The reversible effects of free fatty acids on sulfonylurea-stimulated insulin secretion are related to the expression and dynamin-mediated endocytosis of KATP channels in pancreatic β cells

Abstract

Objective: Lipotoxicity-induced pancreatic β cells-dysfunction results in decreased insulin secretion in response to multiple stimulus. In this study, we investigated the reversible effects of palmitate (PA) or oleate (OA) on insulin secretion and the relationship with pancreatic β cell ATP-sensitive potassium (KATP) channels. Methods: MIN6 cells were treated with PA and OA for 48 hr and then washed out for 24 hr to determine the changes in expression and endocytosis of the KATP channels and insulin secretion under glucose- (GSIS) and sulfonylureas-stimulated (SUs-SIS). Results: MIN6 cells exposed to PA or OA showed both impaired GSIS and SUs-SIS, the former was not restorable, while the latter was reversible with wash out of PA or OA. Decreased expressions of both total and surface Kir6.2 and SUR1 and endocytosis of KATP channels were observed which were also recoverable after washed out. When MIN6 cells exposed to FFAs were cotreated with AICAR or dynasore, we found that endocytosis of KATP channels did not change significantly by AICAR, but was almost completely blocked by dynasore. Meanwhile, the inhibition of endocytosis of KATP channels after washed out could be activated by PIP2. The recovery of SUs-SIS after washed out was significantly weakened by PIP2, but the decrease of SUs-SIS induced by FFAs was not alleviated by dynasore. Conclusions: FFAs can cause reversible impairment of SUs-SIS on pancreatic β cells. The reversibility of the effects is partial because of the changes of expression and endocytosis of Kir6.2 and SUR1 which was mediated by dynamin.