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

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 Ca 2+ 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. • GLP1R is enriched as nanodomains on the beta cell membrane facing alpha cells • GLP1R nanodomains are disrupted with aging and metabolic stress • Beta cells next to alpha cells pre-internalize GLP1R at low glucose • GLP1R pre-internalization allows earlier and more robust responses to high glucose Tong et al. utilize advanced imaging approaches to reveal that beta cells located next to alpha cells are specially adapted as glucagon sensors by virtue of their high expression levels of GLP1R. These beta cells respond first to rising glucose, triggering robust responses across the pancreatic islet.