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

• Published in: eLife Vol. 10
• Main Authors: Trogden, Kathryn P, Lee, Justin, Bracey, Kai M, Ho, Kung-Hsien, McKinney, Hudson, Zhu, Xiaodong, Arpag, Goker, Folland, Thomas G, Osipovich, Anna B, Magnuson, Mark A, Zanic, Marija, Gu, Guoqiang, Holmes, William R, Kaverina, Irina
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 16-11-2021; eLife Sciences Publications, Ltd
• Subjects: Animals; Beta cells; biphasic secretion; Calcium influx; Calcium signalling; Cell Biology; computational cluster analysis; Cytoskeleton; Depolymerization; Diabetes; Extracellular matrix; Female; Gene expression; Glucose; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Male; Medicine; Metabolism; Metabolites; Mice; microtubule dynamics; microtubule stability; Microtubules; Microtubules - metabolism; Pancreas; Secretion; Spatio-Temporal Analysis; stimulus-secretion coupling; mouse; cell biology; computational cluster analysis; stimulus-secretion coupling; microtubule stability; biphasic secretion; microtubule dynamics; medicine; diabetes
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.59912

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 Ca
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 Ca
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.