Microtubules regulate pancreatic beta cell heterogeneity via spatiotemporal control of insulin secretion hot spots

Abstract

37Heterogeneity of glucose-stimulated insulin secretion (GSIS) in pancreatic islets is 38 physiologically important but poorly understood. Here, we utilize whole mouse islets to 39 determine how microtubules affect secretion toward the vascular extracellular matrix. Our data 40indicate that microtubule stability in the β-cell population is heterogenous, and that cells with 41 more stable microtubules secrete less in response to a stimulus. Consistently, microtubule 42hyper-stabilization prevents, and microtubule depolymerization promotes β-cell activation. 43Analysis of spatiotemporal patterns of secretion events shows that microtubule 44 depolymerization activates otherwise dormant β-cells via initiation of secretion clusters (hot 45 spots). Microtubule depolymerization also enhances secretion from individual cells, introducing 46both additional clusters and scattered events. Interestingly, without microtubules, the timing of 47 clustered secretion is dysregulated, extending the first phase of GSIS. Our findings uncover a 48 novel microtubule function in tuning insulin secretion hot spots, which leads to accurately 49 measured and timed response to glucose stimuli and promotes functional β-cell heterogeneity. 50

Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model

“…Microtubules are critical in glucose stimulated insulin secretion [ 56 ], regulating the availability of insulin [ 57 ] and allowing the travel of insulin granules along tubulin tracks [ 58 ]. Upon microtubule destabilisation, a subset of insulin granules are released [ 59 ]. High AGE environments consistently reduce the ability of β-cells to secrete insulin which has been attributed to an increase in oxidative stress [ 11 , 13 , 16 ].…”

“…High AGE environments consistently reduce the ability of β-cells to secrete insulin which has been attributed to an increase in oxidative stress [ 11 , 13 , 16 ]. What would be interesting to substantiate in the future, is if high AGE environments result in changes or depolymerisation [ 14 ] or hyper-stabilization of the dense microtubular structure in the β-cell, resulting in insulin secretory dysfunction [ 59 , 60 ].…”