Regulation of Coupled beta-Cell Electrical Dynamics

Pancreatic beta-cells are the only cell type responsible for secreting insulin; a hormone necessary for maintaining glucose homeostasis. beta-cells are a naturally heterogeneous in expression of genes regulating glucose metabolism and electrophysiology; leading to a population of cells with unique electrical dynamics. Electrical communication between beta-cells through connexin36 gap junctions act to synchronize electrical activity and coordinate insulin secretion dynamics to promote efficacy of glucose clearing. In models of diabetes there is disruption to the coordinated electrical dynamics within pancreatic islets. However, what role functional subpopulations play in mediating this disruption or the extent to which this disruption occurs in human islets is poorly understood.;The objectives of this thesis is to determine (1) develop a computational multicellular model of pancreatic islet electrophysiology and test if it can recapitulate two aspects of Cx36 mediated electrical dysfunction (2) determine what role subpopulations play in controlling electrical activity and coordination within pancreatic islets (3) test if age and type2 diabetes in humans correlate with decreases to electrical coordination within islets. To recapitulate in-vivo models of pancreatic islet dysfunction we expanded on an established single-cellular computational model of beta-cell electrophysiology by generating a coupled beta-cell network with islet architecture. I found the model was able to correctly predict critical loss in electrical activity and coordination; mediated by the electrical coupling between beta-cells. To determine the role of functional subpopulations I created a transgenic mouse model with beta-cell specific expression of Channelrhodopsin-2 and implemented a protocol of spatiotemporal [Ca2+] activation combined with two-photon imaging of metabolic activity which showed subpopulations of cells were spatially orientated and showed preferential control over electrical activity and dynamics within islets. Lastly, we tested the hypothesis that advanced age and type2 diabetes correlate with decreases to electrical coordination within human pancreatic islets through imaging of [Ca2+] activity and developing a novel image analysis algorithm to quantify electrical coordination. I found that both advanced age and history of type2 diabetes correlated with significant decreases to electrical activity and coordination within human islets. Furthermore, we found that a Cx36 activator could restore electrical coordination within aged and type2 diabetic human islets.;The results presented herein provide insight into regulating factors of coordinated electrical dynamics between beta-cells and show potential for a novel therapeutic to recover pancreatic beta-cell function.