Functional architecture of the pancreatic islets reveals first responder cells which drive the first-phase [Ca2+] response

Insulin-secreting β-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine ‘first responder’ cells, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation, distinct from previously identified “hub” and “leader” cells. First responder cells showed characteristics of high membrane excitability and lower electrical coupling to their neighbors. The first-phase response time of β-cells in the islet was spatially organized, dependent on the cell’s distance to the first responder cell, and consistent over time up to ∼24 h. When first responder cells were laser ablated, the first-phase [Ca2+] was slowed down, diminished, and discoordinated compared to random cell ablation. Cells that were next earliest to respond often took over the role of the first responder upon ablation. In summary, we discover and characterize a distinct first responder β-cell state, critical for the islet first-phase response to glucose. ### Competing Interest Statement The authors have declared no competing interest.