Post-Inhibitory Rebound by δ-Cells Transforms Inhibition into Excitation and Redefines Islet Plasticity

The coordination of hormone secretion within the pancreatic islet remains incompletely understood. Here we identify post-inhibitory rebound (PIR), a transient excitatory overshoot of glucoregulatory hormones following inhibitory signaling within the islet, as a fundamental and previously unrecognized feature of islet physiology, further dissected through δ-cell–specific chemogenetic modulation. Human islets from donors with type 2 diabetes displayed concomitantly elevated insulin and somatostatin secretion with tightly correlated dynamics, a pattern reproduced in islets from high-fat-diet–fed mice. Chemogenetic δ-cell activation and silencing revealed that inhibitory δ-cell signals consistently trigger rebound excitation of β- and α-cells, generating glucose-dependent, synchronized oscillations of insulin and glucagon release that are partially mediated by somatostatin receptors. Physiological δ-cell stimuli, including urocortin-3 and ghrelin, elicited comparable rebound responses, linking this mechanism to native signaling pathways. In vivo, selective δ-cell modulation in islet grafts bidirectionally regulated systemic glucose tolerance, confirming δ-cell control over endocrine output. Beyond the pancreas, this work broadens somatostatin biology, revealing rebound excitation as a conserved motif across neuroendocrine, proliferative, inflammatory, and sensory systems. By reframing somatostatin from static inhibition to rhythmic modulation, these findings show that somatostatin confers system plasticity when needed, establishing δ-cell–driven PIR as a unifying principle of adaptive excitability and endocrine resilience.