American Diabetes Association
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Glucose controls glucagon secretion by regulating fatty acid oxidation in pancreatic alpha cells 

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posted on 2023-07-26, 20:24 authored by Sarah L Armour, Alexander Frueh, Margarita V Chibalina, Haiqiang Dou, Lidia Argemi-Muntadas, Alexander Hamiltion, Georgios Katzilieris-Petras, Peter Carmeliet, Benjamin Davies, Thomas Moritz, Lena Eliasson, Patrik Rorsman, Jakob G Knudsen

Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic α-cells remain unclear. Here we show that in α-cells the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarisation and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the α-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion.


A.H is supported by a fellowship from Svenska Sällskapet for Medicinsk Forskning (SSMF). Financial support for the transgenic core at the Wellcome Centre for Human Genetics was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. P.C. is supported by long term structural funding - Methusalem funding by the Flemish government, the Fund for Scientific Research-Flanders (FWO-Vlaanderen), ERC Advanced Research Grant EU- (ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (Denmark). TM is supported by the Novo Nordisk Foundation (grant number NNF18CC0034900) LE is supported by the Swedish Research grant (SRA-Exodiab and project grant), the Swedish Foundation for Strategic Research (IRC-LUDC), and The Swedish Diabetes Foundation, P.R. is supported by the Swedish Research Council, the Helmsley Trust and the Medical Research Council (MRC); J.G.K. is supported by a Novo Nordisk Fonden Excellence Emerging Investigator Grant- Endocrinology & Metabolism (#0054300) and a Sapere Aude Fellowship from the Independent Research Fund Denmark.