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

GLP-1 和 CCK 在胰岛中促进 β 细胞存活的作用

• 批准号: 9357570
• 负责人: Dawn B Davis
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357570
• 关键词: Adverse effects; Affect; Agonist; Alpha Cell; Animal Model; Apoptosis; Beta Cell; Binding Proteins; Biological Preservation; Cell Death; Cell Line; Cell Survival; Cell physiology; Cells; Characteristics; Cholecystokinin; Cholecystokinin A Receptor; Cholecystokinin B Receptor; Cholecystokinin Receptor; Clinical; Critical Pathways; Cyclic AMP; Cytoprotection; Development; Diabetes Mellitus; Diabetes prevention; Elements; Event; Exocrine pancreas; Functional disorder; GLP-I receptor; Goals; Hormonal; Hormones; Human; Inflammation; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intestines; Islets of Langerhans; Knock-out; Knockout Mice; Knowledge; Lead; Mediating; Mission; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Peptides; Physiological; Prevention; Production; Public Health; Receptor Signaling; Regulation; Regulatory Pathway; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Stress; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Translations; United States; United States National Institutes of Health; Work; base; combat; cytokine; diabetes mellitus therapy; glucagon-like peptide 1; improved; in vivo; innovation; insight; islet; loss of function; mouse model; new therapeutic target; novel; overexpression; paracrine; peptide hormone; prevent; programs; promoter; receptor; receptor-mediated signaling; response; stressor; targeted treatment

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.

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，识别能够保护细胞免于凋亡的因子将满足关键的治疗需求。 预防和治疗糖尿病的迫切需要。胰高血糖素样肽-1（GLP-1）和胆囊收缩素 (CCK)是通常在肠道中产生的肽激素，对胰岛细胞质量和功能有有益的影响， 是的。GLP-1和CCK均在胰岛应激条件下在胰岛内产生。GLP-1 基础疗法广泛用于治疗2型糖尿病，并且有大量证据表明， 在细胞系和啮齿类动物模型中，GLP-1可以保护细胞免于凋亡。同样，我们已经证明， 在小鼠模型中，CCK是防止β细胞凋亡的必要和充分的保护剂。虽然CCK已经广泛应用于 在胰腺外分泌细胞中进行的研究中，关于CCK在胰岛细胞中的作用的信息有限。我们提出 胰岛中这些激素的产生代表了一种代偿性生理机制， 微粒体细胞存活。长期的目标是确定新的途径，关键是在保存的胰岛细胞团。 本申请的总体目标是确定当地生产的GLP-1和CCK的调节， 它们在保护细胞免于凋亡中的作用。核心假设是胰岛内信号网络， 因此，α-细胞中产生的GLP-1和β-细胞中产生的CCK共同调节并共同发挥作用 以促进胰岛细胞存活。为实现这一目标，提出了三个具体目标。在目标1中，我们将阻止- 我的GLP-1和CCK生产是如何在胰岛调节。初步证据表明， 假设CCK和GLP-1信号在胰岛内以旁分泌方式相互共调节。我们 将使用转基因过表达的β细胞CCK和受体敲除小鼠模型，以阐明这些基因是如何表达的。 胰岛内激素相互调节。在目的2中，我们将确定CCK介导的保护机制， 从苦参碱诱导的细胞凋亡中恢复。我们将使用受体拮抗剂和基因敲除来确定哪种CCK 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 在牢房里。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 人胰岛细胞凋亡。我们有有趣的证据表明GLP-1在细胞存活中的作用是依赖性的， CCK受体信号的研究。这表明了GLP-1对细胞增殖的影响的创新概念。 β-细胞依赖于其刺激CCK的能力。由于人类胰岛与小鼠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我们的翻译至关重要。 糖尿病治疗的发现。这些研究将有助于我们对这部小说的基本理解- 反胰岛激素调节途径和GLP-1和CCK促进胰岛细胞存活的机制。 这一贡献是重要的，因为它将促进对适应性和治疗机制的认识， 细胞存活，允许开发具有最大功效和最小副作用的靶向疗法。