Mechanisms of Beta cell Compensation and Failure

β 细胞补偿和衰竭的机制

• 批准号: 7071186
• 负责人: John L. Leahy
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071186
• 关键词: apoptosis; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; confocal scanning microscopy; cytotoxicity; disease /disorder model; gene expression; genetic regulation; glucose metabolism; hormone regulation /control mechanism; hyperglycemia; hyperlipidemia; immunofluorescence technique; insulin; laboratory rat; lipid metabolism; molecular pathology; noninsulin dependent diabetes mellitus; pancreatectomy; pancreatic islets; proinsulin

DESCRIPTION (provided by applicant): A key pathogenic feature of type 2 diabetes is loss of the beta-cell compensation to the insulin resistance that occurs in this disease. The biochemical and molecular nature of this beta-cell failure are poorly known, in part because of lack of animal models that faithfully reproduce the natural history of the human disease. This proposal makes use of a newly developed rat model, the 60% pancreatectomy Zucker rat that incorporates the characteristic features of human adipogenic diabetes - obesity, insulin resistance, and hyperlipidemia. They are characterized by a 3-week period of relative normoglycemia after the partial pancreatectomy (compensation phase) that is followed by the onset of beta-cell dysfunction and mild hyperglycemia (decompensation phase). We will use this model to test the hypothesis of this application that enhanced then impaired a-cell anaplerosis and lipid partitioning are the mechanistic basis for the beta-cell compensation and subsequent beta-cell failure in these rats. A notable aspect of this application is it stems as a joint effort from the laboratories of Drs. Jack Leahy (Burlington, VT) and Marc Prentki (Montreal, Canada) who have complimentary research expertise in the fields of beta cell anaplerosis/lipid partitioning and the beta cell failure in rodent models of type 2 diabetes. Aim 1 will determine the cellular mechanisms and signaling pathways for beta-cell compensatory growth or loss of beta-cell mass in the 60% Px ZF rat model at different stages during the progression to diabetes. Aim 2 will test the hypothesis that the mechanism of beta-cell decompensation in the 60% Px ZF rat model is related to failure of compensatory enhanced anaplerosis and lipid signaling processes. Aim 3 will test the hypothesis that the beta-cell failure in 60% Px ZF rats is in part due to inadequate proinsulin synthesis relative to secretion. 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.

描述（由申请人提供）：2型糖尿病的关键致病特征是β细胞补偿损失了这种疾病中发生的胰岛素抵抗。该β细胞衰竭的生化和分子性质是鲜为人知的，部分原因是缺乏忠实地再现人类疾病自然史的动物模型。该建议利用了新开发的大鼠模型，即60％胰腺切除术Zucker大鼠，其中包含人类脂肪糖尿病的特征 - 肥胖，胰岛素抵抗和高脂血症。它们的特征是部分胰腺切除术（补偿阶段）3周的相对正常血糖时期，随后是β细胞功能障碍和轻度性高血糖（代偿阶段）的发作。 我们将使用该模型来测试该应用的假设，该假设增强了，然后损害了A细胞的旋律和脂质分配是β细胞补偿的机械基础，以及随后在这些大鼠中的β细胞衰竭。该应用程序的一个显着方面是，它是DRS实验室的共同努力。杰克·利希（Jack Leahy）（伯灵顿，弗吉尼亚州）和马克·普伦特基（Marc Prentki）（加拿大蒙特利尔），在β细胞腐败/脂质分配的领域具有免费的研究专业知识，以及2型糖尿病啮齿动物模型中的β细胞失败。 AIM 1将确定在糖尿病发展期间不同阶段的60％PX ZF大鼠模型中Beta细胞代偿性生长或β细胞质量损失的细胞机制和信号传导途径。 AIM 2将检验以下假设：60％PX ZF大鼠模型中β细胞代偿的机制与补偿性增强的静孢子菌病和脂质信号传导过程的失败有关。 AIM 3将检验以下假设：60％PX ZF大鼠的β细胞衰竭部分是由于与分泌相对于分泌的促硫素合成不足所致。 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。