Impact of the Microtubule Cytoskeleton on Insulin Transport in Beta Cells: A 3D Computational Study

Abstract

Glucose-stimulated insulin secretion (GSIS) in pancreatic {beta} cells is vital to metabolic homeostasis. Recent evidence has highlighted the critical role of the cells microtubule (MT) cytoskeleton in regulating transport and availability of insulin containing vesicles. How these vesicles move within the cell and how that mobility is influenced by the MT network is however not well understood. The MT network in these cells is dense and randomly oriented. Further insulin vesicles are relatively large compared to the spaces in this dense meshwork. Here we develop a 3D computational model that simulates vesicle motions in the dense MT network of the {beta} cell. The structure of this MT network, along with the dynamics of vesicle motions, are calibrated to microscopy data from {beta} cells to ensure physiological relevance. Our results reveal a number of key observations. 1) The MT network in {beta} cells likely impairs motion of larger vesicles (200 - 300nm in diameter). 2) This is in part a consequence of their "caging" by the MT network. 3) This results in a substantial reduction in the likelihood of vesicles transiting from the cells interior to the plasma membrane, a pre-cursor to GSIS. 4) Dynamic remodeling of the MT network reduces the strength of these effects. 5) That same remodeling however introduces anomalous (sub-diffusion) motion characteristics. Taken together, these results indicate that the dense MT network of the {beta} cell substantially inhibits mobility and availability (for GSIS) of insulin. It further sheds light on how the complex filament network in cells leads to statistically anomalous motions. Finally, this modeling further provides a test-bed for determining how potential manipulations of the structure and dynamics of this network would tune GSIS. SIGNIFICANCEInsulin release from pancreatic {beta} cells is crucial for blood sugar regulation, and recent research suggests the microtubule network inside these cells plays a key role in how insulin is transported and released. This study developed a 3D computational model to explore how insulin vesicles move through this dense network. Results show that the microtubules can "cage" larger vesicles, making it difficult for them to reach the cell surface for insulin release. Dynamic remodeling of the network can however increase insulin mobility and availability. These findings highlight the impact of the microtubule network on insulin transport and secretion and provide insight into potential ways to tune this process.