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α-cell glucokinase suppresses glucose-regulated glucagon secretion

Basco, Davide; Zhang, Quan LU ; Salehi, Albert LU ; Tarasov, Andrei; Dolci, Wanda; Herrera, Pedro; Spiliotis, Ioannis; Berney, Xavier; Tarussio, David and Rorsman, Patrik LU , et al. (2018) In Nature Communications 9(1).
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... (More)

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.

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Nature Communications
volume
9
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85041512927
ISSN
2041-1723
DOI
10.1038/s41467-018-03034-0
language
English
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yes
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d354da7f-440e-45cd-b1a2-b3d3f07ad05b
date added to LUP
2018-02-20 07:56:53
date last changed
2018-05-29 11:42:32
@article{d354da7f-440e-45cd-b1a2-b3d3f07ad05b,
  abstract     = {<p>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<sub>ATP</sub> 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.</p>},
  articleno    = {546},
  author       = {Basco, Davide and Zhang, Quan and Salehi, Albert and Tarasov, Andrei and Dolci, Wanda and Herrera, Pedro and Spiliotis, Ioannis and Berney, Xavier and Tarussio, David and Rorsman, Patrik and Thorens, Bernard},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {α-cell glucokinase suppresses glucose-regulated glucagon secretion},
  url          = {http://dx.doi.org/10.1038/s41467-018-03034-0},
  volume       = {9},
  year         = {2018},
}