Beta-cell Compensation in Partial Pancreatectomy Mice

部分胰腺切除小鼠的β细胞补偿

• 批准号: 6824198
• 负责人: John L. Leahy
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824198
• 关键词: biological signal transduction; cell proliferation; confocal scanning microscopy; enzyme activity; fatty acid metabolism; gene expression; genetically modified animals; glucokinase; homeostasis; hyperglycemia; immunocytochemistry; insulin sensitivity /resistance; laboratory mouse; pancreatectomy; pancreatic duct; pancreatic islet function; peroxisome proliferator activated receptor; polymerase chain reaction; protein localization; protein structure function; regeneration; terminal nick end labeling; troglitazone

The islet Beta-cell is the key regulatory element of the glucose homeostasis system. Changes in insulin sensitiveity or Beta-cell mass elicit precise adaptations from the remaining Beta-cells so normoglycemia is maintained. How is that accomplished? The paradox is the presumed normal driving force for insulin secretion and Beta-celt mass is glycemic status which is unchanged. Little is known about this fundamental aspect of Beta-cell function. This application continues our studies of the Beta-cell adaptive mechanisms to a reduction in Beta-cell mass such as occurs in evolving type 1 diabetes, likely also type 2 diabetes, using the experimental model of 60% pancreatectomy in normally insulin sensitive rodents. These rats are normoglycemic following the reduction in Beta-cell mass because of a multifacted adaptive response in islet Beta-cells and pancreatic ducts that results in a normal level of insulin. We plan to test a well-defined mechanistic schema for the adaptive responses. Specifically, we propose a regulatory role for glucokinase in the hyperproliferation and enhanced function that characterize the Beta-cell adaptation, for PPARgamma in subsequently restraining the Beta-cell hyperproliferation, and for IRS-2/Akt signaling in the duct-derived islet neogenesis. We will test these hypotheses by performing partial pancreastectomies in mice with genetically altered expression of key elements in the proposed regulatory pathways - glucokinase (Beta-cell specific knockout), PPARgamma (Beta-cell specific knockout), and IRS-2 (global knockout). These studies will provide a better understanding of the molecular basis for Beta-cell compensation and failure, and they hold considerable promise to provide targets for novel pharmaceutical approaches to the prevention or more effective treatment of type 2 diabetes.

胰岛β细胞是葡萄糖稳态系统的关键调节元件。胰岛素敏感性或β细胞质量的变化引起其余β细胞的精确适应性，因此可以保持正常血糖。那是如何成就的？悖论是胰岛素分泌和βCELT肿块的假定正常驱动力是血糖状态，这是不变的。关于Beta细胞功能的这一基本方面知之甚少。 该应用程序继续我们对β细胞自适应机制的研究，以减少β细胞质量的减少，例如在不断发展的1型糖尿病中发生，也可能使用正常胰岛素敏感啮齿动物的60％胰腺切除术的实验模型，也可能使用6型糖尿病。这些大鼠在β细胞质量减少后是正常的，因为胰岛β细胞和胰管导致胰岛素水平正常的自适应反应。我们计划测试定义明确的机械架构以进行自适应响应。具体来说， 我们提出了葡萄糖酶在表征Beta细胞适应性的高增殖和增强功能中的调节作用，PPARGAMMA在随后限制了β细胞的高增殖和IRS-2/AKT信号传导中的ppargamma。我们将通过在拟议的调节途径中遗传元素表达的小鼠中进行部分胰腺切除术来检验这些假设 - 葡萄糖酶（β细胞特异性敲除），ppargamma（β细胞特异性敲除）和IRS-2（IRS-2）（全球敲除）。 这些研究将更好地理解β细胞补偿和失败的分子基础，并且它们具有相当大的希望，可以为预防的新型药物方法提供目标，或者对2型糖尿病的预防治疗或更有效治疗。