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

• Published in: Cell metabolism 2006-01, Vol.3 (1), p.47-58
• Main Authors: Xu, Elaine, Kumar, Mohan, Zhang, Yi, Ju, William, Obata, Toshiyuki, Zhang, Nina, Liu, Shiying, Wendt, Anna, Deng, Shaoping, Ebina, Yousuke, Wheeler, Michael B., Braun, Matthias, Wang, Qinghua
• Format: Article
• Language: English
• Subjects: Animals; CELLBIO; Female; GABA-A Receptor Antagonists; Glucagon - antagonists & inhibitors; Glucagon - secretion; Glucagon-Secreting Cells - physiology; Glucagon-Secreting Cells - secretion; Guinea Pigs; Humans; HUMDISEASE; Insulin - physiology; Insulin Resistance - physiology; Islets of Langerhans - physiology; Islets of Langerhans - secretion; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - biosynthesis; Receptors, GABA-A - genetics; Receptors, GABA-A - physiology; SIGNALING
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2005.11.015

Excessive 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.