G protein mediated mechanisms of beta-cell compensation and failure in type 2 diabetes

糖尿病是一种代价高昂且复杂的慢性病，是一个严重的公共卫生问题。目前，流行率 退伍军人中糖尿病的发病率约为25%，更多的退伍军人因 肥胖、衰老和不良生活方式，以及因公接触已知的糖尿病致化学物质。 在接下来的几十年里，患有糖尿病的退伍军人的数量肯定会增加，就像今天的孩子一样 据估计，患糖尿病的总终身风险接近50%。因此，开发新的方法来 预防糖尿病，识别和妥善治疗糖尿病患者是非常及时和重要的意义。 根据定义，当胰腺的β细胞产生的胰岛素不足时，就会发生糖尿病 刺激身体细胞从血液中吸收葡萄糖，并切断更多葡萄糖的产生。当他们 有不同的病因，1型(免疫介导的)和2型(肥胖相关)糖尿病的病理生理学 越来越多地被作用于胰岛素的功能失调的细胞和分子信号过程联系在一起- 分泌β细胞。有一种分子是我们研究计划的基石，名为Gαz，它有可能 在一个或多个影响β细胞功能、复制、生长和/或存活的信号过程中发挥枢纽作用。 因此，针对这些功能失调的Gαz信号转导过程可能有助于改善β细胞的功能 在两种类型的糖尿病中都有肿块。我们的长期目标是完全表征Gαz的激活和信号转导 在组织、组织、细胞和分子水平上的糖尿病状态的通路，指导我们调节 这一途径用于预防和治疗目的。这项工作的总体目标，也就是下一步 我们追求目标的合乎逻辑的一步，是确定分子和细胞信号通路的特征 了解G-α-z信号在糖尿病病理生理学中的作用。我们的中心假设是激活的β-细胞Gαz 负性调节对β细胞至关重要的特定细胞内和自分泌/旁分泌信号通路 补偿，最终导致β-细胞死亡和功能障碍，并加剧糖尿病的情况。我们 将在多种糖尿病临床前模型中检验我们的中心假设，从而实现这一目标 通过追求以下两个具体目标来实现这一应用：1.确定胰岛检查的要求 和/或GLP1R在G-αz缺失小鼠T2D保护中的作用及其机制 保护；以及2.确定构成活性和下游的分子机制 激动剂刺激的EP3以及这些在高度代偿和T2Dβ细胞中是如何改变的。在这两个地方 AIMS，胰岛EP3剪接变异体激动剂依赖和非依赖信号之间的关系 将确定对GLP1-RAS的反应性。随着这些目标的实现，我们预计会有更多 全面了解β细胞及其信号分子在糖尿病病理生理学中的作用。 最终，分离Gαz对β细胞的影响并充分表征其信号机制将有助于合理地 并在β细胞中特异性靶向该通路以改善糖尿病β细胞功能障碍和功能丧失 β-细胞团。

Diabetes is a costly and complex chronic illness and a serious public health problem. Currently, the prevalence of diabetes in the VA patient population is approximately 25%, with many more Veterans at risk for diabetes due to obesity, aging, and poor lifestyle, as well as exposure to known diabetogenic chemicals in the line of duty. The number of Veterans with diabetes is certain to increase over the next decades, as the children of today have an estimated overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods for preventing diabetes and identifying and properly treating diabetic patients is very timely and of great significance. By definition, diabetes occurs when insufficient insulin is produced from the β-cells of the pancreas to properly stimulate the body cells to take up glucose from the blood and shut off production of more glucose. While they have different etiologies, the pathophysiology of type 1 (immune-mediated) and type 2 (obesity-related) diabetes is increasingly being linked by dysfunctional cellular and molecular signaling processes that act in the insulin- secreting β-cells. One molecule that is a cornerstone of our research program, termed Gαz, has the potential to act as a hub in one or more signaling processes impacting on β-cell function, replication, growth and/or survival. Thus, targeting these dysfunctional Gαz signaling processes could potentially help to improve functional β-cell mass in both types of diabetes. Our long-term goal is to fully characterize the Gαz activation and signaling pathways in the diabetic state at the organismal, tissue, cellular, and molecular levels, guiding us in modulating this pathway for preventative and therapeutic purposes. The overall objective of this work, which is the next logical step in pursuit of our goal, is to characterize the molecular and cellular signaling pathways responsible for the impact of Gαz signaling on diabetes pathophysiology. Our central hypothesis is activated β-cell Gαz negatively modulates specific intracellular and autocrine/paracrine signaling pathways critical for β-cell compensation, ultimately leading to β-cell death and dysfunction and exacerbating the diabetic condition. We will test our central hypothesis in multiple pre-clinical models of diabetes and, thereby, accomplish the objective of this application, by pursuing the following two specific aims: 1. Determine the requirement of islet CCKAR and/or GLP1R in the T2D protection of full-body Gαz-null mice and the mechanisms behind this protection; And 2. Determine the molecular mechanisms downstream of constitutively-active and agonist-stimulated EP3 and how these are altered in the highly-compensating and T2D beta-cell. In both aims, the relationship between agonist-dependent and -independent signaling of EP3 splice variants in islet responsiveness to GLP1-RAs will be determined. With the completion of these aims, we anticipate a much more complete understanding of the role of the β-cell and its signaling molecules in the pathophysiology of diabetes. Ultimately, isolating Gαz effects to the β-cell and fully characterizing its signaling mechanisms will aid in rationally and specifically targeting this pathway in the β-cell to improve diabetic β-cell dysfunction and loss of functional β-cell mass.