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Glucagon secretion by pancreatic α-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 α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATPchannels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO 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 α-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.

Original publication

DOI

10.1038/s41467-018-03034-0

Type

Journal article

Journal

Nat Commun

Publication Date

07/02/2018

Volume

9

Keywords

Adenosine Diphosphate, Adenosine Triphosphate, Animals, Biological Transport, Female, Gene Expression, Glucagon, Glucagon-Secreting Cells, Glucokinase, Glucose, Glucose Intolerance, Hypoglycemia, Insulin, KATP Channels, Liver, Male, Mice, Mice, Knockout