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 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.