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

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.