Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system

SummaryExcessive secretion of glucagon is a major contributor to the development of diabetic hyperglycemia. Secretion of glucagon is regulated by various nutrients, with glucose being a primary determinant of the rate of α cell glucagon secretion. The intra-islet action of insulin is essential to exert the effect of glucose on the α cells since, in the absence of insulin, glucose is not able to suppress glucagon release in vivo. However, the precise mechanism by which insulin suppresses glucagon secretion from α cells is unknown. In this study, we show that insulin induces activation of GABAA receptors in the α cells by receptor translocation via an Akt kinase-dependent pathway. This leads to membrane hyperpolarization in the α cells and, ultimately, suppression of glucagon secretion. We propose that defects in this pathway(s) contribute to diabetic hyperglycemia.