Arsenite and methylarsonite inhibit mitochondrial metabolism and glucose-stimulated insulin secretion in INS-1 832/13 β cells

Arch Toxicol. 2018 Feb;92(2):693-704. doi: 10.1007/s00204-017-2074-y. Epub 2017 Sep 27.

Abstract

Growing evidence suggests that exposure to environmental contaminants contributes to the current diabetes epidemic. Inorganic arsenic (iAs), a drinking water and food contaminant, is one of the most widespread environmental diabetogens according to epidemiological studies. Several schemes have been proposed to explain the diabetogenic effects of iAs exposure; however, the exact mechanism remains unknown. We have shown that in vitro exposure to low concentrations of arsenite (iAsIII) or its trivalent methylated metabolites, methylarsonite (MAsIII) and dimethylarsinite (DMAsIII), inhibits glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets, with little effect on insulin transcription or total insulin content. The goal of this study was to determine if exposure to trivalent arsenicals impairs mitochondrial metabolism, which plays a key role in the regulation of GSIS in β cells. We used a Seahorse extracellular flux analyzer to measure oxygen consumption rate (OCR), a proxy for mitochondrial metabolism, in cultured INS-1 832/13 β cells exposed to iAsIII, MAsIII, or DMAsIII and stimulated with either glucose or pyruvate, a final product of glycolysis and a substrate for the Krebs cycle. We found that 24-h exposure to 2 μM iAsIII or 0.375-0.5 μM MAsIII inhibited OCR in both glucose- and pyruvate-stimulated β cells in a manner that closely paralleled GSIS inhibition. In contrast, 24-h exposure to DMAsIII (up to 2 µM) had no effects on either OCR or GSIS. These results suggest that iAsIII and MAsIII may impair GSIS in β cells by inhibiting mitochondrial metabolism, and that at least one target of these arsenicals is pyruvate decarboxylation or downstream reactions.

Keywords: Arsenic; Diabetes; Insulin secretion; Mitochondrial respiration; β cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenites / toxicity*
  • Cacodylic Acid / analogs & derivatives*
  • Cacodylic Acid / toxicity
  • Cell Line
  • Cell Survival
  • Glucose / metabolism
  • Insulin Secretion / drug effects*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxygen / metabolism
  • Rats

Substances

  • Arsenites
  • dimethylarsinous acid
  • methylarsonite
  • Cacodylic Acid
  • Glucose
  • arsenite
  • Oxygen