B-CELL COMPENSATION IN PARTIAL PANCREATECTOMY RATS

部分胰腺切除术大鼠的 B 细胞补偿

• 批准号: 6033254
• 负责人: John L. Leahy
• 金额: $ 34.5万
• 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 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6033254
• 关键词: apoptosis; cell growth regulation; confocal scanning microscopy; enzyme activity; enzyme substrate; glucokinase; glucose metabolism; glycolysis; glycosides; glycosuria; homeostasis; hyperglycemia; insulin receptor; laboratory rat; northern blottings; pancreatectomy; pancreatic islets; peptide hormone biosynthesis; posttranslational modifications; proinsulin; radiotracer

The islet beta-cell is the critical regulatory element in the glucose homeostasis system. Changes in insulin sensitivity and/or beta-cell mass elicit precise functional adaptions of the remaining beta-cells, thereby maintaining normoglycemia. How is that accomplished? The paradox is the normal driving force for insulin secretion and synthesis is glycemia, which is unchanged. The current application explores the mechanistic basis for the beta-cell adaptive changes that accompany a 60% pancreatectomy (Px) in rats. These rats maintain normoglycemia through a multiplicity of beta-cell adaptive responses: insulin secretion is upregulated to the "normal" level because of an enhanced beta-cell glucose responsiveness, partial regeneration of the excised beta-cells, and maintenance of normal beta-cell insulin stores despite the augmented insulin secretion. This application proposes a model based on extensive preliminary data which integrates these diverse beta-cell adaptions into a defined sequence of events. The core element is a posttranslational upregulation of glucokinase catalytic activity; the increased flux through glycolysis augments insulin secretion and also "tricks" the beta-cells to act as if in an hyperglycemic environment with a key response being to increase the islet Insulin Receptor Substrate-2 level (IRS-2) which recent information has suggested is an important regulator of proinsulin biosynthesis and the beta-cell replication rate. The result is a coordinated augmentation of insulin secretion and proinsulin synthesis which maintains a normoglycemic environment. This application uses biochemical, microscopic, and functional techniques to validate this model by fully characterizing the beta-cell adaptive responses in 60% Px rats and testing predicted perturbations with targeted pharmacologic agents by 1) Performing a comprehensive biochemical analysis of glycolysis in Px islets to identify the basis for the enhanced beta-cell glucose responsiveness; 2) Determining the regulation of islet IRS-2 in 60% Px rats; 3) Determining the role of hyperglycemia in initiating the enhanced beta-cell glucose sensing/responsiveness and increased IRS-2 level using phloridzin; 4) Determining the regulation of the beta-cell mass post 60% Px correlated to indices of beta-cell growth (both hyperplasia and hypertrophy) and apoptotic cell death; 5) Determining the regulation of the pancreas insulin content by focusing on proinsulin synthesis. These studies will provide fundamental mechanistic information regarding beta-cell adaptive mechanisms and how they regulate glucose homeostasis.

胰岛β细胞是葡萄糖稳态系统中的关键调节元件。 胰岛素敏感性和/或β细胞质量的变化引起其余β细胞的精确功能适应，从而维持正常血糖。 那是如何成就的？ 悖论是胰岛素分泌和合成的正常驱动力是血糖，它没有变化。 当前的应用探讨了大鼠胰腺细胞自适应变化的机理基础。这些大鼠通过多种β细胞自适应反应保持正常血糖：胰岛素的分泌被上调至“正常”水平，因为β细胞葡萄糖的反应增强，尽管增强的胰岛素分泌增强了正常的β细胞胰岛素储存，但对所切除的β-细胞的部分再生进行了部分再生。 该应用程序提出了一个基于广泛的初步数据的模型，该模型将这些不同的Beta细胞适应性整合到定义的事件序列中。 核心元素是葡萄糖酶催化活性的翻译后上调。通过糖酵解增加胰岛素分泌的通量增加，并“欺骗”β细胞的作用，好像在高血糖环境中，关键反应是增加胰岛胰岛素受体底物-2水平（IRS-2），最近信息表明，这是Proinsulin Biosynthesissis和Beta-cell-cell-cell-cell-cell-cell-cell-cell-cell replitication and beta-cell operlication and beta-closection and Beta-cells。 结果是维持正常血糖环境的胰岛素分泌和促硫素合成的协调增强。 This application uses biochemical, microscopic, and functional techniques to validate this model by fully characterizing the beta-cell adaptive responses in 60% Px rats and testing predicted perturbations with targeted pharmacologic agents by 1) Performing a comprehensive biochemical analysis of glycolysis in Px islets to identify the basis for the enhanced beta-cell glucose responsiveness; 2）确定60％PX大鼠中IRS-2的调节； 3）确定高血糖在启动增强的β细胞葡萄糖传感/反应性以及使用菲洛德津升高的IRS-2水平上的作用； 4）确定60％PX的β细胞质量调节与β细胞生长指数（增生和肥大）和凋亡细胞死亡相关； 5）通过关注促硫素合成来确定胰腺胰岛素含量的调节。 这些研究将提供有关β细胞自适应机制以及它们如何调节葡萄糖稳态的基本机械信息。