Role of IRS-2 in Diabetes and Beta Cell Function

IRS-2 在糖尿病和 β 细胞功能中的作用

• 批准号: 6583856
• 负责人: XUEYING LIN
• 金额: $ 1.93万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-18 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583856
• 关键词: apoptosis; biological signal transduction; cell growth regulation; cell proliferation; gene deletion mutation; genetically modified animals; insulin receptor; laboratory mouse; membrane proteins; noninsulin dependent diabetes mellitus; pancreatic islets; polymerase chain reaction; protein signal sequence; protein structure function; western blottings

DESCRIPTION (provided by applicant): Pancreatic Beta-cell function and insulin secretion is essential in the pathogenesis of type II diabetes Previous studies reveal that IRS-2 disruption causes overt type II diabetes in mice due to insulin resistance and failure of Beta-cell compensation Mice with specific IRS-2 deletion in pancreatic t3-cells exhibit progressively elevated blood glucose levels at fasting and fed states, and impairment of glucose tolerance (preliminary data) However, IRS-2 deletion was also detected in certain hypothalamic neurons in the latter mice Although these data suggest an autonomous role of IRS-2 in Beta-cells, the effect of IRS-2 deletion in hypothalamus can not be rifled out This proposal aims to determine whether IRS-2 disruption in Beta-cell alone is sufficient to induce diabetes, how IRS-2 disruption causes failed B-cell expansion, and whether there is any complementary effect between IRS-I and IRS-2 on B-cell function IRS-2 deletion in Beta-cells will be achieved by Cre-loxP mediated gene disruption system Three lines of transgenic Cre mice, which all express Cre under the control of I_-cell specific promoters, will be used to rule out potential complication of IRS-2 deletion in other tissues Glucose homeostasis and Beta-cell mass will be examined and compared in knockout mice Defects at Beta-cell expansion will be assessed by examining B-cell differentiation, proliferation and apoptosis. Expression and activities of critical molecules potentially involved in these processes will be studied, including transcription factors, cell cycle regulators, and apoptotic proteins To assess the presence of complementary role between IRS proteins, mice lacking both IRS-2 and IRS-I in Beta-cells will be created and assessed Insights gained from these studies may advance our understanding on the pathogenesis of type II diabetes and provide novel therapeutic strategy for the treatment of diabetes.

描述(申请人提供)：胰岛β细胞功能和胰岛素分泌在II型糖尿病的发病机制中是必不可少的。先前的研究表明，由于胰岛素抵抗和胰岛β细胞代偿失败，IRS-2的干扰导致了显性的II型糖尿病小鼠胰腺T3细胞中特异性IRS-2缺失的小鼠在空腹和进食状态下表现出进行性的血糖水平升高，以及糖耐量下降(初步数据)然而，在后一组小鼠的某些下丘脑神经元中也检测到IRS-2缺失，尽管这些数据表明IRS-2在β细胞中发挥自主作用，下丘脑中IRS-2缺失的影响尚不清楚。本研究旨在确定IRS-2在β细胞中的缺失是否足以诱发糖尿病，IRS-2的缺失是如何导致B细胞增殖失败的，以及IRS-I和IRS-2在B细胞功能中是否存在互补作用。将被用来排除其他组织中IRS-2缺失的潜在并发症，葡萄糖稳态和β细胞质量将被检测并在基因敲除小鼠中进行比较，β细胞扩张缺陷将通过检测B细胞的分化、增殖和凋亡来评估。将研究可能参与这些过程的关键分子的表达和活性，包括转录因子、细胞周期调节因子和凋亡蛋白，以评估IRS蛋白之间是否存在互补作用，将创建和评估在Beta细胞中同时缺乏IRS-2和IRS-I的小鼠。这些研究获得的见解可能会加深我们对II型糖尿病发病机制的理解，并为糖尿病的治疗提供新的治疗策略。