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

Abstract

Two key prerequisites for glucose-stimulated insulin secretion (GSIS) in b cells are the proximity of insulin granules to the plasma membrane and their anchoring or docking to the plasma membrane (PM). Although recent evidence has indicated that both of these factors are altered in the context of diabetes, it is unclear what regulates localization of insulin granules and their interactions with the PM within single cells. Here, we demonstrate that microtubule (MT)-motor-mediated transport dynamics have a critical role in regulating both factors. Super-resolution imaging shows that whereas the MT cytoskeleton resembles a random meshwork in the cells' interior, MTs near the cell surface are preferentially aligned with the PM. Computational modeling suggests two consequences of this alignment. First, this structured MT network preferentially 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 or breaking interactions between the PM and the remaining nearby insulin granules. These results predict that altering MT network structure in b cells can be used to tune GSIS. Thus, our study points to the potential of an alternative therapeutic strategy for diabetes by targeting specific MT regulators.

Granular detail of β cell structures for insulin secretion

“…This is similar to other differentiated cells (5) but in contrast to previous data suggesting that in β cells most microtubules originate at the Golgi (6). The microtubule cytoskeleton negatively regulates insulin granule exocytosis in unstimulated cells (7). Yet, the FIB-SEM data suggest that the effect of glucose is not simply to disinhibit this effect.…”

Microtubules and Gαo-signaling independently regulate the preferential secretion of newly synthesized insulin granules in pancreatic islet β cells

“…This network is essential for quick/long-range IG movement but is ill-suited for bulk directional cargo transport (34)(35)(36)(37)(38)(39). Disrupting these MTs acutely enhances GSIS (34,35,40), while stabilizing the MTs represses secretion (34,35,41). A model that is supported by these 100 findings is that β-cell MTs allow active IG-movement between cell interior and cell 101 periphery; however, MTs also compete with the PM for IG binding to acutely reduce 102 the RRP.…”

“…Henceforth, kinesin-or dynein-mediated transport mediates the bulk flow of cargo toward the cell periphery or interior, respectively (33). In contrast, most of the β-cell MTs originate from organizing centers in the Golgi and form a non-directional meshwork (34,35). This network is essential for quick/long-range IG movement but is ill-suited for bulk directional cargo transport (34)(35)(36)(37)(38)(39).…”

“…In contrast, most of the β-cell MTs originate from organizing centers in the Golgi and form a non-directional meshwork (34,35). This network is essential for quick/long-range IG movement but is ill-suited for bulk directional cargo transport (34)(35)(36)(37)(38)(39). Disrupting these MTs acutely enhances GSIS (34,35,40), while stabilizing the MTs represses secretion (34,35,41).…”

Atomistic molecular dynamics simulations of tubulin heterodimers explain the motion of a microtubule

“…Microtubules are known to be involved in the regulation of localization and availability of insulin in pancreaticcells, which makes microtubules interesting candidates for the drug design against diabetes (Bracey et al 2020). Moreover, these species are often seen associated with tumor suppressors in breast cancer and therefore can become biomarkers for this disease (Rodrigues-Ferreira et al 2020;Rong et al 2004).…”