APPL2 deficiency suppresses glucose-stimulated insulin secretion by disrupting F-actin remodeling in pancreatic β cells

Abstract

Defective glucose-stimulated insulin secretion (GSIS) is a key characteristic of type 2 diabetes at late stage. Previous studies have shown that the adaptor protein APPL1 potentiates first-phase GSIS by modulating the exocytotic machinery SNARE proteins in an Akt-dependent manner, whereas the role of its close homolog APPL2 in pancreatic β cells remains obscure. Here we show that APPL2 regulates GSIS in a distinct mechanism from APPL1. Mice lacking APPL2 in pancreatic β cells displayed a dramatic reduction of first-phase and second-phase GSIS, resulting in glucose intolerance. APPL2 deficiency had no effect on glucose metabolism, calcium signaling and SNARE protein expression but impaired glucose-stimulated F-actin (Filamentous actin) remodeling in pancreatic islets. Defective GSIS in the islets lacking APPL2 was reserved by the F-actin depolymerizing drug Latrunculin A. Further analysis revealed that RNAi-mediated knockdown of APPL2 largely abolishes glucose-stimulated activation of Rac1, a small GTPase is known to regulate F-actin remodeling in pancreatic β cells. Therefore, deciphering the role of APPL2 in F-actin remodeling might provide a potential therapeutic target for type 2 diabetes by continuously evoking first- and second-phase GSIS.