American Diabetes Association
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Glucose regulates microtubule disassembly and the dose of insulin secretion via tau phosphorylation

Version 2 2020-09-04, 15:18
Version 1 2020-06-15, 21:40
posted on 2020-09-04, 15:18 authored by Ada AdminAda Admin, Kung-Hsien Ho, Xiaodun Yang, Anna B. Osipovich, Over Cabrera, Mansuo L. Hayashi, Mark A. Magnuson, Guoqiang Gu, Irina Kaverina
The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau-knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau-knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning-over to restrict insulin over-secretion at basal conditions and preserve the insulin pool that can be released in following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.


This work was supported by National Institutes of Health (NIH) grant R01-DK106228 (to I.K. and G.G.), DK065949 for GG, R35-GM127098 and R01-GM078373 (to I.K.), and Eli Lilly and Company LIFA fellowship 0101420 (to K. H.).