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Arsenite and its trivalent methylated metabolites inhibit glucose-stimulated calcium influx and insulin secretion in murine pancreatic islets

  • Inorganic Compounds
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Abstract

Chronic exposure to inorganic arsenic (iAs), a common drinking water and food contaminant, has been associated with an increased risk of type 2 diabetes in population studies worldwide. Several mechanisms underlying the diabetogenic effects of iAs have been proposed through laboratory investigations. We have previously shown that exposure to arsenite (iAs(III)) or its methylated trivalent metabolites, methylarsonite (MAs(III)) and dimethylarsinite (DMAs(III)), inhibits glucose-stimulated insulin secretion (GSIS) in pancreatic islets, without significant effects on insulin expression or insulin content. The goal of the present study was to determine if iAs(III) and/or its metabolites inhibit Ca2+ influx, an essential mechanism that regulates the release of insulin from β cells in response to glucose. We found that in vitro exposures for 48 h to non-cytotoxic concentrations of iAs(III), MAs(III), and DMAs(III) impaired Ca2+ influx in isolated murine pancreatic islets stimulated with glucose. MAs(III) and DMAs(III) were more potent inhibitors of Ca2+ influx than iAs(III). These arsenicals also inhibited Ca2+ influx and GSIS in islets treated with depolarizing levels of potassium chloride in the absence of glucose. Treatment with Bay K8644, a Cav1.2 channel agonist, did not restore insulin secretion in arsenical-exposed islets. Tolbutamide, a KATP channel blocker, prevented inhibition of insulin secretion in MAs(III)- and DMAs(III)-exposed islets, but only marginally in islets exposed to iAs(III). Our findings suggest that iAs(III), MAs(III), and DMAs(III) inhibit glucose-stimulated Ca2+ influx in pancreatic islets, possibly by interfering with KATP and/or Cav1.2 channel function. Notably, the mechanisms underlying inhibition of GSIS by iAs(III) may differ from those of its trivalent methylated metabolites.

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Funding

This work was supported by a grant from the National Institutes of Environmental Health sciences [R01ES022697] to M.S., a National Research Service Award from the National Institute of Environmental Health Sciences [T32 ES007126] to M.H., and the UNC Nutrition Obesity Research Center funded by the National Institute of Diabetes and Digestive and Kidney Diseases [DK056350].

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  1. Madelyn Huang

    Present address: National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA

Authors and Affiliations

  1. Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7325, USA

    Madelyn Huang

  2. Department of Nutrition, CB# 7461, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7461, USA

    Christelle Douillet & Miroslav Stýblo

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  1. Madelyn Huang
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Correspondence to Miroslav Stýblo.

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Huang, M., Douillet, C. & Stýblo, M. Arsenite and its trivalent methylated metabolites inhibit glucose-stimulated calcium influx and insulin secretion in murine pancreatic islets. Arch Toxicol 93, 2525–2533 (2019). https://doi.org/10.1007/s00204-019-02526-2

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