methionine, being unable to distinguish between the two [10]. To be able to be utilized for the synthesis of selenoproteins, proteins containing selenomethionine must first be catabolized and the selenomethionine converted to hydrogen selenide (via selenocysteine and the trans-sulfuration pathway) [10].Thus selenomethionine, the form of selenium used in the largest randomized trial to date, cannot be utilized directly.

A proportion of body selenium is also present as low-molecular-weight species, some of which are derived from foods and some of which are products of metabolism [10]. Such species include methylselenocysteine and γ-glutamylmethylselenocysteine (found in some foods and in selenium yeast) [10], [11], [12], both of which can give rise to the unstable, reactive methyl selenol. Methyl selenol, the volatile dimethylselenol, and the trimethylselenonium ion are on the excretory pathway together with various selenosugars, these being the predominant metabolites of dietary selenium [10], [13], [14]. Selenosugars can be recycled to serve as substrates for the production of selenoproteins [15], [16]. Thus, selenoproteins may not be the only characters in the selenium–diabetes story.

The potential of the selenoproteins to protect against oxidative stress led to the expectation that selenium would be protective against type 2 diabetes, and indeed in the 1990s, selenium (as selenate) was shown to have antidiabetic and insulin mimetic effects (see below) [17]. However, more recently, findings from observational epidemiological studies and randomized clinical trials have raised concern that high selenium exposure may lead to type 2 diabetes or insulin resistance, at least in well-nourished populations [18].

The degree to which populations are adequately supplied with a nutrient is more variable for selenium than for many nutrients. Because of wide differences in geology, soil, and climatic factors, foods and fodder from various parts of the world vary greatly in their ability to provide selenium for dietary intake [1], [19]. Thus intake ranges from deficient to excessive in China, is generally low in Europe, is adequate in North America and Japan, and is high in Venezuela [1], [2]. Selenium status—often measured as serum, plasma, or toenail selenium—varies accordingly, reflecting the difference in intake in these locations [2]. Fig. 1 illustrates the difference in selenium status in European countries compared to those of North and South America (e.g., the United States and Venezuela) (adapted from [20]). The fact that Finland has higher selenium status than other European countries reflects the mandated use of selenized fertilizers in Finland since the mid-1980s [21]. The figure also shows the levels of serum/plasma selenium required for maximal activity of plasma glutathione peroxidase (GPx3) [22] and maximal concentration of selenoprotein P (SeP)[23], the latter being the carrier of selenium in the plasma that has shown an association with type 2 diabetes risk (see below). We need to bear these very significant differences in selenium status in mind when interpreting epidemiological data.