The reversible effects of free fatty acids on sulfonylurea-stimulated insulin secretion are related to the expression and dynamin-mediated endocytosis of K _ATP 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 investigated the reversible effects of palmitate (PA) or oleate (OA) on insulin secretion and the relationship with pancreatic β-cell ATP-sensitive potassium (K _ATP) 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 K _ATP 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 K _ATP channels were observed, which were also recoverable after washout. When MIN6 cells exposed to free fatty acids (FFAs) were cotreated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or dynasore, we found that endocytosis of K _ATP channels did not change significantly by AICAR but was almost completely 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 alleviated 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 of expression and endocytosis of Kir6.2 and SUR1 which was mediated by dynamin.