The role of GLP-1 and CCK in the pancreatic islet to promote beta-cell survival

细胞质量减少和细胞凋亡增加是1型和2型糖尿病病理生理学的关键 2型糖尿病。因此，确定能够保护-细胞凋亡的因素将满足一个关键的理论。 糖尿病防治中的儿科需要。胰升糖素样肽-1(GLP-1)与胆囊收缩素 (CCK)是一种多肽激素，通常在肠道中产生，对细胞质量和功能有有益影响。 提顿。在胰岛应激条件下，胰岛内产生GLP-1和CCK。GLP-1 基础疗法被广泛用于2型糖尿病的治疗，而且有大量证据表明 在细胞系和啮齿动物模型中，GLP-1可以保护-细胞免于凋亡。同样，我们已经证明了 在小鼠模型中，CCK是保护-细胞凋亡的必要条件和充分条件。而CCK已经被广泛地 在胰腺外分泌细胞的研究中，关于CCK在细胞中的作用的信息有限。我们建议 胰岛中这些激素的产生代表了一种代偿生理机制，以促进 微尘-细胞存活。长期目标是确定在保存细胞团中至关重要的新途径。 本申请的总体目标是确定本地生产的GLP-1和CCK的调节以及 它们在保护-细胞凋亡中的作用。中心假设是，一个胰岛内的信令网络不存在 在α细胞中产生的GLP-1和在细胞中产生的CCK共同调节并共同工作 以促进细胞的存活。为了实现这一目标，提出了三个具体目标。在目标1中，我们将阻止- 我想知道GLP-1和CCK是如何在胰岛中被调节的。初步证据支持 假设CCK和GLP-1在胰岛内以旁分泌方式发出信号，相互协同调节。我们 将使用转基因过表达的细胞CCK和受体敲除小鼠模型来阐明这些 在胰岛中，荷尔蒙相互调节。在目标2中，我们将确定CCK介导的Protec-2的机制。 抗细胞因子诱导的细胞凋亡。我们将使用受体拮抗剂和基因敲除来确定哪个CCK 受体调节细胞存活，我们将确定CCK激活的细胞内信号通路 在-cell中。在目标3中，我们将确定GLP-1和CCK是否可以协同和相互依赖地保护 人类胰岛不受细胞凋亡的影响。我们有有趣的证据表明，GLP-1在-细胞存活中的作用是依赖的 细胞系中CCK受体信号的研究。这表明了创新的概念，即GLP-1对 -细胞依赖于其刺激CCK的能力。由于人的胰岛与小鼠的胰岛具有非常不同的特征， 研究GLP-1和CCK在人类胰岛中的特异性作用对于翻译我们的 糖尿病治疗的发现。这些研究将有助于我们从根本上理解这部小说-- 胰岛激素调节途径及其促进-细胞存活的机制。 这一贡献意义重大，因为它将促进对适应和治疗机制的了解。 细胞存活，允许开发具有最大疗效和最小副作用的靶向治疗。

Reduced -cell mass and increased -cell apoptosis are key to the pathophysiology of both type 1 and type 2 diabetes. Therefore, identifying factors that can protect from -cell apoptosis will meet a critical thera- peutic need in the prevention and treatment of diabetes. Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are peptide hormones normally produced in the intestine with beneficial effects on -cell mass and func- tion. Both GLP-1 and CCK are produced within the pancreatic islet under conditions of islet stress. GLP-1 based therapies are in widespread use for the treatment of type 2 diabetes, and there is substantial evidence in cell lines and rodent models that GLP-1 can protect from -cell apoptosis. Similarly, we have shown that CCK is necessary and sufficient to protect from -cell apoptosis in mouse models. While CCK has been widely studied in exocrine pancreatic cells, there is limited information about the role of CCK in the -cell. We propose that the production of these hormones in the islet represents a compensatory physiologic mechanism to pro- mote -cell survival. The long-term goal is to identify novel pathways critical in the preservation of -cell mass. The overall objective of this application is to determine the regulation of locally produced GLP-1 and CCK and their role in protection from -cell apoptosis. The central hypothesis is that an intra-islet signaling network ex- ists, whereby GLP-1 produced in the α-cell and CCK produced in the -cell are co-regulated and work together to promote -cell survival. To achieve the objective, three Specific Aims are proposed. In Aim 1, we will deter- mine how GLP-1 and CCK production are regulated in the pancreatic islet. Preliminary evidence support the hypothesis that CCK and GLP-1 signal in a paracrine manner within the islet to co-regulate one another. We will use transgenic overexpression of -cell CCK and receptor knockout mouse models to clarify how these hormones regulate one another in the islet. In Aim 2, we will identify the mechanism of CCK-mediated protec- tion from cytokine-induced apoptosis. We will use receptor antagonists and knockouts to determine which CCK receptor regulates -cell survival and we will determine the intracellular signaling pathways activated by CCK in the -cell. In Aim 3, we will determine if GLP-1 and CCK can synergistically and interdependently protect human islets from apoptosis. We have intriguing evidence that the role of GLP-1 in -cell survival is dependent on CCK receptor signaling in a cell line. This suggests the innovative concept that the impact of GLP-1 on the -cell relies on its ability to stimulate CCK. As human islets have very different characteristics than mouse islet, examining the role of GLP-1 and CCK specifically in human islets is of critical importance to translation of our findings to diabetes therapies. These studies will contribute to our fundamental understanding of this novel in- tra-islet hormonal regulatory pathway and the mechanisms whereby GLP-1 and CCK promote -cell survival. This contribution is significant as it will advance knowledge of both adaptive and therapeutic mechanisms of - cell survival, allowing development of targeted therapies with maximal efficacy and minimal side effects.