Gap Junction Communication and Islet Function in Diabetes

2型糖尿病是由胰岛内分泌胰岛素的β细胞无法分泌胰岛素引起的。 足够的胰岛素以补偿增加的胰岛素抵抗。胰岛微环境中的许多因素 包括促炎细胞因子的局部和全身升高，循环游离脂肪酸增加， 升高的葡萄糖可导致随后的β细胞质量和功能的下降。然而， 这些因子破坏β细胞功能的机制尚不清楚。胰岛内的β细胞不起作用 自主地：β细胞之间以及与其他控制细胞的内分泌细胞之间发生广泛的相互作用。 调节胰岛素分泌。以前，我们和其他人建立了间隙连接介导的关键作用， β细胞之间的电通信，协调电活动的动力学，[Ca 2 +]升高 和胰岛素释放。这项研究计划的总体目标是了解生理作用， 缝隙连接通道在调节胰岛功能中的作用及缝隙连接失调的作用 糖尿病与胰岛功能障碍和糖尿病进展的关系。在上一个融资期，我们证明， 在2型糖尿病进展的早期， 动物模型和人类糖尿病，PKCδ在介导这种破坏中发挥了关键作用。我们进一步 表明，间隙连接偶联升高可以保护β细胞死亡，这表明潜在的 治疗靶点然而，对调节细胞凋亡的分子机制知之甚少。 胰岛内的缝隙连接通道以及缝隙连接破坏的信号机制 糖尿病进展中的沟通。指导我们解决这一未决问题的总体假设 致糖尿病条件破坏间隙连接通道的转录和翻译后运输 蛋白质;靶向这些途径可以保持适当的细胞间通讯，胰岛功能和 改善糖尿病进展。为了验证这一假设，我们将进行两个具体的目标：1）确定 兴奋性依赖性Cx 36间隙连接形成在健康状况和糖尿病中的作用，以及2）了解 Cx 36间隙连接运输和功能在健康状况和糖尿病中的潜在机制。通过 了解胰岛内间隙连接调节的分子机制，我们 将能够确定间隙连接通讯和协调[Ca 2 +]和胰岛素分泌的方式， 在2型糖尿病和糖尿病前期可以恢复。这对于改善胰岛功能障碍将是重要的 以及改善血糖控制以防止2型糖尿病中β细胞功能和质量的下降。

Type2 diabetes is caused by an inability of insulin-secreting β-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 β-cell mass and function. Yet, the mechanisms by which these factors disrupt β-cell function are poorly understood. β-cells within the islet do not function autonomously: extensive interactions occur between β-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 β-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 PKCδ played a key role in mediating this disruption. We further demonstrated that elevated gap junction coupling could be protective against β-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 β-cell function and mass in type2 diabetes.