Targeting an atypical signaling hub to restore and protect whole body glucose homeostasis

2型糖尿病（T2 D）目前已在全球范围内达到流行病的比例。期间 糖尿病前期，血糖升高和心血管后果的风险，如中风，心肌梗死， 梗死和死亡率已经增加了2-4倍。尽管如此， 了解糖尿病前期的发展方式和原因。阻止或逆转T2 D发展的战略需要 多管齐下的方法，因为病理生理学涉及胰腺β细胞葡萄糖功能障碍， 刺激胰岛素释放，以及在骨骼肌（skm）中从循环中摄取/清除葡萄糖。因素 与这两个过程中的失败相关的被认为是最佳的治疗靶点。我们已经确定了p21- 活化的激酶PAK 1，作为这样一种因子;它是β细胞和skm中的信号中枢，协调 葡萄糖稳态的多个方面。PAK 1在T2 D中缺乏，这表明其丢失可能是一个“路障” 阻止了T2 D患者的正常信号传导为了克服PAK 1缺陷的障碍，我们需要了解 PAK 1在β细胞和皮肤中的作用机制。我们的长期目标是了解β细胞如何 并且skm信号传导可以被操纵以预防或逆转前驱糖尿病并阻止向T2 D的进展。我们 中心假设是1）通过β细胞中的PAK 1枢纽的信号传导控制功能性β细胞群， 逆转HFD诱导的葡萄糖耐受不良，以及2）皮肤中的PAK 1信号提供胰岛素保护 抵抗并参与组织串扰以增强β细胞功能。拟议研究的基本原理是 一旦PAK 1效应子的这些新机制被阐明， 可以操纵毂以防止或逆转T2 D。在上一个融资周期中，我们发现， T2 D人胰岛β细胞中的PAK 1逆转功能失调的胰岛素分泌，同时减少β细胞线粒体 功能障碍和凋亡。我们还发现，PAK 1富集在skm中可以保护HFD诱导的葡萄糖 不耐受，并参与组织串扰以改善β细胞功能。我们最新的初步数据 还表明哪些PAK 1效应子执行这些基本功能。因此，本申请的目的 目的是测试这些候选机制，这些机制将PAK 1效应物富集与β细胞和skm的保护联系起来， 致糖尿病应激和评价候选PAK 1效应物富集治疗剂。我们会用我们的诱导剂 用于这些研究的组织特异性小鼠模型和人组织/细胞。在目标1中，我们将确定PAK 1 在目标2中，我们将阐明PAK 1效应子保护β细胞功能的机制。 β细胞群;在目标3中，我们将辨别skm PAK 1促进外周胰岛素分泌的机制。 敏感性和β细胞健康。我们将使用创新的分子工具来测试关于这些PAK 1的新假设。 在City of Hope以预防为重点的制度环境背景下，采取有效行动。这项工作将 积极影响糖尿病研究通过评估一个有前途的候选战略，以扭转糖尿病前期， 阻止进展为T2 D和发现新的葡萄糖稳态机制。

Project Summary/Abstract – Type 2 diabetes (T2D) has now reached epidemic proportions worldwide. During pre-diabetes, blood sugars rise and the risk of cardiovascular consequences, such as stroke, myocardial infarction and mortality, is already increasing by 2-4-fold. Despite this, there remains a fundamental gap in understanding how and why pre-diabetes develops. Strategies to halt or reverse T2D development require a multi-pronged approach, since the pathophysiology involves both dysfunction in pancreatic β-cell glucose- stimulated insulin release, and in skeletal muscle (skm) glucose uptake/clearance from the circulation. Factors linked to failures in both processes are considered optimal therapeutic targets. We have identified the p21- activated kinase, PAK1, as such a factor; it is a signaling hub in both the β-cells and skm that orchestrates multiple aspects of glucose homeostasis. PAK1 is deficient in T2D, suggesting that its loss may be a “roadblock” that prevents normal signaling in T2D. To overcome the roadblock of PAK1 deficiency, we need to understand the mechanisms linking PAK1 to its functions in β-cells and skm. Our long-term goal is to understand how β-cell and skm signaling can be manipulated to prevent or reverse pre-diabetes and halt the progression to T2D. Our central hypothesis is that 1) signaling through the PAK1 hub in the β-cell controls functional β-cell mass to reverse HFD-induced glucose intolerance, and that 2) PAK1 signals in skm confer protection from insulin resistance and engage in tissue crosstalk to enhance β-cell function. The rationale for the proposed research is that once these new mechanisms of the PAK1 effectors are elucidated, select signaling pathways from the PAK1 hub can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed that restoring PAK1 in T2D human islet β-cells reverses dysfunctional insulin secretion while reducing β-cell mitochondrial dysfunction and apoptosis. We also showed that PAK1 enrichment in skm protects against HFD-induced glucose intolerance, and engages in tissue crosstalk to improve β-cell function. Our provocative new preliminary data also indicate which PAK1 effectors carry out these essential functions. Therefore, the objective of this application is to test these candidate mechanisms linking PAK1 effector enrichment and protection of β-cells and skm from diabetogenic stress and to evaluate candidate PAK1 effector enrichment therapeutics. We will use our inducible tissue-specific mouse models and human tissues/cells for these studies. In Aim 1, we will identify how the PAK1 effectors restore β-cell function; in Aim 2, we will elucidate the mechanism(s) by which PAK1-effectors protect β-cell mass; in Aim 3, we will discern the mechanisms by which skm PAK1 contributes to peripheral insulin sensitivity and β-cell health. We will use innovative molecular tools to test novel hypotheses about these PAK1 effector actions in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse pre-diabetes and halt progression to T2D and by uncovering novel mechanisms of glucose homeostasis.