ArticleThe Journal of biological chemistry2022
Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Dual Glucagon and GLP-1 Receptor Agonist Survodutide Improves Biomarkers of Beta-Cell Function and Insulin Sensitivity in People With Type 2 Diabetes or Living With Overweight/Obesity.Diabetes, obesity & metabolism · 2026Trial
- Postnatal refinement of CaChannels (Austin, Tex.) · 2026Article
- Intra-Islet Paracrine Regulation of Glucagon Secretion During Hypoglycemia, Euglycemia, and Hyperglycemia.Annals of the New York Academy of Sciences · 2026Review
- Article
- Pancreatic α cells are required for nutrient homeostasis by regulating dynamic β cell networks in islets.Science advances · 2026Article
- GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice.Molecular metabolism · 2026Article
- Assessing the rate dependence of the first phase of glucose-stimulated insulin secretion: dynamic perifusion studies with isolated human pancreatic islets.American journal of physiology. Endocrinology and metabolism · 2025Article
- Constructing chimeric mouse islets to study alpha- and delta-cell influence on beta-cell feature.Molecular metabolism · 2025Article
- Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication.Cell metabolism · 2025Article
- Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance.Nature communications · 2025Article
- Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs.Scientific reports · 2024Article
- Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet.American journal of physiology. Endocrinology and metabolism · 2024Review
- Intra-islet α-cell Gs signaling promotes glucagon release.Nature communications · 2024Article
- Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function.Comprehensive Physiology · 2024Review
- High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans.Diabetes · 2024 · on this mapArticle
- A primer on modelling pancreatic islets: from models of coupled β-cells to multicellular islet models.Islets · 2023Review
- Review
- Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.Diabetes · 2023Article
- Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice.Diabetes · 2023Article
- Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
We report that intra-islet glucagon secreted from α-cells signals through β-cell glucagon and GLP-1 receptors (GcgR and GLP-1R), thereby conferring to rat islets their competence to exhibit first-phase glucose-stimulated insulin secretion (GSIS). Thus, in islets not treated with exogenous glucagon or GLP-1, first-phase GSIS is abolished by a GcgR antagonist (LY2786890) or a GLP-1R antagonist (Ex[9-39]). Mechanistically, glucose competence in response to intra-islet glucagon is conditional on β-cell cAMP signaling because it is blocked by the cAMP antagonist prodrug Rp-8-Br-cAMPS-pAB. In its role as a paracrine hormone, intra-islet glucagon binds with high affinity to the GcgR, while also exerting a "spillover" effect to bind with low affinity to the GLP-1R. This produces a right shift of the concentration-response relationship for the potentiation of GSIS by exogenous glucagon. Thus, 0.3 nM glucagon fails to potentiate GSIS, as expected if similar concentrations of intra-islet glucagon already occupy the GcgR. However, 10 to 30 nM glucagon effectively engages the β-cell GLP-1R to potentiate GSIS, an action blocked by Ex[9-39] but not LY2786890. Finally, we report that the action of intra-islet glucagon to support insulin secretion requires a step-wise increase of glucose concentration to trigger first-phase GSIS. It is not measurable when GSIS is stimulated by a gradient of increasing glucose concentrations, as occurs during an oral glucose tolerance test in vivo. Collectively, such findings are understandable if defective intra-islet glucagon action contributes to the characteristic loss of first-phase GSIS in an intravenous glucose tolerance test that is diagnostic of type 2 diabetes in the clinical setting.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.