The microtubule (MT) cytoskeleton of pancreatic β cells is important for glucose-stimulated insulin secretion (GSIS). We have recently shown that the MT-mediated transportation of insulin vesicles away from the plasma membrane limits insulin secretion, and that the disassembly of MTs is necessary for robust GSIS. Here, we report that high glucose induces rapid MT disassembly at the cell periphery measured by real-time imaging of photoconverted MTs in islet β cells. The MT-associated protein Tau regulates this process. Tau is known to stabilize MTs by direct association, and Tau hyperphosphorylation leads to MT disassembly. Along this line, we found that high glucose induced Tau hyperphosphorylation and dissociation from MTs in mouse islet β cells. ShRNA-based Tau knockdown in islets directly destabilized MTs, eliminating the glucose responsiveness of the MT dynamics, increasing basal insulin secretion, and impairing GSIS. Moreover, we showed that the glucose-induced Tau hyperphosphorylation relied on kinase GSK3, which is likely regulated by the PI3K-Akt, but not insulin signaling. We propose that Tau stabilizes MTs in low glucose to restrict basal secretion. In high glucose, Tau is hyperphosphorylated by GSK3 to promote MT disassembly at cell periphery to facilitate the release of the secretable insulin pool.
K. Ho: Research Support; Self; Eli Lilly and Company. G. Gu: None. I. Kaverina: None.