Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication

Jason C L Tong¹, Charlotte Frazer-Morris¹, Ali H Shilleh¹, Katrina Viloria¹, Anne de Bray¹, Adithya Muraleedaran Nair¹, Paul R V Johnson², Rebecca Spiers², Ahmad Kobiita³, Oladapo E Olaniru⁴, Shanta J Persaud⁴, Robert Hauffe⁵, André Kleinridders⁵, Carsten Schultz⁶, C Bruce Verchere⁷, Canqi Cui⁸, Jonathan E Campbell⁹, Malgorzata Cyranka¹⁰, Alexey Epanchintsev¹⁰, Carina Ämmälä¹⁰, Johannes Broichhagen¹¹, David J Hodson¹²

Affiliations

¹ Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
³ Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
⁴ Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
⁵ Institute of Nutritional Science, Department of Molecular and Experimental Nutritional Medicine, University of Potsdam, 14558 Nuthetal, Germany.
⁶ Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L334, Portland, OR 97239, USA.
⁷ Departments of Surgery and Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
⁸ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
⁹ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
¹⁰ Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK.
¹¹ Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
¹² Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Electronic address: david.hodson@ocdem.ox.ac.uk.

PMID: 40664215
PMCID: PMC12276844 (available on 2026-07-14)
DOI: 10.1016/j.cmet.2025.06.009

Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication

Jason C L Tong et al. Cell Metab. 2025.

. 2025 Aug 5;37(8):1698-1714.e5.

doi: 10.1016/j.cmet.2025.06.009. Epub 2025 Jul 14.

Authors

Affiliations

¹ Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
³ Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
⁴ Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
⁵ Institute of Nutritional Science, Department of Molecular and Experimental Nutritional Medicine, University of Potsdam, 14558 Nuthetal, Germany.
⁶ Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L334, Portland, OR 97239, USA.
⁷ Departments of Surgery and Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
⁸ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
⁹ Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
¹⁰ Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK.
¹¹ Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
¹² Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Electronic address: david.hodson@ocdem.ox.ac.uk.

PMID: 40664215
PMCID: PMC12276844 (available on 2026-07-14)
DOI: 10.1016/j.cmet.2025.06.009

Abstract

Pancreatic alpha cells modulate beta cell function in a paracrine manner through the release of glucagon. However, the detailed molecular architecture underlying alpha-to-beta cell regulation remains poorly characterized. Here, we show that the glucagon-like peptide-1 receptor (GLP1R) is enriched as nanodomains on beta cell membranes that contact alpha cells, in keeping with increased single-molecule transcript expression. At low glucose, beta cells next to alpha cells directly sense micromolar glucagon release by pre-internalizing GLP1R. Pre-internalized GLP1R is associated with earlier beta cell Ca²⁺ responses to high glucose, which are then propagated across the islet. Beta cells adjacent to alpha cells are more secretory than beta cells next to other beta cells. Localized GLP1R signaling occurs in vitro and in vivo, is operative in the post-prandial state, and GLP1R contacts decrease between beta cells and alpha cells during metabolic stress. Thus, we detail a regulated pathway through which glucagon modulates insulin release.

Keywords: Ca(2+); GLP1R; alpha cell; beta cell; diabetes; glucagon; insulin; islet; pancreas; signaling.

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Conflict of interest statement

Declaration of interests M.C., A.E., and C.Ä. are employees of Novo Nordisk A/S. J.E.C. has received funding for research from Eli Lilly, Novo Nordisk, Merck, Structure Therapeutics, Fractyl Therapeutics, Alticore, and Prostasis. J.E.C. has served as a consultant/advisory in the past 12 months with Arrowhead Therapeutics, Boehringer Ingelheim, Neurocrine Biosciences, Protagonist Therapeutics, Prostasis, and Structure Therapeutics. A. Kleinridders has received speaker’s fees from Novo Nordisk A/S and Daiichi Sankyo. D.J.H. and J.B. have filed a patent on GLP1R and GIPR chemical probes. D.J.H. and J.B. receive licensing revenue from Celtarys Research for provision of GLP1R/GIPR chemical probes. D.J.H., A.H.S. and K.V. have filed patents related to type 2 diabetes therapy and GLP1R agonism.

References

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Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication

Affiliations

Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous