Elsevier

Free Radical Biology and Medicine

Volume 65, December 2013, Pages 1548-1556
Free Radical Biology and Medicine

Serial Review
Selenium and diabetes—Evidence from animal studies

https://doi.org/10.1016/j.freeradbiomed.2013.07.012Get rights and content

Highlights

  • Prolonged high Se intake shows a prodiabetic potential in several species.

  • High Se intake dysregulates islet insulin synthesis, secretion, and function.

  • High Se intake affects key regulators of glycolysis, gluconeogenesis, and lipogenesis.

  • Diabetogenic action of high Se intake may be mediated in part by selenoproteins.

  • Selenoproteins regulate body glucose metabolism via redox-sensitive signaling.

Abstract

Whereas selenium was found to act as an insulin mimic and to be antidiabetic in earlier studies, recent animal experiments and human trials have shown an unexpected risk of prolonged high Se intake in potentiating insulin resistance and type 2 diabetes. Elevating dietary Se intake (0.4 to 3.0 mg/kg of diet) above the nutrient requirements, similar to overproduction of selenoproteins, led to insulin resistance and/or diabetes-like phenotypes in mice, rats, and pigs. Although its diabetogenic mechanism remains unclear, high Se intake elevated activity or production of selenoproteins including GPx1, MsrB1, SelS, and SelP. This upregulation diminished intracellular reactive oxygen species and then dysregulated key regulators of β cells and insulin synthesis and secretion, leading to chronic hyperinsulinemia. Overscavenging intracellular H2O2 also attenuated oxidative inhibition of protein tyrosine phosphatases and suppressed insulin signaling. High Se intake might affect expression and/or function of key regulators of glycolysis, gluconeogenesis, and lipogenesis. Future research is needed to find out if certain forms of Se metabolites in addition to selenoproteins and if mechanisms other than intracellular redox control mediate the diabetogenic effects of high Se intake. Furthermore, a potential interactive role of high Se intake in the interphase of carcinogenesis and diabetogenesis should be explored to make optimal use of Se in human nutrition and health.

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.).

References (139)

  • J. Zeng et al.

    Effect of selenium on pancreatic proinflammatory cytokines in streptozotocin-induced diabetic mice

    J. Nutr. Biochem.

    (2009)
  • M. Navarro-Alarcon et al.

    Serum and urine selenium concentrations as indicators of body status in patients with diabetes mellitus

    Sci. Total Environ

    (1999)
  • M. Roman et al.

    Plasma selenoproteins concentrations in type 2 diabetes mellitus—a pilot study

    Transl. Res.

    (2010)
  • J.N. Thompson et al.

    Impaired lipid and vitamin E absorption related to atrophy of the pancreas in selenium-deficient chicks

    J. Nutr

    (1970)
  • A.S. Reddi et al.

    Selenium-deficient diet induces renal oxidative stress and injury via TGF-β1 in normal and diabetic rats

    Kidney Int

    (2001)
  • X. Yan et al.

    Dietary selenium deficiency partially rescues type 2 diabetes-like phenotypes of glutathione peroxidase-1-overexpressing male mice

    J. Nutr.

    (2012)
  • H.R. Rasekh et al.

    Effect of selenium on plasma glucose of rats: role of insulin and glucocorticoids

    Toxicol. Lett.

    (1991)
  • A.S. Mueller et al.

    Redox regulation of protein tyrosine phosphatase 1B by manipulation of dietary selenium affects the triglyceride concentration in rat liver

    J. Nutr.

    (2008)
  • A.S. Mueller et al.

    Regulation of the insulin antagonistic protein tyrosine phosphatase 1B by dietary Se studied in growing rats

    J. Nutr. Biochem.

    (2009)
  • M.S. Zeng et al.

    A high-selenium diet induces insulin resistance in gestating rats and their offspring

    Free Radic. Biol. Med.

    (2012)
  • Y. Liu et al.

    Prolonged dietary selenium deficiency or excess does not globally affect selenoprotein gene expression and/or protein production in various tissues of pigs

    J. Nutr.

    (2012)
  • A. Pinto et al.

    Supranutritional selenium induces alterations in molecular targets related to energy metabolism in skeletal muscle and visceral adipose tissue of pigs

    J. Inorg. Biochem.

    (2012)
  • M. Ayaz et al.

    Selenium-induced alterations in ionic currents of rat cardiomyocytes

    Biochem. Biophys. Res. Commun.

    (2005)
  • S. Lenzen et al.

    Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues

    Free Radic. Biol. Med.

    (1996)
  • P. Maechler et al.

    Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells

    J. Biol. Chem.

    (1999)
  • B. Armann et al.

    Quantification of basal and stimulated ROS levels as predictors of islet potency and function

    Am. J. Transplant.

    (2007)
  • V.P. Bindokas et al.

    Visualizing superoxide production in normal and diabetic rat islets of Langerhans

    J. Biol. Chem.

    (2003)
  • S. Collins et al.

    Uncoupling and reactive oxygen species (ROS)—a double-edged sword for β-cell function? “Moderation in all things.”

    Best Pract. Res. Clin. Endocrinol. Metab

    (2012)
  • M.J. Boucher et al.

    Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms

    J. Biol. Chem.

    (2006)
  • K. Loh et al.

    Reactive oxygen species enhance insulin sensitivity

    Cell Metab.

    (2009)
  • B.A. Carlson et al.

    Specific excision of the selenocysteine tRNA[Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function

    J. Biol. Chem.

    (2004)
  • P. Walter et al.

    Stimulation of selenoprotein P promoter activity in hepatoma cells by FoxO1a transcription factor

    Biochem. Biophys. Res. Commun.

    (2008)
  • B. Speckmann et al.

    Attenuation of hepatic expression and secretion of selenoprotein P by metformin

    Biochem. Biophys. Res. Commun.

    (2009)
  • H. Misu et al.

    A liver-derived secretory protein, selenoprotein P, causes insulin resistance

    Cell Metab.

    (2010)
  • Y. Gao et al.

    Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress—SelS is a novel glucose-regulated protein

    FEBS Lett.

    (2004)
  • P. Whanger et al.

    Metabolism of subtoxic levels of selenium in animals and humans

    Ann. Clin. Lab. Sci.

    (1996)
  • D.C. Moir et al.

    Hepatosis dietetica, nutritional myopathy, mulberry heart disease and associated hepatic selenium level in pigs

    Aust. Vet. J.

    (1979)
  • K. Schwarz et al.

    Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration

    J. Am. Chem. Soc.

    (1957)
  • J.T. Rotruck et al.

    Selenium: biochemical role as a component of glutathione peroxidase

    Science

    (1973)
  • L.C. Clark et al.

    Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study Group

    JAMA

    (1996)
  • National diabetes statistics: 2007 fact sheet

    (2008)
  • W. Yang et al.

    Prevalence of diabetes among men and women in China

    N. Engl. J. Med.

    (2010)
  • N. Houstis et al.

    Reactive oxygen species have a causal role in multiple forms of insulin resistance

    Nature

    (2006)
  • J.L. Evans et al.

    Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes

    Endocr. Rev.

    (2002)
  • S. Stranges et al.

    Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial

    Ann. Intern. Med.

    (2007)
  • S.M. Lippman et al.

    Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

    (2009)
  • J. Bleys et al.

    Serum selenium and diabetes in U.S. adults

    Diabetes Care

    (2007)
  • M. Laclaustra et al.

    Serum selenium concentrations and diabetes in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2003–2004

    Environ. Health Perspect.

    (2009)
  • S. Stranges et al.

    A prospective study of dietary selenium intake and risk of type 2 diabetes

    BMC Public Health

    (2010)
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