Microtubules and Gαo-signaling modulate the preferential secretion of young insulin secretory granules in islet β cells via independent pathways

For sustainable function, each pancreatic islet beta cell maintains thousands of insulin secretory granules (SGs) at all times. Glucose stimulation induces the secretion of a small portion of these SGs and simultaneously boosts SG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, young insulin SGs are more likely secreted during glucose-stimulated insulin secretion (GSIS) for unknown reasons, while older SGs tend to lose releasability and be degraded. Here, we examine the roles of microtubule (MT) and G alpha o-signaling in regulating the preferential secretion of young versus old SGs. We show that both MT-destabilization and G alpha o inactivation results in more SGs localization near plasma membrane (PM) despite higher levels of GSIS and reduced SG biosynthesis. Intriguingly, MT-destabilization or G alpha o-inactivation results in higher secretion probabilities of older SGs, while combining both having additive effects on boosting GSIS. Lastly, G alpha o inactivation does not detectably destabilize the beta-cell MT network. These findings suggest that G alpha o and MT can modulate the preferential release of younger insulin SGs via largely parallel pathways.

Automated summary

For sustainable function, each pancreatic islet beta cell maintains thousands of insulin secretory granules (SGs). Glucose stimulation induces the secretion of a small portion of these SGs and simultaneously boosts SG biosynthesis to sustain this stock. Young insulin SGs are more likely secreted during glucose-stimulated insulin secretion (GSIS), while older SGs tend to lose releasability and be degraded. The roles of microtubule (MT) and G alpha o-signaling in regulating the preferential secretion of young versus old SGs are examined in this study.