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细胞质量的变化会引起剩余β细胞的精确适应，从而维持正常血糖。这是如何实现的？悖论是胰岛素分泌的假定正常驱动力，而β-细胞质量是未改变的血糖状态。人们对β细胞功能的这一基本方面知之甚少。 该应用继续我们对β细胞质量减少的β细胞适应性机制的研究，例如在不断发展的1型糖尿病（也可能是2型糖尿病）中发生的情况，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。这些大鼠在β细胞质量减少后血糖正常，因为胰岛β细胞和胰管中的多方面适应性反应导致胰岛素水平正常。我们计划测试一个明确定义的自适应响应机制模式。具体来说， 我们提出葡萄糖激酶在β细胞适应的过度增殖和功能增强中的调节作用，PPARγ在随后抑制β细胞过度增殖中的调节作用，以及IRS-2/Akt信号在导管源性胰岛新生中的调节作用。我们将通过对小鼠进行部分胰腺切除术来测试这些假设，这些小鼠的调节途径中的关键元件的表达发生了基因改变——葡萄糖激酶（β细胞特异性敲除）、PPARgamma（β细胞特异性敲除）和IRS-2（全局敲除） 。 这些研究将有助于更好地理解β细胞补偿和衰竭的分子基础，并且有望为预防或更有效治疗2型糖尿病的新药物方法提供靶点。