SH2B1蛋白通过胰岛素/IGF信号通路介导胰岛β32454;胞增殖及血糖稳定机制研究

项目名称： SH2B1蛋白通过胰岛素/IGF信号通路介导胰岛β32454;胞增殖及血糖稳定机制研究

项目编号： No.30871189

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 段朝军

作者单位： 中南大学

项目金额： 30万元

中文摘要： 胰岛β32454;胞功能的探讨是2型糖尿病领域的研究热点之一。为了确定SH2B1作为胰岛素样生长因子受体内源性增强子通过IGFlR-IRS2-PI3K信号通路参与IGF-1促胰岛β32454;胞生长维持胰岛β32454;胞生存和对抗高血脂等因素诱导β32454;胞凋亡，维持血糖稳定。 以小鼠胰岛素瘤细胞系Min 6和SH2B1基因敲除小鼠为研究对象，比较敲除小鼠、杂合子及野生型小鼠血糖、血清胰岛素等生理学指标和小鼠胰岛β32454;胞生长和凋亡率以及胰岛素/胰岛素样生长因子信号传导通路生长和凋亡相关分子表达的变化，结果为：⑴SH2B1基因缺失导致小鼠胰岛增生和胰岛素代偿性表达增加并发展为高血糖、胰岛素抵抗及糖尿病。⑵H2B1基因缺失削弱IGF促进β32454;胞生长增殖、增加FAA等诱导β32454;胞凋亡；⑶H2B1的SH2结构域通过IGFlR-IRS2-PI3K/Akt信号通路参与上述过程。⑷移植野生型胰岛SH2B1-/-小鼠高血糖、高血脂症等症状得到缓解。本研究不仅有助于揭示糖尿病发生的机制，而且能为研发控制糖尿病及其相关疾病新药提供靶分子。

中文关键词： SH2B1；β32454;胞；糖尿病；胰岛素/IGF信号通路；凋亡

英文摘要： Pancreatic-cell function is one of the hot spots in type 2 diabetes research. In order to determine whether SH2B1 is a physiological enhancer of insulin/ insulin-like growth factor signaling pathway and plays a key role in regulation of IGF1 on pancreatic βellular growth and protection against apoptosis by high blood glucose , high blood lipids, and other factors intruducing via IGFR1-IRS2-PI3K signaling pathway，and blood glucose level stability maintaining. This project will be used to SH2B1 gene knockout mice and Min6 cells model. The data including the concentration of blood glucose, plasma-free fatty acids, plasma-insulin from SH2B1+/+, SH2B1+/- , SH2B1-/- and other physiological indicators and mouse pancreatic βell growth and apoptosis rates, and the molecular expression of insulin / IGFR signaling pathways were analysed. The results showed that the deficiency of SH2B1 in mice causes islet hyperplasia and compensatory increased expression of insulin and developed hyperglycemia, insulin resistance and diabetes. Deficiency of SH2B1 in mice was impaired βellular growth and proliferation by IGF and increased the βllular apoptosis by FFA; the SH2 domain of SH2B1 and the IGFlR-IRS2-PI3K/Akt signaling pathway were involved in this process. The hyperglycemia, hyperlipidemia symptoms of the SH2B1-/- mice have been alleviated after the transplantation of wild type islets. The results obtained from this project will not only help reveal the mechanism of diabetes, but also for the control of diabetes research and development of new drugs and its related diseases provide potential therapeutic target for the treatment of type2 diabetes.

英文关键词： SH2B1；βll；diabetes；Insulin/IGF signal pathway；apoptosis