Glycemia Shift Pancreatic Islets Rhythmicity via δ-α Cell in vivo, Impairment in Diabetes

Blood glucose homeostasis relies on the well-coordinated rhythmic activity of millions of islets throughout the pancreas. Glucose triggers islet rhythmicity, and paracrine signaling shapes it, but population-level dynamics in healthy and diabetic pancreases in vivo remain unclear. Using simultaneous multi-islet Ca2+ imaging (20-100 islets per experiment) in both live mice and pancreatic tissue slices, 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. At high glucose, individual islets behaved largely as autonomous oscillators and differed in phase and period. In diabetic mice with unstable glycemia, islets lost HESF, showed reduced sustained activity at hyperglycemia, and displayed blunted glucose-dependent tuning both in vivo and in vitro. Notably, HESF persisted in β-cell knockout Gcgr transgenetic mice in vivo and in vitro, suggesting HESF’s dependence on Glp1r. Indeed, semaglutide restored HESF in diabetic mice while stabilizing glycemia. These findings offer a comprehensive understanding of how δ and α cells encode glycemic state into islet rhythmicity to support stable blood glucose and how this encoding fails in diabetes. Video. 1 In vivo imaging of Ins1-Cre+/-; GCaMP6ff/+ mice. Hyperglycemia-to-Euglycemia Induces a coordinated Slow-to-Fast (HESF) Islet Ca2+ Oscillation Transition in vivo. Blood glucose, 3 islet Ca2+ traces from Ins1-Cre+/- ; GCaMP6ff/+ mice are shown.