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α-cell glucokinase suppresses glucose-regulated glucagon secretion

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. Usi...

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Autores principales: Basco, Davide, Zhang, Quan, Salehi, Albert, Tarasov, Andrei, Dolci, Wanda, Herrera, Pedro, Spiliotis, Ioannis, Berney, Xavier, Tarussio, David, Rorsman, Patrik, Thorens, Bernard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803227/
https://www.ncbi.nlm.nih.gov/pubmed/29416045
http://dx.doi.org/10.1038/s41467-018-03034-0
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author Basco, Davide
Zhang, Quan
Salehi, Albert
Tarasov, Andrei
Dolci, Wanda
Herrera, Pedro
Spiliotis, Ioannis
Berney, Xavier
Tarussio, David
Rorsman, Patrik
Thorens, Bernard
author_facet Basco, Davide
Zhang, Quan
Salehi, Albert
Tarasov, Andrei
Dolci, Wanda
Herrera, Pedro
Spiliotis, Ioannis
Berney, Xavier
Tarussio, David
Rorsman, Patrik
Thorens, Bernard
author_sort Basco, Davide
collection PubMed
description 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(ATP) 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.
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spelling pubmed-58032272018-02-09 α-cell glucokinase suppresses glucose-regulated glucagon secretion Basco, Davide Zhang, Quan Salehi, Albert Tarasov, Andrei Dolci, Wanda Herrera, Pedro Spiliotis, Ioannis Berney, Xavier Tarussio, David Rorsman, Patrik Thorens, Bernard Nat Commun Article 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(ATP) 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. Nature Publishing Group UK 2018-02-07 /pmc/articles/PMC5803227/ /pubmed/29416045 http://dx.doi.org/10.1038/s41467-018-03034-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Basco, Davide
Zhang, Quan
Salehi, Albert
Tarasov, Andrei
Dolci, Wanda
Herrera, Pedro
Spiliotis, Ioannis
Berney, Xavier
Tarussio, David
Rorsman, Patrik
Thorens, Bernard
α-cell glucokinase suppresses glucose-regulated glucagon secretion
title α-cell glucokinase suppresses glucose-regulated glucagon secretion
title_full α-cell glucokinase suppresses glucose-regulated glucagon secretion
title_fullStr α-cell glucokinase suppresses glucose-regulated glucagon secretion
title_full_unstemmed α-cell glucokinase suppresses glucose-regulated glucagon secretion
title_short α-cell glucokinase suppresses glucose-regulated glucagon secretion
title_sort α-cell glucokinase suppresses glucose-regulated glucagon secretion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803227/
https://www.ncbi.nlm.nih.gov/pubmed/29416045
http://dx.doi.org/10.1038/s41467-018-03034-0
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