Pancreatic islet-autonomous effect of arsenic on insulin secretion through endoplasmic reticulum stress-autophagy pathway

Food Chem Toxicol. 2018 Jan;111:19-26. doi: 10.1016/j.fct.2017.10.043. Epub 2017 Oct 27.

Abstract

Inorganic arsenic is a worldwide environmental pollutant. Arsenic's relationship with the incidence of diabetes arouses concerns on its etiological mechanism. In this study, the glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets of As2O3-treated mice was significantly lower than that of control mice. It indicated that the effect of As2O3-inhibited GSIS was pancreatic islet-autonomous. The level of phospho-PERK (p-PERK), a biomarker of endoplasmic reticulum (ER) stress, in pancreas of As2O3-treated mice was increased significantly. After treatment with NaAsO2, the p-PERK level in INS-1 rat pancreatic β- cells was increased correspondingly. After treatment with PERK inhibitor, the GSIS from isolated pancreatic islets of As2O3-treated mice was recovered. Arsenic induced autophagy in pancreatic islets, as evidenced by elevated LC3-II level and depressed P62 level in vivo and in vitro. In NaAsO2-treated INS-1 cells, the initiation of ER stress preceded the stimulation of autophagy, which was a key factor controlling pancreatic β cell function. Furthermore, knockdown of PERK attenuated NaAsO2-induced autophagy in INS-1 cells. These data indicated that arsenic impaired β cell function through ER stress-autophagy pathway. The present study will provide new mechanistic insights into arsenic-related diabetes.

Keywords: Arsenic; Autophagy; Endoplasmic reticulum stress; Insulin secretion; PERK.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Arsenic Trioxide
  • Arsenicals
  • Autophagy / drug effects*
  • Biomarkers
  • Endoplasmic Reticulum Stress / drug effects*
  • Indoles / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Oxides / toxicity*
  • Specific Pathogen-Free Organisms
  • Tissue Culture Techniques
  • eIF-2 Kinase / antagonists & inhibitors

Substances

  • 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
  • Arsenicals
  • Biomarkers
  • Indoles
  • Insulin
  • Oxides
  • PERK kinase
  • eIF-2 Kinase
  • Adenine
  • Arsenic Trioxide