Gap Junction Communication and Islet Function in Diabetes

2型糖尿病是由于郎格汉斯胰岛内分泌胰岛素的β细胞不能分泌胰岛素所致 足够的胰岛素来补偿增加的胰岛素抵抗。胰岛微环境中的许多因素 包括局部和全身促炎细胞因子的升高，循环中游离脂肪酸的增加，以及 血糖升高会导致随后的β细胞质量和功能下降。然而，这些机制通过 这些因素在哪些方面干扰了β细胞的功能，目前还知之甚少。β-胰岛内的细胞不起作用 自主的：在β细胞之间以及与其他内分泌细胞之间发生广泛的相互作用 胰岛素分泌的调节。在此之前，我们和其他人确定了缝隙连接介导的关键作用 β细胞之间的电通讯协调电活动的动态，[Ca~(2+)]升高 和胰岛素的释放。这项研究计划的总体目标是了解生理作用和 缝隙连接通道在胰岛功能调节中的作用及缝隙连接失调的作用 从糖尿病到胰岛功能障碍和糖尿病的进展。在上一个资助期，我们证明了 在2型糖尿病进展的早期，缝隙连接通道和协调的[Ca~(2+)]被破坏 动物模型和人类糖尿病，而PKCδ在调节这种干扰中发挥了关键作用。我们进一步 证明了升高的缝隙连接偶联可以防止β细胞死亡，这表明 治疗靶点。然而，人们对其调控的分子机制知之甚少。 胰岛内的缝隙连接通道以及可能导致缝隙连接中断的信号机制 糖尿病进展中的沟通。指导我们解决这一悬而未决问题的总体假设 导致糖尿病的条件破坏了缝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 改善糖尿病的进展。为了验证这一假设，我们将进行两个具体目标：1)确定 兴奋性依赖的Cx36缝隙连接形成在健康条件和糖尿病中的作用，以及2)理解 Cx36缝隙连接转运的机制及其在健康条件和糖尿病中的作用。通过 了解朗格汉斯胰岛缝隙连接调控的分子机制，我们 将能够识别缝隙连接通讯和协调[钙]和胰岛素分泌的方式 可以在2型糖尿病和糖尿病前期恢复。这对于改善胰岛功能障碍具有重要意义。 改善血糖控制，防止2型糖尿病患者β细胞功能和质量下降。

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.