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Exposures to arsenite and methylarsonite produce insulin resistance and impair insulin-dependent glycogen metabolism in hepatocytes

  • Inorganic Compounds
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Abstract

Environmental exposure to inorganic arsenic (iAs) has been shown to disturb glucose homeostasis, leading to diabetes. Previous laboratory studies have suggested several mechanisms that may underlie the diabetogenic effects of iAs exposure, including (i) inhibition of insulin signaling (leading to insulin resistance) in glucose metabolizing peripheral tissues, (ii) inhibition of insulin secretion by pancreatic β cells, and (iii) dysregulation of the methylation or expression of genes involved in maintenance of glucose or insulin metabolism and function. Published studies have also shown that acute or chronic iAs exposures may result in depletion of hepatic glycogen stores. However, effects of iAs on pathways and mechanisms that regulate glycogen metabolism in the liver have never been studied. The present study examined glycogen metabolism in primary murine hepatocytes exposed in vitro to arsenite (iAs3+) or its methylated metabolite, methylarsonite (MAs3+). The results show that 4-h exposures to iAs3+ and MAs3+ at concentrations as low as 0.5 and 0.2 µM, respectively, decreased glycogen content in insulin-stimulated hepatocytes by inhibiting insulin-dependent activation of glycogen synthase (GS) and by inducing activity of glycogen phosphorylase (GP). Further investigation revealed that both iAs3+ and MAs3+ inhibit insulin-dependent phosphorylation of protein kinase B/Akt, one of the mechanisms involved in the regulation of GS and GP by insulin. Thus, inhibition of insulin signaling (i.e., insulin resistance) is likely responsible for the dysregulation of glycogen metabolism in hepatocytes exposed to iAs3+ and MAs3+. This study provides novel information about the mechanisms by which iAs exposure impairs glucose homeostasis, pointing to hepatic metabolism of glycogen as one of the targets.

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Acknowledgements

This work was supported by Grants from the National Institute of Health (R01ES022697 and DK 056350). The authors thank Dr. Rosalind Coleman (Department of Nutrition, University of North Carolina at Chapel Hill) for her helpful suggestions regarding the methods used in this study and result interpretation.

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  1. Department of Nutrition, CB# 7461, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA

    Chongben Zhang, Emily M. J. Fennel, Christelle Douillet & Miroslav Stýblo

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  1. Chongben Zhang
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  2. Emily M. J. Fennel
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Correspondence to Miroslav Stýblo.

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Zhang, C., Fennel, E.M.J., Douillet, C. et al. Exposures to arsenite and methylarsonite produce insulin resistance and impair insulin-dependent glycogen metabolism in hepatocytes. Arch Toxicol 91, 3811–3821 (2017). https://doi.org/10.1007/s00204-017-2076-9

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