α-cell glucokinase suppresses glucose-regulated glucagon secretion

Nat Commun. 2018 Feb 7;9(1):546. doi: 10.1038/s41467-018-03034-0.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Insulin
  • KATP Channels
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Glucagon
  • Glucokinase
  • Glucose