α-cell glucokinase suppresses glucose-regulated glucagon secretion

Davide Basco, Quan Zhang, Albert Salehi, Andrei Tarasov, Wanda Dolci, Pedro Herrera, Ioannis Spiliotis, Xavier Berney, David Tarussio, Patrik Rorsman, Bernard Thorens

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)
43 Downloads (Pure)

Abstract

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 KATP channels 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 languageEnglish
Article number546
Pages (from-to)1-9
Number of pages9
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 7 Feb 2018

Keywords

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

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