Spatially bound functional heterogeneity drives modular organization in β-cell networks

Coordinated responses of pancreatic β-cell networks to changes in extracellular nutrient concentrations are a well-established phenomenon with significant implications for insulin secretion. This study investigates the organization and spatiotemporal activity patterns of collective β-cell dynamics and their relationship to functional network structures. Our findings highlight that functional heterogeneity among β-cells is reflected in oscillatory Ca²⁺ activity that varies within the islet, with spatially adjacent β-cells often exhibiting similar signaling characteristics. We observe a progressive response of β-cells to increasing glucose levels, where they become activated in smaller clusters as glucose levels transition from substimulatory to stimulatory. Furthermore, we show that functional β-cell networks are highly modular, with community structures strongly influenced by the cells' spatial positions and aligning partially with Ca²⁺ activity clusters and, more significantly, with clusters of simultaneous activations in response to glucose increases, highlighting the interrelated nature of these phenomena and the presence of general organizational principles that hold true in both mouse and human islets. We also observe that specific subpopulations, i.e., first responder, wave initiator, and hub cells, are principally distributed across different communities. In mouse islets, their presence is more dependent on their location within the islet, while in human islets, it is more influenced by the activity of the given subregion.