Post-Inhibitory Rebound by δ-Cells Transforms Inhibition into Excitationand Redefines Islet Plasticity.

Abstract

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, as a fundamental and previously unrecognized feature of islet physiology. 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. Using a combination of cell-type-specific chemogenetic and optogenetic approaches, high-resolution triple-hormone perifusion, Ca{superscript 2} imaging, in vivo islet grafts, and physiological ligands, we demonstrate that transient {delta}-cell activation or inhibition consistently triggers rebound excitation of {beta}- and -cells. These responses generate glucose-dependent, synchronized oscillations of insulin and glucagon secretion that are partially mediated by somatostatin receptor signaling. Mechanistic insights obtained in mouse islets were recapitulated using translatable approaches in human islets, establishing the relevance of this dynamic signaling framework across species. In vivo, selective {delta}-cell modulation bidirectionally regulated systemic glucose tolerance, confirming {delta}-cell control over endocrine output. These findings support a model in which somatostatin signaling encodes hormone output through temporal dynamics rather than tonic inhibition. By reframing somatostatin as a dynamic regulator of excitability, we identify {delta}-cell-driven rebound as a mechanism that converts inhibition into coordinated endocrine output. Together, this work establishes a revised framework for intra-islet paracrine crosstalk in which temporal dynamics, rather than static inhibition, govern endocrine coordination. Significance StatementHormone secretion in the pancreatic islet has long been explained by inhibitory feedback loops, with somatostatin viewed as a static suppressor of insulin and glucagon release. Our study overturns this paradigm by identifying post-inhibitory rebound (PIR) as a dynamic property of intra-islet signaling. {delta}-cell-driven PIR synchronizes - and {beta}-cell activity, enabling adaptive, glucose-dependent hormone release and revealing that somatostatin confers system plasticity when needed. This work establishes a revised model of intra-islet paracrine crosstalk in which {delta}-cell-driven rebound dynamics, rather than static inhibition, determine endocrine coordination and system plasticity. Our discovery reframes inhibition as a rhythmic and regenerative force, positioning PIR as a potentially generalizable mechanism of excitability across biological systems. HighlightsO_LI{delta}-cells convert inhibition into excitation. Transient somatostatin signals trigger post-inhibitory rebound (PIR) in {beta}- and -cells, generating glucose-dependent synchronized hormone oscillations. C_LIO_LIProvides a mechanistic explanation for a long-standing paradox in human type 2 diabetes. Elevated basal insulin and somatostatin secretion are positively correlated; PIR explains this co-hypersecretion. C_LIO_LIAsymmetric {delta}-cell control confers islet plasticity. Stronger inhibition of -cells versus {beta}-cells enables balanced insulin/glucagon output during feeding or glucagon-skewed surges for hypoglycemia protection. C_LIO_LIMulti-scale validation across species. Chemogenetics, optogenetics, native ligands, Ca{superscript 2} imaging, in vivo grafts, and a data-informed phenomenological model demonstrate conservation from mouse to human islets. C_LIO_LIInhibition is instructive. A revised model of intra-islet paracrine crosstalk in which cell-type-specific temporal dynamics encode hormone output through rebound. C_LI Graphical AbstractSomatostatin, long considered a static inhibitor of growth and secretion, instead acts as a dynamic modulator that transforms inhibition into robust, context-dependent excitation. In the islet, amplified SST pulses drive rebound excitation to promote balanced insulin and glucagon output during anabolic demand, while dampening produces glucagon-skewed surges for protection against hypoglycemia. Inhibition in the islet is not merely suppressive but instructive, encoding future hormone output through rebound dynamics. The same pulse-rebound principle may operate in SST-rich systems such as the brain, gut, and tumors, where dynamic modulation of SST signaling confers adaptability and robustness rather than tonic suppression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/687745v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1a88336org.highwire.dtl.DTLVardef@3e618aorg.highwire.dtl.DTLVardef@175d94forg.highwire.dtl.DTLVardef@decf4_HPS_FORMAT_FIGEXP M_FIG C_FIG