Both Maximal Expression of Selenoproteins and Selenoprotein Deficiency Can Promote Development of Type 2 Diabetes-Like Phenotype in Mice

Abstract

Selenium (Se) is an essential trace element in mammals that has been shown to exert its function through selenoproteins. Whereas optimal levels of Se in the diet have important health benefits, a recent clinical trial has suggested that supplemental intake of Se above the adequate level potentially may raise the risk of type 2 diabetes mellitus. However, the molecular mechanisms for the effect of dietary Se on the development of this disease are not understood. In the present study, we examined the contribution of selenoproteins to increased risk of developing diabetes using animal models. C57BL/6J mice (n = 6-7 per group) were fed either Se-deficient Torula yeast-based diet or diets supplemented with 0.1 and 0.4 parts per million Se. Our data show that mice maintained on an Se-supplemented diet develop hyperinsulinemia and have decreased insulin sensitivity. These effects are accompanied by elevated expression of a selective group of selenoproteins. We also observed that reduced synthesis of these selenoproteins caused by overexpression of an i 6 A -mutant selenocysteine tRNA promotes glucose intolerance and leads to a diabetes-like phenotype. These findings indicate that both high expression of selenoproteins and selenoprotein deficiency may dysregulate glucose homeostasis and suggest a role for selenoproteins in development of diabetes.

Selenoproteins: Molecular Pathways and Physiological Roles

“…Furthermore, these symptoms worsened when animals were subjected to Se deficiency leading to development of obesity and hypercholesterolemia (309). The data suggest that the metabolic perturbations caused by the lack of SCL might be due to defects in selenoprotein synthesis and are in line with the recently observed link between selenoprotein deficiency and disrupted glucose homeostasis in mice (198). It remains to be tested which selenoproteins are most involved in the development of this phenotype in mice lacking SCL.…”

“…In accordance with these observations, the results of several clinical trials that investigated the chemopreventive effects of dietary Se supplementation revealed that increased intake of Se above the nutrient requirements may raise the risk of type 2 diabetes mellitus in humans (222,327). Although the exact mechanism of the diabetogenic effect of high Se intake remains unclear, increased expression of GPx1, SelP, MsrB1, and SelS has been implicated in the development of type 2 diabetes and insulin resistance (198,256,287,382). At least some of these effects could be attributed to diminished intracellular H 2 O 2 levels as a result of high GPx1 activity leading to suppression of insulin signaling and increased insulin secretion, similar to GPx1-overexpressing mice (386).…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…Further, transgenic mice overexpressing Gpx1 developed a type-2 diabetes-like phenotype characterized by insulin resistance, hyperglycemia, hyperinsulinemia, and obesity (161). In fact, perturbing the axis of selenoprotein expression toward either deficient or over-expressed levels may dysregulate glucose homeostasis and promote the development of diabetes (139).…”

Deletion of Selenoprotein M Leads to Obesity without Cognitive Deficits

“…Conversely, mice with a targeted deletion of another selenoprotein gene, the type 2 deiodinase (Dio2), were observed to have increased adiposity and to be less responsive to insulin stimulation in comparison with wild-type mice (20). Also, studies on transgenic mice in which selenoprotein expression was reduced by overexpression of a mutant i 6 A Ϫ selenocysteine tRNA revealed impaired glycemic control and increased insulin levels in these mutant mice relative to controls (21). Recent findings in this laboratory have documented that mice lacking selenocysteine lyase, an enzyme involved in cellular selenium recycling, exhibit diminished selenoprotein expression and develop metabolic syndrome when fed a low selenium diet (22).…”