Serial ReviewSelenium and diabetes—Evidence from animal studies
Graphical abstract
Introduction
Selenium (Se) was discovered in 1817 and reported in 1818 by Jöns Jacob Berzelius [1]. It was initially found as a toxic element because of Se poisoning in animals and humans [2]. However, Se deficiency was later shown to be more practically problematic and deleterious or fatal in animals [3], [4] and humans [5]. In 1957, Se was recognized as an essential nutrient for animals [6] and 15 years later cellular glutathione peroxidase (GPx1)1 became the first identified Se-dependent enzyme [7], [8]. Another landmark of Se biology was seen in 1996 when Clark and colleagues reported a striking effect of Se supranutrition on decreasing mortality of three types of human cancers [9].
Diabetes mellitus is one of the most costly chronic diseases, with an estimated worldwide prevalence of 366 million in 2011 and an expected rise to 552 million by 2030 [10]. In 2007, the prevalence of diabetes in the United States was 7.8% [11]. Meanwhile, China has the largest diabetic population in the world, accounting for 92.4 million adults in 2007–2008 [12]. There are four types of diabetes: type 1 diabetes, type 2 diabetes, gestational diabetes, and maturity-onset diabetes of the young. Type 2 diabetes accounts for 90% of all diabetes and is characterized by peripheral insulin resistance, with an insulin-secretory defect that varies in severity. Although mechanisms for insulin resistance and diabetes are not fully understood, a growing body of evidence suggests that oxidative stress plays an important role in both their onset and their progress [13], [14]. Although there was high hope for using antioxidants, including Se, to prevent and treat diabetes and its complications, a number of recent human trials have actually shown an alarming correlation between high Se intake or body Se status and diabetic risk [15], [16], [17], [18], [19], [20], [21]. Before this revelation, overexpression of GPx1, the “oldest” and most abundant Se-dependent protein, was shown to induce type 2 diabetes-like phenotypes in mice [22], [23], [24]. After this initial linking of selenoprotein to glucose and lipid metabolism, several new animal studies have provided compelling evidence and mechanisms for the prodiabetic potential of prolonged high Se intake in various species.
Section snippets
Se as an insulin mimic
Early studies indicated that inorganic Se acted as an insulin mimic [25]. High doses of sodium selenate (0.1 to 10 mM for 10 or 20 min) stimulated glucose uptake in isolated rat adipocytes by enhancing the translocation of glucose transporters to the plasma membrane and activating serine/threonine kinases including p70 S6 kinase [26], [27]. Moreover, sodium selenate also produced dose-dependent stimulation of glucose uptake in dissected skeletal muscle of rats with the maximal response reached at
ROS on islet insulin synthesis and secretion
Compared with liver, islets contain only 1% catalase, 2% GPx1, and 29% SOD1 activities [65], [66], [67]. Accordingly, β cells are considered to be low in antioxidant defenses and susceptible to oxidative stress. In diabetic subjects, β-cell apoptosis seems to be more of a deciding factor than replication in controlling the cell mass compared with control subjects [68]. Thus, maintaining pancreatic islet β-cell mass is recognized as a pivotal protection from pathogenesis of both types 1 and 2
Perspective and conclusion
Feeding mice, rats, and pigs high-Se diets containing 0.4 to 3.0 mg of Se/kg of diet for extended periods of time induced hyperinsulinemia, hyperglycemia, insulin resistance, glucose intolerance, and altered lipid metabolism. This type of effect seems to be independent of the form of Se source, composition of basal diet, and physiological stage. Thus, it is hard to deny a causative relationship between prolonged high Se intakes and prodiabetic potential.
As illustrated in Fig. 1, high Se intake
Acknowledgments
The research conducted by the authors was supported in part by NIH Grant DK53018 (X.G.L.), the National Natural Science Foundation of China (J.Z., Nos. 21001045 and 31270870), and the Fundamental Research Funds for the Central Universities, HUST: No. 2012QN145 (J.Z.).
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