Glucose-induced electrical activities and insulin secretion in pancreatic islet ?-cells are modulated by CFTR.

ABSTRACT: The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in ?-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca(2+) oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse ?-cells or RINm5F ?-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 ?-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in ?-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.

SUBMITTER: Guo JH 

PROVIDER: S-EPMC4104438 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature