δ-α cell-to-cell interactions modulate pancreatic islet Ca2+ oscillation modes

Abstract

Glucose-induced pancreatic islet hormone release is tightly coupled with oscillations in cytoplasmic free Ca2+ concentration of islet cells, which is regulated by a complex interplay between intercellular and intracellular signaling. Delta cells, which entangle with alpha cells located at the islet periphery, are known to be important paracrine regulators. However, the role of delta cells in regulating Ca2+ oscillation pattern remains unclear. Here we show that delta-alpha cell-to-cell interactions are the source of variability in glucose-induced Ca2+ oscillation pattern. Somatostatin secreted from delta cells prolonged the islet's oscillation period in an alpha cell mass-dependent manner. Pharmacological and optogenetic perturbations of delta-alpha interactions led islets to switch between fast and slow Ca2+ oscillations. Continuous adjustment of delta-alpha coupling strength caused the fast oscillating islets to transition to mixed and slow oscillations. We developed a mathematical model, demonstrating that the fast-mixed-slow oscillation transition is a Hopf bifurcation. Our findings provide a comprehensive understanding of how delta cells modulate islet Ca2+ dynamics and reveal the intrinsic heterogeneity of islets due to the structural composition of different cell types.