Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots.
Microtubules regulate pancreatic β-cell heterogeneity via spatiotemporal control of insulin secretion hot spots.
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DOI：
10.7554/elife.59912
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发表时间：
2021-11-16
期刊：
影响因子：
7.7
通讯作者：
Kaverina I
中科院分区：
文献类型：
--
作者：
Trogden KP;Lee J;Bracey KM;Ho KH;McKinney H;Zhu X;Arpag G;Folland TG;Osipovich AB;Magnuson MA;Zanic M;Gu G;Holmes WR;Kaverina I
胰岛中葡萄糖刺激的胰岛素分泌（GSIS）的异质性在生理上是重要的，但知之甚少。在这里，我们利用小鼠胰岛，以确定如何微管（MT）影响分泌向血管细胞外基质在单细胞和亚细胞水平。我们的数据表明，MT在β细胞群中的稳定性是异质的，并且GSIS在具有高度稳定MT的细胞中受到抑制。因此，MT的超稳定化可阻止单个β细胞发生GSIS，而MT的解聚可促进单个β细胞发生GSIS。对分泌事件的时空模式的分析显示，MT解聚通过分泌簇（热点）的起始激活原本休眠的β细胞。MT解聚也增强了单个细胞的分泌，引入了额外的簇和分散的事件。有趣的是，没有MT，聚集分泌的时间失调，延长了GSIS的第一阶段并导致分泌过度。与此相反，葡萄糖诱导的Ca2+内流不受MT解聚的影响，但需要在这些条件下的分泌，表明MT依赖性调节的分泌热点与Ca2+信号传导平行。我们的研究结果揭示了一种新的MT功能，调节胰岛素分泌热点，这导致准确测量和定时响应葡萄糖刺激，并促进功能β细胞异质性。
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.