Re-evaluating Intra-Islet Paracrine Signaling: Precision, Pulsatility and the Path toward Mechanistic Clarity

The pancreas regulates glucose homeostasis through the rhythmic secretion of insulin and glucagon into the portal circulation-an essential process that is disrupted early in the pathogenesis of type 2 diabetes. While the metabolic relevance of this pulsatile hormone release is well recognized, the underlying regulatory mechanisms remain incompletely understood. This review highlights emerging insights that redefine pancreatic islets not merely as hormone-producing cell clusters, but as integrated oscillatory networks, capable of coordinating hormone output via tightly controlled intraislet paracrine signaling. We emphasize the critical role of cell-to-cell communication-including interactions between endocrine and non-endocrine cells-in shaping the timing, amplitude, and composition of hormone pulses. Recent findings demonstrate that these intra-islet signals establish systemic glucose thresholds in both mice and humans, thresholds that delineate normoglycemia, prediabetes, and diabetes. Despite their clinical relevance, these mechanisms remain underexplored. We discuss conceptual advances such as Post-Inhibitory Rebound (PIR) responses and propose that systemic hormone pulsatility emerges from coordinated activity across endocrine, neural, and vascular networks. Additionally, we address experimental limitations including receptor desensitization, ligand promiscuity, and artifacts introduced by islet isolation and static incubation assays, which lack the temporal resolution to capture dynamic paracrine interactions. To advance this field, we advocate for the adoption of high-resolution perifusion systems and live-cell biosensor imaging. These technologies offer integrated spatial, temporal, and functional insights that are essential for uncovering the mechanisms governing hormone pulsatility and its dysregulation in diabetes.