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?-cell glucokinase suppresses glucose-regulated glucagon secretion.

ABSTRACT: Glucagon secretion by pancreatic ?-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 ?-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with ?-cell-specific inactivation of Gck (?GckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in ?-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. ?GckKO 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 ?-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.

SUBMITTER: Basco D

PROVIDER: S-EPMC5803227 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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α-cell glucokinase suppresses glucose-regulated glucagon secretion.

Basco Davide D Zhang Quan Q Salehi Albert A Tarasov Andrei A Dolci Wanda W Herrera Pedro P Spiliotis Ioannis I Berney Xavier X Tarussio David D Rorsman Patrik P Thorens Bernard B

Nature communications 20180207 1

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 ...[more]

PMID: 29416045

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Project description:ObjectiveWhile the molecular events controlling insulin secretion from β-cells have been documented in detail, the exact mechanisms governing glucagon release by α-cells are understood only partially. This is a critical knowledge gap, as the normal suppression of glucagon secretion by elevated glucose levels fails in type 2 diabetes (T2D) patients, contributing to hyperglycemia through stimulation of hepatic glucose production. A critical role of glycolytic flux in regulating glucagon secretion was supported by recent studies in which manipulation of the activity and expression of the glycolytic enzyme glucokinase altered the setpoint for glucose-suppression of glucagon secretion (GSGS). Given this precedent, we hypothesized that genetic activation of glucokinase specifically in α-cells would enhance GSGS and mitigate T2D hyperglucagonemia.MethodsWe derived an inducible, α-cell-specific glucokinase activating mutant mouse model (GckLoxPGck∗/LoxPGck∗; Gcg-CreERT2; henceforth referred to as "α-mutGCK") in which the wild-type glucokinase gene (GCK) is conditionally replaced with a glucokinase mutant allele containing the ins454A activating mutation (Gck∗), a mutation that increases the affinity of glucokinase for glucose by almost 7-fold. The effects of α-cell GCK activation on glucose homeostasis, hormone secretion, islet morphology, and islet numbers were assessed using both in vivo and ex vivo assays. Additionally, the effect of α-cell GCK activation on GSGS was investigated under diabetogenic conditions of high-fat diet (HFD) feeding that dysregulate glucagon secretion.ResultsOur study shows that α-mutGCK mice have enhanced GSGS in vivo and ex vivo, independent of alterations in insulin levels and secretion, islet hormone content, islet morphology, or islet number. α-mutGCK mice maintained on HFD displayed improvements in glucagonemia compared to controls, which developed the expected obesity, glucose intolerance, elevated fasting blood glucose, hyperinsulinemia, and hyperglucagonemia.ConclusionsUsing our novel α-cell specific activation of GCK mouse model, we have provided additional support to demonstrate that the glycolytic enzyme glucokinase is a key determinant in glucose sensing within α-cells to regulate glucagon secretion. Our results contribute to our fundamental understanding of α-cell biology by providing greater insight into the regulation of glucagon secretion through α-cell intrinsic mechanisms via glucokinase. Furthermore, our HFD results underscore the potential of glucokinase as a druggable target which, given the ongoing development of allosteric glucokinase activators (GKAs) for T2D treatment, could help mitigate hyperglucagonemia and potentially improve blood glucose homeostasis.

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?-cell glucokinase suppresses glucose-regulated glucagon secretion.

Publications

α-cell glucokinase suppresses glucose-regulated glucagon secretion.

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