α-cell glucokinase suppresses glucose-regulated glucagon secretion.

Details

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State: Public
Version: Final published version
Serval ID
serval:BIB_C69CB1A44E4C
Type
Article: article from journal or magazin.
Collection
Publications
Title
α-cell glucokinase suppresses glucose-regulated glucagon secretion.
Journal
Nature communications
Author(s)
Basco D., Zhang Q., Salehi A., Tarasov A., Dolci W., Herrera P., Spiliotis I., Berney X., Tarussio D., Rorsman P., Thorens B.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
07/02/2018
Peer-reviewed
Oui
Volume
9
Number
1
Pages
546
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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 K javax.xml.bind.JAXBElement@dee6e8 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.

Keywords
Adenosine Diphosphate/metabolism, Adenosine Triphosphate/metabolism, Animals, Biological Transport, Female, Gene Expression, Glucagon/secretion, 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
Pubmed
Web of science
Open Access
Yes
Create date
22/02/2018 14:56
Last modification date
20/08/2019 15:42
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