Microtubules Regulate Localization and Availability of Insulin Granules in Pancreatic Beta Cells

Two key prerequisites for glucose stimulated insulin secretion (GSIS) in beta cells are the proximity of insulin granules to the plasma membrane and their anchoring or docking to the plasma membrane (PM). To this point, it is unclear what regulates localization of insulin granules and their interactions with the PM within single cells. We demonstrate that microtubule (MT) motor transport dynamics have a critical role in regulating both factors. Super-resolution imaging shows that while the MT cytoskeleton resembles a random meshwork in the cells’ interior, MTs near the cell surface are aligned with the PM. Computational modeling suggests two consequences of this. First, this structured MT network withdraws granules from the PM. Second, the binding and transport of insulin granules by MT motors prevents their stable anchoring to the PM. These findings suggest the MT cytoskeleton may negatively regulate GSIS by both limiting the amount of insulin proximal to the PM and preventing stable docking of insulin granules to the PM. These results predict that altering MT network structure in beta cells can be used to tune GSIS. Thus, our study points to a potential of an alternative therapeutic strategy for diabetes by targeting specific MT regulators.