Localized GLP-1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication

Journal article

Pancreatic alpha cells modulate beta cell function in a paracrine manner through the release of glucagon. Failure of alpha- to beta-cell communication leads to impaired insulin secretion and hyperglycemia. However, the detailed molecular architecture underlying alpha- to beta-cell regulation remains poorly characterized. Here, we show that glucagon-like peptide-1 receptor (GLP1R) is enriched as nanodomains on beta cell membranes in close contact with alpha cells, in keeping with increased single molecule transcript expression. At low glucose, beta cells located next to alpha cells directly sense micromolar glucagon release by pre-internalizing GLP1R. Preinternalized 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 signalling occurs in vitro and in vivo, is operative in the postprandial state, and GLP1R contacts decrease between beta cells and alpha cells with advancing age and high fat diet. Thus, we detail a regulated pathway through which glucagon modulates insulin release. More broadly, we provide a framework for how G protein-coupled receptors and promiscuous signalling fine-tune intercellular communication in complex tissue.

Authors: Tong, J; Frazer-Morris, C; Shilleh, A; Viloria, K; De Bray, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Metabolism
• Publication date: 2025-07-14
• Acceptance date: 2025-05-07
• DOI: 10.1016/j.cmet.2025.06.009
• EISSN: 1932-7420
• ISSN: 1550-4131
• Language: English