Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

The arrangement of beta cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual b cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the beta cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.