Pancreatic α and β cells are globally phase-locked

Abstract

SUMMARYThe Ca2+ modulated pulsatile secretion of glucagon and insulin by pancreatic α and β cells plays a key role in glucose homeostasis. However, how α and β cells coordinate via paracrine interaction to produce various Ca2+ oscillation patterns is still elusive. Using a microfluidic device and transgenic mice in which α and β cells were labeled with different colors, we were able to record islet Ca2+ signals at single cell level for long times. Upon glucose stimulation, we observed heterogeneous Ca2+ oscillation patterns intrinsic to each islet. After a transient period, the oscillations of α and β cells were globally phase-locked, i.e., the two types of cells in an islet each oscillate synchronously but with a phase shift between the two. While the activation of α cells displayed a fixed time delay of ~20 s to that of β cells, β cells activated with a tunable delay after the α cells. As a result, the tunable phase shift between α and β cells set the islet oscillation period and pattern. Furthermore, we demonstrated that the phase shift can be modulated by glucagon. A mathematical model of islet Ca2+ oscillation taking into consideration of the paracrine interaction was constructed, which quantitatively agreed with the experimental data. Our study highlights the importance of cell-cell interaction to generate stable but tunable islet oscillation patterns.