Microtubules regulate pancreatic β cell heterogeneity via spatiotemporal control of insulin secretion hot spots.

Heterogeneity of glucose-stimulated insulin secretion (GSIS) in pancreatic islets is physiologically important but poorly understood. Here, we utilize mouse islets to determine how microtubules affect secretion toward the vascular extracellular matrix at single cell and subcellular levels. Our data indicate that microtubule stability in the β-cell population is heterogenous, and that GSIS is suppressed in cells with highly stable microtubules. Consistently, microtubule hyper-stabilization prevents, and microtubule depolymerization promotes capacity of single β-cell for GSIS. Analysis of spatiotemporal patterns of secretion events shows that microtubule depolymerization activates otherwise dormant β-cells via initiation of secretion clusters (hot spots). Microtubule depolymerization also enhances secretion from individual cells, introducing both additional clusters and scattered events. Interestingly, without microtubules, the timing of clustered secretion is dysregulated, extending the first phase of GSIS and causing oversecretion. In contrast, glucose-induced Ca2+ influx was not affected by microtubule depolymerization yet required for secretion under these conditions, indicating that microtubule-dependent regulation of secretion hot spots acts in parallel with Ca2+ signaling. Our findings uncover a novel microtubule function in tuning insulin secretion hot spots, which leads to accurately measured and timed response to glucose stimuli and promotes functional β-cell heterogeneity.