Aging And The Pancreas

衰老与胰腺

• 批准号: 8931484
• 负责人: Josephine Egan
• 金额: $ 35.41万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8931484
• 关键词: Age; Aging; Agonist; Alpha Cell; Anabolism; Animals; Apoptosis; Beta Cell; Blood Glucose; Cardiovascular Diseases; Cell Count; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Diabetes Mellitus; Failure; Financial compensation; Functional disorder; Glucokinase; Hormones; Human; Hyperactive behavior; Insulin; Insulin Resistance; Islets of Langerhans; Kidney Failure; Maintenance; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Phenotype; Process; Proteins; Research; Research Personnel; Rodent; Work; cytokine; exenatide; glucagon-like peptide 1; glucose sensor; islet; new therapeutic target; prevent; receptor; transcription factor

A major component of our research in the Diabetes Section is to understand what controls beta cell function and mass in the pancreas. With age and type 2 diabetes failure of beta cells to respond to rising blood glucose levels (beta cell dysfunction) becomes evident and there appears to be a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased neogenesis. We have been studying the mechanisms of action of GLP-1, a gut hormone, as they relate to insulin release. We found that not only is GLP-1 a potent insulinotropic agent, it upregulates insulin biosynthesis, increases translocation of pdx-1, a transcription factor necessary for maintenance of the beta cell phenotype, to the nucleus and it increases glucokinase protein levels (the essential glucose sensor in beta cells). We also found that it increases beta cell mass in rodents by increasing beta cell proliferation in islets of Langerhans. Other investigators demonstrated antiapoptotic effects of GLP-1 in beta cell lines and whole islets. A GLP-1 receptor agonist, exendin-4, is now available for treating type 2 diabetes. A component of our basic work is investigating how GLP-1 increases beta cell turnover. Of relevance to aging, we have found that the ability of GLP-1 receptor agonists to increase beta cell turnover is reduced in islets from old rodents: however, continuous, unremitting treatment of the animals with GLP-1 receptor agonists can overcome this. In addition to defective beta cell function and proliferation, we have found that alpha cells are increased. This led us to speculate that proper beta cell function is needed to control alpha cell function and numbers. Additionally, free fatty levels are increased in aging and type 2 diabetes. We are hypothesizing a unifying mechanism covering beta cell dysfunction, alpha cell hyperactivity, insulin resistance and increased cytokine levels. Eventually, we hope to outline novel therapeutic targets within this concept.

我们在糖尿病部分的研究的一个主要组成部分是了解是什么控制了胰腺中的β细胞功能和质量。随着年龄和2型糖尿病，β细胞对血糖水平升高的反应变得明显(β细胞功能障碍)，并且似乎出现了β细胞团的扩张失败。这可能是由于现有的β细胞凋亡增加以及新生细胞减少所致。我们一直在研究胃肠激素GLP-1的作用机制，因为它们与胰岛素释放有关。我们发现，GLP-1不仅是一种强大的胰岛素促进剂，它还上调胰岛素的生物合成，增加PDX-1的转位，PDX-1是维持β细胞表型所必需的转录因子，它还增加葡萄糖激酶蛋白水平(β细胞中必不可少的葡萄糖感受器)。我们还发现，它通过促进朗格汉斯胰岛中的β细胞增殖，增加了啮齿类动物的β细胞质量。其他研究人员证实了GLP-1在β细胞系和整个胰岛中的抗凋亡作用。GLP-1受体激动剂exendin-4现在可用于治疗2型糖尿病。我们基础工作的一个组成部分是研究GLP-1是如何增加β细胞周转的。与衰老相关的是，我们发现GLP-1受体激动剂增加老年啮齿动物胰岛β细胞周转的能力降低：然而，用GLP-1受体激动剂持续、坚持不懈地治疗动物可以克服这一点。除了β细胞功能和增殖缺陷外，我们还发现阿尔法细胞增加。这让我们推测，需要适当的β细胞功能来控制阿尔法细胞的功能和数量。此外，衰老和2型糖尿病患者的游离脂肪水平也会增加。我们正在假设一个统一的机制，涵盖β细胞功能障碍、阿尔法细胞过度活动、胰岛素抵抗和细胞因子水平升高。最终，我们希望在这一概念中勾勒出新的治疗靶点。