Type2 diabetes is caused by an inability of insulin-secreting ?-cells within the islets of Langerhans to secrete sufficient insulin to compensate for increased insulin resistance. Many factors within the islet microenvironment including local and systemic elevations in pro-inflammatory cytokines, increased circulating free-fatty acids, and elevated glucose can contribute to a subsequent decline in ?-cell mass and function. Yet, the mechanisms by which these factors disrupt ?-cell function are poorly understood. ?-cells within the islet do not function autonomously: extensive interactions occur between ?-cells and with other endocrine cells that control the regulation of insulin secretion. Previously, we and others established a critical role for gap-junction mediated electrical communication between ?-cells that coordinates the dynamics of electrical activity, [Ca2+] elevations and insulin release. The overall goal of this research program is to understand the physiological role and regulation of gap junction channels in regulating islet function and the contribution of gap junction dysregulation in diabetes to islet dysfunction and diabetes progression. In the previous funding period, we demonstrated that gap junction channels and coordinated [Ca2+] were disrupted early in the progression of type2 diabetes in both animal models and human diabetes, and that PKC? played a key role in mediating this disruption. We further demonstrated that elevated gap junction coupling could be protective against ?-cell death, suggesting a potential therapeutic target. However very little is known about the molecular mechanisms underlying the regulation of gap junction channels within the islet and what signaling mechanisms may underlie the disruption to gap junction communication in diabetes progression. The overall hypothesis guiding our work to address this open question is that diabetogenic conditions disrupt transcription and post-translational trafficking of gap junction channel proteins; and targeting these pathways can retain proper inter-cellular communication, islet function and ameliorate diabetes progression. To test this hypothesis, we will conduct two specific aims: 1) Determine the role for excitability dependent Cx36 gap junction formation in healthy conditions and diabetes, and 2) Understand the mechanisms underlying Cx36 gap junction trafficking and function in healthy conditions and diabetes. By understanding the molecular mechanisms underlying gap junction regulation within the islet of Langerhans, we will be able to identify means by which gap junction communication and coordinated [Ca2+] and insulin secretion can be recovered in type2 diabetes and pre-diabetes. This will be important for ameliorating islet dysfunction and improving glucose control to prevent the decline in ?-cell function and mass in type2 diabetes.
Dysfunction to insulin secreting cells causes diabetes. Insulin-secreting cells show extensive electrical communication to regulate insulin secretion, and this communication is disrupted during diabetes. Understanding how this electrical communication is disrupted in diabetes will identify targets for retaining normal electrical communication and insulin secretion, thus providing potential drug targets for diabetes prevention.
