100 years of glucagon and 100 more
Open accessAbstract
The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled 'A hundred years with glucagon and a hundred more', held in Copenhagen, Denmark, in November 2022. The scientific and therapeutic focus of glucagon biology has mainly been related to its role in diabetes. In type 1 diabetes, the glucose-raising properties of glucagon have been leveraged to therapeutically restore hypoglycaemia. The hyperglucagonaemia evident in type 2 diabetes has been proposed to contribute to hyperglycaemia, raising questions regarding underlying mechanism and the importance of this in the pathogenesis of diabetes. Mimicry experiments of glucagon signalling have fuelled the development of several pharmacological compounds including glucagon receptor (GCGR) antagonists, GCGR agonists and, more recently, dual and triple receptor agonists combining glucagon and incretin hormone receptor agonism. From these studies and from earlier observations in extreme cases of either glucagon deficiency or excess secretion, the physiological role of glucagon has expanded to also involve hepatic protein and lipid metabolism. The interplay between the pancreas and the liver, known as the liver-alpha cell axis, reflects the importance of glucagon for glucose, amino acid and lipid metabolism. In individuals with diabetes and fatty liver diseases, glucagon's hepatic actions may be partly impaired resulting in elevated levels of glucagonotropic amino acids, dyslipidaemia and hyperglucagonaemia, reflecting a new, so far largely unexplored pathophysiological phenomenon termed 'glucagon resistance'. Importantly, the hyperglucagonaemia as part of glucagon resistance may result in increased hepatic glucose production and hyperglycaemia. Emerging glucagon-based therapies show a beneficial impact on weight loss and fatty liver diseases and this has sparked a renewed interest in glucagon biology to enable further pharmacological pursuits.
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A longer duration of type 2 diabetes is associated with a diminished counter-regulatory response to hypoglycemia.
“A longer duration of type 2 diabetes is associated with a diminished counter-regulatory response to hypoglycemia [1, 17–21].”
From Systematic review of oral carbohydrate treatment for hypoglycemia in people living with type 2 diabetes mellitus (2026) · cites this paper as [21]
The ‘Influence of extra-islet factors’ section says the glucagon response to hypoglycaemia can be deficient or absent in people with long-standing type 2 diabetes. This supports the duration-related point, but the passage addresses the glucagon response specifically, not the counter-regulatory response as a whole. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAlthough T2D is associated with hyperglucagonemia, glucagon's action and potency may gradually wane over time.
“Although T2D is associated with hyperglucagonemia, glucagon’s action and potency may gradually wane over time [1, 19–21].”
From Systematic review of oral carbohydrate treatment for hypoglycemia in people living with type 2 diabetes mellitus (2026) · cites this paper as [21]
The “Glucagon in diabetes” section reports hyperglucagonaemia in type 2 diabetes and suggests that hepatic glucagon-receptor signalling may be impaired when hepatic steatosis is present. The paper does not say that glucagon’s overall action or potency gradually wanes over time; it also reports increased glucagon-driven hepatic glucose production in type 2 diabetes. No page numbers were provided for these passages. (LLM, conf=0.87)
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Self-citationPancreatic Islet Cell Hormones: Secretion, Function, and Diabetes Therapy
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The role of fibroblast growth factors in cell and cancer metabolism
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Self-citationNutrigenomic Insights and Cardiovascular Benefits of Jujube Tree ( Ziziphus lotus L.)
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- Authors
- Wewer Albrechtsen, N. J., Holst, J. J., Cherrington, A. D., Finan, B., Gluud, L. L., Dean, E. D., Campbell, J. E., Bloom, S. R., Tan, T. M.-M., Knop, F. K., & Müller, T. D.
- Affiliations
- University of Copenhagen (DK)
- Vanderbilt University (US)
- Duke University (US)
- Imperial College London (GB)
- Helmholtz Munich (DE)
- ORCID
- Venue
- Diabetologia
- Published
- 2023-06-27
- Volume
- 66
- Issue
- 8
- Pages
- 1378-1394
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC13288116
- OpenAlex
- W4382182595
- Cited by
- 117
- References
- 126
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 36 · 2023: 7
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (GRK 2816/1, SFB1123, TRR152, TRR296)
- Novo Nordisk Fonden (NNF21OC0072718)
- European Foundation for the Study of Diabetes (NNF21SA0072746)
- H2020 European Research Council (101044445)
- Deutsche Diabetes Gesellschaft
- Danmarks Frie Forskningsfond (1052-00003B)
- National Institute for Health and Care Research (R01DK132669)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- glucagon, glucagon receptor, hyperglucagonaemia, glucagon resistance, type 1 diabetes, type 2 diabetes, glucagon receptor agonist, glucagon receptor antagonists, hepatic glucose production, hepatic lipid metabolism, glucagon deficiency, hepatic steatosis, weight loss, metabolic homeostasis
- MeSH terms
- Amino Acids, Diabetes Mellitus, Type 2, Glucagon, Glucose, Humans, Hyperglycemia, Non-alcoholic Fatty Liver Disease
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