alpha-cell glucokinase suppresses glucose-regulated glucagon secretion

作者：Basco Davide; Zhang Quan; Salehi Albert; Tarasov Andrei; Dolci Wanda; Herrera Pedro; Spiliotis Ioannis; Berney Xavier; Tarussio David; Rorsman Patrik; Thorens Bernard^*

来源：Nature Communications, 2018, 9(1): 546.

DOI：10.1038/s41467-018-03034-0

Glucagon secretion by pancreatic alpha-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that alpha-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with alpha-cell-specific inactivation of Gck (alpha GckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of K-ATP channels in alpha-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. alpha GckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an alpha-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype.

• 出版日期2018-2-7