The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice
Open accessAbstract
To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.
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In vitro potency and preclinical efficacy data directly assessing the relationships between receptor potency ratios are lacking and confounded by the apparent reduction in potency of GIPR agonists in rodents and the compensatory sensitization of incretin receptors in genetic knockout mouse lines.
“However, in vitro potency and preclinical efficacy data directly assessing these relationships is lacking and confounded by the apparent reduction in potency of GIPR agonists in rodents [61] and the compensatory sensitization of incretin receptors in genetic knockout mouse lines [62,63].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [63]
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- Authors
- Ahrén, B., Yamada, Y., & Seino, Y.
- Affiliations
- Akita University (JP)
- Kansai Electric Power (Japan) (JP)
- Venue
- Peptides
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 135
- Pages
- 170434
- ISSN
- 0196-9781 (ISSN-L)
- OpenAlex
- W3093756511
- Cited by
- 12
- References
- 49
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 2
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Peptides (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Vetenskapsrådet
- Medicinska Fakulteten, Lunds Universitet
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- GLP-1 receptor, glucagon, insulin secretion, pancreatic beta cells, exendin-9-39, glucose-dependent insulinotropic polypeptide, compensatory mechanisms, pancreatic islets, incretins
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Insulin Secretion, Animals, Blood Glucose, Disease Models, Animal, Glucagon, Glucose, Humans, Insulin, Pancreas, Peptide Fragments, Histone-Lysine N-Methyltransferase, Mice, Knockout, Insulin-Secreting Cells, Mice
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