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  • Review Article
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Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases

Nature Reviews Endocrinology volume 19, pages 321–335 (2023)Cite this article

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Abstract

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.

Key points

  • Glucagon is a 29-amino acid peptide hormone mainly secreted from pancreatic α-cells and has primarily been recognized for its role in glucose homeostasis.

  • Glucagon secretion seems to be partly regulated by the direct effect of glucose on α-cells; however, paracrine regulation from neighbouring β-cells and δ-cells is also important.

  • Several amino acids are glucagonotropic, and glucagon increases hepatic uptake and turnover of amino acids and stimulates ureagenesis — a feedback cycle referred to as the liver–α-cell axis.

  • The importance of α-cell–β-cell crosstalk is increasingly recognized; studies suggest that α-cells are necessary for β-cell function (insulin secretion) and might preserve β-cell mass.

  • Fasting hyperglucagonaemia in diabetes mellitus might be both a pathophysiological trait in glucose metabolism and a helpful metabolic adaptation in hepatic lipid and amino acid metabolism.

  • Glucagon receptor antagonism improves glycaemic control in type 1 diabetes mellitus and type 2 diabetes mellitus but with adverse effects; future strategies targeting obesity and type 2 diabetes mellitus might involve glucagon co-agonism.

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Fig. 1: Tissue-specific proglucagon processing and measurement of glucagon by antibodies.
Fig. 2: The liver–α-cell axis.
Fig. 3: Classical direct and indirect stimulators and inhibitors of glucagon secretion.
Fig. 4: Intra-islet endocrine cell crosstalk.

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Authors and Affiliations

  1. Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark

    Sofie Hædersdal, Andreas Andersen, Filip K. Knop & Tina Vilsbøll

  2. Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark

    Sofie Hædersdal, Andreas Andersen, Filip K. Knop & Tina Vilsbøll

  3. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Filip K. Knop & Tina Vilsbøll

  4. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Filip K. Knop

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S.H. and A.A. researched data for the article. All authors contributed substantially to discussion of the content. S.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Sofie Hædersdal or Tina Vilsbøll.

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Competing interests

S.H. has served as a consultant for Novo Nordisk. F.K.K. has served on scientific advisory panels, been part of speakers bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma and Zucara, and is a minority shareholder in Antag Therapeutics. T.V. has served on scientific advisory panels, been part of speakers bureaus, and served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Gilead, GSK, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi and Sun Pharmaceuticals. A.A. has no competing interests.

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Hædersdal, S., Andersen, A., Knop, F.K. et al. Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases. Nat Rev Endocrinol 19, 321–335 (2023). https://doi.org/10.1038/s41574-023-00817-4

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