TY - JOUR

T1 - Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases

AU - Hædersdal, Sofie

AU - Andersen, Andreas

AU - Knop, Filip K.

AU - Vilsbøll, Tina

N1 - Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023

Y1 - 2023

N2 - Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell–β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell–β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.

AB - Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell–β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell–β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.

U2 - 10.1038/s41574-023-00817-4

DO - 10.1038/s41574-023-00817-4

M3 - Review

C2 - 36932176

AN - SCOPUS:85150035116

VL - 19

SP - 321

EP - 335

JO - Nature reviews. Endocrinology

JF - Nature reviews. Endocrinology

SN - 1759-5029

IS - 6

ER -