Multiscale Synchronization in Beta Cell Networks: Connecting Cellular Oscillations to Hormone Secretion.

Within the islets of Langerhans, pancreatic beta cells coordinate pulsatile insulin release that is essential for metabolic homeostasis. This coordination emerges from complex intercellular coupling and unfolds at least on three nested timescales: (i) slow, metabolism-driven oscillations lasting several minutes; (ii) fast, electrically driven bursts of a few seconds; and (iii) ultrafast action-potential spikes on the order of tens of milliseconds. To unravel the principles governing this multiscale collective behavior and its link to secretion, we developed a phenomenological multicellular mathematical model based on realistic intercellular interaction patterns and combined it with timescale-specific functional connectivity analysis. Despite its deliberate simplicity, the model reproduces the rich dynamics observed experimentally, disentangling how structural coupling and multimodal connectivity patterns shape wave-like signal propagation across all three oscillatory domains. By extending the model with a secretion module, we demonstrate that the metabolic oscillation dictates the period of insulin pulses, whereas burst activity modulates their amplitude by sculpting underlying spike trains and determining the duty cycle or active time. The integrated framework therefore explains how coupling between distinct temporal domains and intercellular interactions supports robust regulation of secretion under different stimulatory conditions. Finally, by imposing changes in the form of decreased intercellular coupling and increased cellular excitability, the model predicts diminished insulin pulsatility together with elevated average secretory output, thereby recapitulating key features of secretory dysregulation observed during the early stages of type 2 diabetes pathogenesis. Thus, our findings provide a unifying multiscale perspective on beta cell network dynamics and identify specific network features whose disruption may underlie disease-related secretory defects, offering quantitative targets for experimental interrogation and therapeutic intervention.