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 (MTs) affect secretion toward the vascular extracellular matrix at single cell and subcellular levels. Our...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	microtubule stability diabetes biphasic secretion stimulus-secretion coupling computational cluster analysis microtubule dynamics Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9506901faa9e40da9a5c9f740c2f02ad
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spelling	oai:doaj.org-article:9506901faa9e40da9a5c9f740c2f02ad2021-12-01T08:29:01ZMicrotubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots10.7554/eLife.599122050-084Xe59912https://doaj.org/article/9506901faa9e40da9a5c9f740c2f02ad2021-11-01T00:00:00Zhttps://elifesciences.org/articles/59912https://doaj.org/toc/2050-084XHeterogeneity 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.Kathryn P TrogdenJustin LeeKai M BraceyKung-Hsien HoHudson McKinneyXiaodong ZhuGoker ArpagThomas G FollandAnna B OsipovichMark A MagnusonMarija ZanicGuoqiang GuWilliam R HolmesIrina KaverinaeLife Sciences Publications Ltdarticlemicrotubule stabilitydiabetesbiphasic secretionstimulus-secretion couplingcomputational cluster analysismicrotubule dynamicsMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microtubule stability diabetes biphasic secretion stimulus-secretion coupling computational cluster analysis microtubule dynamics Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	microtubule stability diabetes biphasic secretion stimulus-secretion coupling computational cluster analysis microtubule dynamics Medicine R Science Q Biology (General) QH301-705.5 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 Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
description	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.
format	article
author	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
author_facet	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
author_sort	Kathryn P Trogden
title	Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
title_short	Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
title_full	Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
title_fullStr	Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
title_full_unstemmed	Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
title_sort	microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/9506901faa9e40da9a5c9f740c2f02ad
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Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots

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