Microtubules regulate pancreatic β cell heterogeneity via spatiotemporal control of insulin secretion hot spots
- Vanderbilt University, United States
Abstract
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.
Data availability
All numerical data generated during this study are included in the manuscript and supporting files. Source data files have been provided for all figures. Code is provided for computational data.
Article and author information
Author details
Funding
National Institutes of Health (T32 DK07061)
- Kathryn P Trogden
National Institutes of Health (1F32DK117529)
- Kathryn P Trogden
National Institutes of Health (R35-GM127098)
- Irina Kaverina
National Institutes of Health (R01-DK65949)
- Guoqiang Gu
National Institutes of Health (DMS1562078)
- William R Holmes
National Institutes of Health (R01-DK106228)
- Guoqiang Gu
- William R Holmes
- Irina Kaverina
National Institutes of Health (R35-GM119552)
- Marija Zanic
National Institutes of Health (F31 DK122650)
- Kai M Bracey
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (protocol M1500060-00) of Vanderbilt University.
Copyright
© 2021, Trogden et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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