EJE PRIZE 2018: A gut feeling about glucagon
Abstract
Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues - most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.
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Higher endogenous glucose production during OGTT vs isoglycemic intravenous glucose infusion
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NAFLD as a Continuum: From Obesity to Metabolic Syndrome and Diabetes
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GIP’s involvement in the pathophysiology of type 2 diabetes
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Self-citationMorettini, M., Burattini, L., Göbl, C., Pacini, G., Ahrén, B., & Tura, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.611147 · Cited by 27 · see citing works
- Authors
- Knop, F. K.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Knop, Filip K
- ORCID
- Knop, Filip K
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-06
- Volume
- 178
- Issue
- 6
- Pages
- R267-R280
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2799823142
- Cited by
- 47
- References
- 107
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 3 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 4
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Steno Diabetes Center Copenhagen (SDCC 3.F CMP)
- 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
- hyperglucagonaemia, glucagon secretion, type 2 diabetes, glucose-dependent insulinotropic polypeptide, proglucagon, enteroendocrine cells, hepatic steatosis, circulating amino acids, obesity, liver fat, glucagon resistance
- MeSH terms
- Diabetes Mellitus, Type 2, Fasting, Fatty Liver, Glucagon, Glucose, Glucose Tolerance Test, Humans, Hyperglycemia, Liver, Enteroendocrine Cells, Gastrointestinal Tract, Glucagon-Secreting Cells, Proglucagon
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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