Role of IRS-2 in Diabetes and Beta Cell Function

描述（申请人提供）：胰腺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，IRS-2破坏由于胰岛素抵抗和β-细胞补偿的失败而导致小鼠中明显的II型糖尿病。在胰腺t3-细胞中具有特异性IRS-2缺失的小鼠在禁食和进食状态下表现出逐渐升高的血糖水平，和葡萄糖耐量受损（初步数据）然而，在后者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细胞中的自主作用，下丘脑IRS-2缺失的影响不能排除。细胞单独足以诱导糖尿病，IRS-2破坏如何引起失败的B细胞扩增，以及IRS-1和IRS-2之间是否对B细胞功能有任何互补作用β细胞中IRS-2缺失将通过Cre-loxP介导的基因破坏系统实现三个转基因Cre小鼠系，它们都在IL-细胞特异性启动子的控制下表达Cre，将用于排除IRS-2在其它组织中缺失的潜在并发症。将在基因敲除小鼠中检查和比较葡萄糖稳态和β细胞质量。细胞分化、增殖和凋亡。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。在β-肾上腺素受体中缺乏IRS-2和IRS-I的小鼠，从这些研究中获得的见解可能会促进我们对II型糖尿病发病机制的理解，并提供新的治疗糖尿病的治疗策略。

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.