Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells
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Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells. / Armour, Sarah L.; Frueh, Alexander; Chibalina, Margarita V.; Dou, Haiqiang; Argemi-Muntadas, Lidia; Hamilton, Alexander; Katzilieris-Petras, Georgios; Carmeliet, Peter; Davies, Benjamin; Moritz, Thomas; Eliasson, Lena; Rorsman, Patrik; Knudsen, Jakob G.
In: Diabetes, Vol. 72, No. 10, 2023, p. 1446-1459.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells
AU - Armour, Sarah L.
AU - Frueh, Alexander
AU - Chibalina, Margarita V.
AU - Dou, Haiqiang
AU - Argemi-Muntadas, Lidia
AU - Hamilton, Alexander
AU - Katzilieris-Petras, Georgios
AU - Carmeliet, Peter
AU - Davies, Benjamin
AU - Moritz, Thomas
AU - Eliasson, Lena
AU - Rorsman, Patrik
AU - Knudsen, Jakob G.
N1 - Publisher Copyright: © 2023 by the American Diabetes Association.
PY - 2023
Y1 - 2023
N2 - 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 repolarization 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. ARTICLE HIGHLIGHTS: It has become clear that dysregulation of glucagon secretion and α-cell function plays an important role in the development of diabetes, but we do not know how glucagon secretion is regulated. Here we asked whether glucose inhibits fatty acid oxidation in α-cells to regulate glucagon secretion. We found that fatty acid oxidation is required for the inhibitory effects of glucose on glucagon secretion through reductions in ATP. These findings provide a new framework for the regulation of glucagon secretion by glucose.
AB - 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 repolarization 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. ARTICLE HIGHLIGHTS: It has become clear that dysregulation of glucagon secretion and α-cell function plays an important role in the development of diabetes, but we do not know how glucagon secretion is regulated. Here we asked whether glucose inhibits fatty acid oxidation in α-cells to regulate glucagon secretion. We found that fatty acid oxidation is required for the inhibitory effects of glucose on glucagon secretion through reductions in ATP. These findings provide a new framework for the regulation of glucagon secretion by glucose.
U2 - 10.2337/db23-0056
DO - 10.2337/db23-0056
M3 - Journal article
C2 - 37494670
AN - SCOPUS:85171901684
VL - 72
SP - 1446
EP - 1459
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 10
ER -
ID: 368723129