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Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication.
Jason C L Tong1, Charlotte Frazer-Morris1, Ali H Shilleh1
1Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Cell Metabolism
|July 15, 2025
Summary
Pancreatic alpha cells use glucagon to regulate beta cells. Researchers found that glucagon-like peptide-1 receptor (GLP1R) nanodomains on beta cells sense glucagon, impacting insulin release and islet communication.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Regulation
Background:
- Pancreatic alpha cells secrete glucagon, paracrinely modulating beta cell function.
- The precise molecular mechanisms of alpha-to-beta cell communication are not fully understood.
Purpose of the Study:
- To elucidate the molecular architecture of alpha-to-beta cell communication.
- To investigate the role of glucagon-like peptide-1 receptor (GLP1R) in this interaction.
Main Methods:
- Single-molecule transcript expression analysis.
- In vitro and in vivo imaging of beta cell membrane nanodomains.
- Calcium (Ca2+) imaging in pancreatic islets.
- Assessment of beta cell secretory function.
Main Results:
- GLP1R is enriched in nanodomains on beta cell membranes contacting alpha cells.
- Beta cells near alpha cells internalize GLP1R to sense glucagon at low glucose.
- GLP1R internalization precedes enhanced beta cell calcium responses to high glucose.
- Beta cells adjacent to alpha cells exhibit higher secretory activity.
Conclusions:
- A regulated pathway for glucagon modulation of insulin release via localized GLP1R signaling is detailed.
- This paracrine signaling is crucial for islet function, particularly in the post-prandial state.
- Disruption of GLP1R contacts between alpha and beta cells occurs during metabolic stress.
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