Glycemia shifts pancreatic islet rhythmicity by influencing interactions between δ cells and α cells

Blood glucose homeostasis relies on coordinated rhythmic activity across pancreatic islets. Glucose triggers islet rhythmicity, but population-level dynamics in pancreases in vivo remain unclear. Using simultaneous multi-islet CA²⁺ imaging in mice and tissue, we systematically studied how glycemia fluctuations and intra-islet paracrine signaling collectively shape the islet rhythmicity. In this study, we report that a transition from hyperglycemia to euglycemia drove a coordinated shift from slow to fast islet CA²⁺ oscillations (HESF) in vivo. HESF was conserved in pancreatic tissue slices but not in dispersed single β cells in vitro, linking the transition to paracrine signaling. Mechanistically, HESF arose from α-cell activation, which is inhibited by δ cells during hyperglycemia. In diabetic mice with unstable glycemia, islets lost HESF both in vivo and in vitro. Semaglutide restored HESF while stabilizing glycemia. These findings reveal how δ and α cells encode the glycemic state into islet rhythmicity to support stable blood glucose. A record of this paper's transparent peer review process is included in the supplemental information.