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Title: Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

Abstract

Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium.more » These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of insulin secretion by arsenite, MAs{sup III} or DMAs{sup III} is reversible. ► Thus, pancreatic β-cells may be primary targets for chronic exposure to arsenic.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [1]
  1. Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)
  2. Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)
  3. Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States)
  4. Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic)
Publication Date:
OSTI Identifier:
22285234
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 267; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOSINE; ARSENIC; ATP; CONCENTRATION RATIO; DIABETES MELLITUS; ENZYME IMMUNOASSAY; GLUCOSE; INSULIN; METABOLITES; METHYL TRANSFERASES; MICE; PANCREAS; POLYMERASE CHAIN REACTION

Citation Formats

Douillet, Christelle, Currier, Jenna, Saunders, Jesse, Bodnar, Wanda M., Matoušek, Tomáš, and Stýblo, Miroslav, E-mail: styblo@med.unc.edu. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2012.12.007.
Douillet, Christelle, Currier, Jenna, Saunders, Jesse, Bodnar, Wanda M., Matoušek, Tomáš, & Stýblo, Miroslav, E-mail: styblo@med.unc.edu. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets. United States. doi:10.1016/J.TAAP.2012.12.007.
Douillet, Christelle, Currier, Jenna, Saunders, Jesse, Bodnar, Wanda M., Matoušek, Tomáš, and Stýblo, Miroslav, E-mail: styblo@med.unc.edu. Fri . "Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets". United States. doi:10.1016/J.TAAP.2012.12.007.
@article{osti_22285234,
title = {Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets},
author = {Douillet, Christelle and Currier, Jenna and Saunders, Jesse and Bodnar, Wanda M. and Matoušek, Tomáš and Stýblo, Miroslav, E-mail: styblo@med.unc.edu},
abstractNote = {Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of insulin secretion by arsenite, MAs{sup III} or DMAs{sup III} is reversible. ► Thus, pancreatic β-cells may be primary targets for chronic exposure to arsenic.},
doi = {10.1016/J.TAAP.2012.12.007},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 267,
place = {United States},
year = {Fri Feb 15 00:00:00 EST 2013},
month = {Fri Feb 15 00:00:00 EST 2013}
}