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 cell-dysfunction results in decreased insulin secretion in response to multiple stimulus. In this study, we i nvestigated 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 h and then washed out for 24 h to determine the changes in expression and endocytosis of the KATP channels and glucose-stimulated insulin secretion (GSIS) and sulfonylurea-stimulated insulin secretion (SU-SIS). Results: MIN6 cells exposed to PA or OA showed both impaired GSIS and SU -SIS; the former was not restorable, while the latter was reversible with washout 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 wash out. When MIN6 cells exposed to free fatty acids (FFAs) were cotreated wi th 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) or dynasore, we found that endocytosis of KATP channels did not change significantly by AICAR but was almost co mpletely blocked by dynasore. Meanwhile, the inhibition of endocytosis of K ATP channels after washout could be activated by PIP2. The recovery of SU-SIS after washout was significantly weakened by PIP2, but the decrease of SU-SIS induced by FFAs was not allevi ated by dynasore. Conclusions: FFAs can cause reversible impairment of SU-SIS on pancreatic β cells. The reversibility of the effects is partial because of the changes o f expression and endocytosis of Kir6.2 and SUR1 which was mediated by dynamin.

Keywords

• diabetes
• free fatty acids
• sulfonylureas
• insulin secretion
• atp-sensitive potassium channels