Investigation of the effects of connexin 36 mediated communication between pancreatic β-cells on intracellular calcium dynamics and diabetes development

β-cells in pancreatic islets are heterogeneous with respect to transcriptional regulation, protein synthesis, hormone secretion and electrical activity. Functional heterogeneity within the islet and its effects on the regulation of hormone secretion have brought new perspectives to diabetes research. Interactions between β-cells within a pancreatic islet are essential for the regulation of insulin secretion and glucose homeostasis. Central to this interaction are gap junction channels, which conduct ionic currents between islet cells and thus enable the cells to coordinate their electrical activity, and the connexin proteins that function in these channels. β-cells are electrically coupled via connexin 36 (Cx36) gap junction channels, which coordinate oscillatory Ca2+ oscillations and insulin secretion within the islet. In this thesis, we obtained genetically defined, inexcitable diabetic β-cell populations, each containing gain of function mutations, and monitored Ca2+ release as an approach to understand the role of heterogeneous cells in the islet in changes in insulin secretion. β-cells in mouse islets expressing mutant KATP channels and thus having high KATP conductance completely silenced Ca2+ release compared to β-cells expressing wild type KATP channels. However, when Cx36 gap junctions were weakened in islets, this suppression of diabetic β-cells expressing mutant type KATP channels was abolished, and oscillations were restored. Again, in an in vitro mouse β-cell model, it was shown that gain of function mutation in Kir6.1 resulted in a significant increase in Cx36 expression. Taken together, these findings suggest that inexcitable β-cell populations can suppress intra islet Ca2+ oscillations, but this suppression can be alleviated by reducing Cx36 mediated conductance, thus restoring oscillatory potential. Supporting the view that Cx36 may be considered a potential target for the treatment of diabetes.