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

Abstract

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 alpha cell glucagon secretion. The intra-islet action of insulin is essential to exert the effect of glucose on the alpha 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 alpha cells is unknown. In this study, we show that insulin induces activation of GABAA receptors in the alpha cells by receptor translocation via an Akt kinase-dependent pathway. This leads to membrane hyperpolarization in the alpha cells and, ultimately, suppression of glucagon secretion. We propose that defects in this pathway(s) contribute to diabetic hyperglycemia.

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

“…Activation of these receptors is coupled to inward Cl K currents that hyperpolarize the a-cell plasma membrane, decreasing glucagon release in rats and guinea pigs (Rorsman et al 1989, Wendt et al 2004. Similar conclusions were obtained in mouse islets and clonal aTC1-9 cells (Xu et al 2006, Bailey et al 2007). The neurotransmitter L-glutamate also accumulates in the a-cell secretory granules because of vesicular glutamate transporters 1 and 2 found in these cells (Hayashi et al 2003a).…”

“…which increases the response to GABA secreted by b-cells, favouring membrane hyperpolarization and suppression of glucagon secretion (Xu et al 2006). Since a-cell Ca 2C signals rely on electrical activity, insulin also inhibits Ca 2C signals induced by low-glucose concentrations (Ravier & Rutter 2005).…”

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

“…4b), under the beta cell injuring conditions (STZ). This is also consistent with recent findings that intra-islet insulin is a major mechanism underlying glucose-mediated suppression of glucagon secretion in alpha cells [36,37].…”

Insulin modulation of glucagon secretion: The role of insulin and other factors in the regulation of glucagon secretion

“…γ-aminobutyric acid (GABA), [2][3][4] Zinc ions 5 and glutamate 6 which are all secreted by β-cells have been reported to modulate glucagon secretion from α-cells. Especially, insulin has been intensively studied for its impact on glucagon secretion.…”