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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. 2013. "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 = 2013,
month = 2
}
  • Glucose metabolism and insulin secretion were studied in isolated rat pacreatic islets of different sizes and the amount of tissue was quantitated by the measurement of DNA. It was found that larger islets (140-210 ng DNA/islet) utilized more glucose (based on the conversion of /sup 3/H-5-glucose to /sup 3/H/sub 2/O) per ng of DNA than islets containing less DNA (60-120 ng/islet). However, the insulin secreted per ng of DNA in response to a given glucose concentration was the same in islets of all sizes. Also, the islet insulin and glucagon content when expressed in terms of DNA did not dependmore » upon islet size. Thus, although glucose utilization rates expressed as a function of islet DNA content were greater in larger islets, no such relationship was found for glucose-induced insulin release or insulin and glucagon content. 17 reference, 1 figure, 3 tables.« less
  • Gastrin releasing peptide (GRP) has recently been shown to increase glucose-induced insulin secretion in vivo. Being present in pancreatic tissue, the 27-amino acid peptide could play a role in the control of the glucose-induced insulin secretion of islets of Langerhans. In the presence of a stimulatory glucose concentration, GRP augmented insulin secretion of isolated islets in batch incubations. The peptide did not affect 86Rb+ efflux in the presence of 3 or 5.6 mM glucose but reduced the increase of 86Rb+ efflux evoked by the calcium ionophore A23187. 45Ca2+ uptake and intracellular recorded electrical activity induced by glucose were amplified bymore » GRP. It is suggested that GRP plays a role in the regulation of glucose-induced insulin secretion by increasing the uptake of Ca2+ directly or by inhibition of the Ca(2+)-dependent K+ channel activity and reduced repolarization of the cell.« less
  • GSIS, the most important function of pancreatic beta cell, is essential for maintaining the glucose homeostasis. Transcription factors are known to control different biological processes such as differentiation, proliferation and apoptosis. In pancreas, some transcription factors are involved in regulating the function of beta cells. In this review, the role of these transcription factors including Pdx-1, FoxO1, SREBP-1c, and MafA in GSIS is highlighted. The related molecular mechanisms are analyzed as well. Furthermore, the association between the role of transcription factors in GSIS and the development of T2DM is discussed.
  • Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 wasmore » down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1 cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of Drp1 in islets evokes loss of glucose-stimulated insulin secretion.« less
  • In order to assess the possible role of L-arginine accumulation in islet cells as a determinant of its insulinotropic action, the uptake of L-arginine and other cationic amino acids (L-ornithine, L-homoarginine, D,L-alpha-methylornithine, D,L-alpha-difluoromethylornithine) by rat pancreatic islets was compared to the ionic and secretory responses of the islets to the same amino acids. A tight correlation was found between the net uptake of these amino acids and their capacity to stimulate 86Rb efflux, 45Ca uptake and efflux, and insulin release. In the latter respect, there was little difference between metabolized and nonmetabolized amino acids. Thus, although L-homoarginine and 4-amino-1-guanylpiperidine-4-carboxylic acidmore » failed to act as a substrate for either arginase or amino acid aminotransferase in islet homogenates, they both stimulated 86Rb efflux, 45Ca uptake and efflux, and insulin secretion in intact islets. These findings are compatible with the view that the accumulation of these positively charged amino acids in islet cells represents an essential determinant of their secretory action. Hence, the release of insulin evoked by these amino acids could be due to depolarization of the plasma membrane with subsequent gating of voltage-sensitive Ca2+ channels and/or to some other biophysical effect, as suggested by the persistence of a sizeable secretory response to L-arginine or L-ornithine in islets perifused at a high concentrations of extracellular K+ (50 mM).« less