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 beta 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 2-3 hours. 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 proinflammatory
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.