Regulation of glucose-dependent insulin secretion by insulin: possible role of AMP-activated protein kinase.

摘要

AIMS: Extracellular insulin affects insulin secretion from pancreatic beta-cells in an autocrine fashion, but the role of glucose in this signaling pathway remains unclear. This study was conducted to evaluate the glucose dependency of extracellular insulin-mediated regulation of insulin secretion and the potential underlying mechanism. MAIN METHODS: Pancreatic beta-cells from male Sprague-Dawley rats and INS-1, a rat insulinoma cell line, were used. The mechanism of extracellular insulin-mediated, glucose-dependent insulin secretion was explored by analyzing the activity of ATP-sensitive K(+) (K(ATP)) channels, changes in cell membrane potential, and cytosolic free Ca2+ concentration ([Ca2+](c)), as well as phosphorylation of the insulin signaling pathway and the metabolic sensor AMP-activated protein kinase (AMPK). KEY FINDINGS: Treatment of native beta-cells with 100 nM insulin under basal glucose conditions (< or =5 mM) reduced subsequent high glucose-induced insulin secretory responses, demonstrating less inhibition of K(ATP) channels and decreased elevation of [Ca2+](c). In contrast, insulin treatment under high glucose conditions potentiated the insulin secretory responses of beta-cells. While insulin treatment attenuated phosphorylation on the Thr172 of AMPK and the Ser789 of insulin receptor substrate (IRS)-1, which was increased by lowering glucose concentration, it enhanced phosphorylation of AMPK and IRS-1, which was decreased by elevating glucose concentration. This glucose-dependent regulation of insulin even occurred in the presence of LY294002, a phosphoinositide-3 kinase inhibitor. SIGNIFICANCE: Considering that the phosphorylated AMPK could inhibit K(ATP) currents in beta-cells, which triggers glucose-stimulated insulin secretion, extracellular insulin may regulate the phosphorylation status of AMPK through IRS-1 to modulate insulin secretion in a glucose-dependent way.