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

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. •The effect of As2O3-inhibited GSIS is pancreatic islet-autonomous.•Arsenic induces ER stress in pancreas in vivo and in vitro.•Knockdown of PERK attenuates NaAsO2-induced autophagy.•Arsenic-caused β cell dysfunction is ER stress-dependent.