Multicellular Interactions and Dynamics of Pancreatic Islet Function in Diabetes

 描述(申请人提供)：2型糖尿病是一种世界性的流行病，困扰着近4亿人，是由朗格汉斯胰岛内的？细胞不能分泌引起的。 足够的胰岛素来补偿胰岛素抵抗，比如肥胖。了解这种缺乏代偿的胰岛功能障碍的机制和糖尿病的原因是开发有效治疗方法的核心。代谢应激导致的许多全身性循环因子或胰岛微环境中的那些因子会降低？细胞功能。然而，它们在糖尿病进展过程中影响胰岛素释放调节的机制还知之甚少。胰岛是多细胞的微器官，细胞间的通讯是调节胰岛素释放的中心。我们已经确定了缝隙连接通道在调节电活动、[Ca~(2+)]和胰岛素释放中的重要作用。我们的初步数据表明，在小鼠模型和人类2型糖尿病病例中，缝隙连接被破坏。重要的是，这种干扰发生在疾病进展的早期，并存在于糖尿病前期。此外，我们的初步数据还表明，缝隙连接可以通过调节[Ca~(2+)]来保护广泛的胰岛功能障碍和细胞死亡。基于这一证据，我们假设，在糖尿病前期或糖尿病发展早期，胰岛缝隙连接被破坏：这影响了胰岛素分泌的动态，包括减少第一时相的释放，但也导致在2型糖尿病进展过程中？细胞对更广泛的功能障碍和死亡的易感性增加。因此，我们预计加强胰岛缝隙连接偶联将保护胰岛免受功能障碍的影响，从而钝化或阻止进展。 糖尿病的症状。我们将通过3个具体目标来验证这一假说：1)确定胰岛中缝隙连接和下游信号被破坏的机制(S)；2)在糖尿病前期和2型糖尿病的小鼠和人类模型中，检测缝隙连接和胰岛素分泌动力学是如何被破坏的；3)测试增强缝隙连接偶联是否可以防止胰岛功能下降和血糖控制丧失。通过了解胰岛作为多细胞单位功能的主要方式的破坏，我们将从根本上表征可能导致2型糖尿病胰岛功能障碍的新机制。因此，我们还可能发现新的、新颖的方法来保存？细胞功能和胰岛。这对于为2型糖尿病的预防性治疗确定新的治疗靶点将是重要的。

 DESCRIPTION (provided by applicant): Type2 diabetes, a world-wide epidemic afflicting close to 400M people, is caused by a failure of ß-cells within the islets of Langerhans to secrete sufficient insulin to compensate for insulin resistance, such as arises in obesity. Understanding the mechanisms of islet dysfunction underlying this lack of compensation and cause of diabetes is central to developing effective treatments. Many systemic circulating factors or those within the islet microenvironment that result from metabolic stress can reduce ß-cell function. However, the mechanisms by which they affect the regulation of insulin release, during the progression of diabetes, are poorly understood. Islets are multi-cellular micro-organs and central to the regulation of insulin release is the communication between cells. We have established an important role for gap junction channels, which electrically couple ß-cells in the islet, in regulating electrical activity, [Ca2+] and insulin release. Our preliminary data suggests that gap junctions are disrupted in mouse models and human cases of type2 diabetes. Importantly this disruption occurs early in disease progression and is present in pre-diabetes. Furthermore, our preliminary data also shows that gap junctions can protect against extensive islet dysfunction and cell death upon ß-cell-stress, via regulating [Ca2+]. Based on this evidence, we hypothesize that islet gap junctions are disrupted in pre-diabetes or early in the development of diabetes: this impacts the dynamics of insulin secretion, including reducing first phase release, but also leads to increased susceptibility of ß-cells to more extensive dysfunction and death during the progression of type2 diabetes. Therefore we anticipate that enhancing islet gap junction coupling will protect the islet from dysfunction and thus blunt or prevent the progression of diabetes. We will test this hypothesis through 3 specific aims: 1) determine the mechanisms(s) by which gap junctions and downstream signaling are disrupted in the islet; 2) examine how gap junctions and insulin secretion dynamics are disrupted in mouse and human models of pre-diabetes and type2 diabetes; 3) test whether enhancing gap junction coupling protects against a decline in islet function and loss of glucose control. By understanding disruptions to the main way the islet functions as a multi- cellular unit, we will characterize fundamentally new mechanisms that can underlie islet dysfunction in type2 diabetes. Thus we may also discover new and novel ways of preserving ß-cell function and islet. This will be important for identifying new therapeutic targets for preventative treatments for type2 diabetes.