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 型糖尿病的一个关键致病特征是β细胞对这种疾病中发生的胰岛素抵抗的补偿丧失。这种β细胞衰竭的生化和分子性质鲜为人知，部分原因是缺乏忠实再现人类疾病自然史的动物模型。该提案利用了新开发的大鼠模型，即 60% 胰腺切除的 Zucker 大鼠，该模型融合了人类脂肪性糖尿病的特征——肥胖、胰岛素抵抗和高脂血症。其特点是部分胰腺切除术后 3 周内血糖相对正常（补偿期），随后出现 β 细胞功能障碍和轻度高血糖（失代偿期）。 我们将使用该模型来测试该应用的假设，即增强然后受损的 a 细胞回补和脂质分配是这些大鼠中 β 细胞补偿和随后的 β 细胞衰竭的机制基础。该应用的一个值得注意的方面是它源于博士实验室的共同努力。 Jack Leahy（佛蒙特州伯灵顿）和 Marc Prentki（加拿大蒙特利尔）在 2 型糖尿病啮齿动物模型中的 β 细胞回补/脂质分配和 β 细胞衰竭领域拥有互补的研究专业知识。目标 1 将确定 60% Px ZF 大鼠模型在糖尿病进展过程中不同阶段的 β 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。 目标 2 将检验以下假设：60% Px ZF 大鼠模型中 β 细胞失代偿机制与代偿性增强回补和脂质信号传导过程的失败有关。 目标 3 将检验以下假设：60% Px ZF 大鼠的 β 细胞衰竭部分是由于胰岛素原合成相对于分泌不足所致。 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。