eLife (Nov 2021)

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

  • Kathryn P Trogden,
  • Justin Lee,
  • Kai M Bracey,
  • Kung-Hsien Ho,
  • Hudson McKinney,
  • Xiaodong Zhu,
  • Goker Arpag,
  • Thomas G Folland,
  • Anna B Osipovich,
  • Mark A Magnuson,
  • Marija Zanic,
  • Guoqiang Gu,
  • William R Holmes,
  • Irina Kaverina

DOI
https://doi.org/10.7554/eLife.59912
Journal volume & issue
Vol. 10

Abstract

Read online

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 (MTs) affect secretion toward the vascular extracellular matrix at single cell and subcellular levels. Our data indicate that MT stability in the β-cell population is heterogenous, and that GSIS is suppressed in cells with highly stable MTs. Consistently, MT hyper-stabilization prevents, and MT depolymerization promotes the capacity of single β-cell for GSIS. Analysis of spatiotemporal patterns of secretion events shows that MT depolymerization activates otherwise dormant β-cells via initiation of secretion clusters (hot spots). MT depolymerization also enhances secretion from individual cells, introducing both additional clusters and scattered events. Interestingly, without MTs, 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 MT depolymerization yet required for secretion under these conditions, indicating that MT-dependent regulation of secretion hot spots acts in parallel with Ca2+ signaling. Our findings uncover a novel MT function in tuning insulin secretion hot spots, which leads to accurately measured and timed response to glucose stimuli and promotes functional β-cell heterogeneity.

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