糖尿病前期胰岛微血管内皮细胞SIRT1表达异常对胰岛α及β细胞功能的影响

项目名称： 糖尿病前期胰岛微血管内皮细胞SIRT1表达异常对胰岛α及β细胞功能的影响

项目编号： No.81200612

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 杨菊红

作者单位： 天津医科大学

项目金额： 23万元

中文摘要： 2型糖尿病时胰岛微血管内皮细胞（IEC）数量下降是胰岛β细胞功能进行性衰退的重要原因。前期工作中我们发现OLETF大鼠于糖尿病前期IEC数量已经下降，胰岛处于低氧状态，同时发现SIRT1表达下降，而SIRT1具有促进内皮细胞增殖及血管新生的作用。据此提出"糖尿病前期SIRT1下调导致IEC增殖及血管新生异常，进而促进胰岛α细胞及β细胞功能损伤"的假说。为此，本研究采用SIRT1 siRNA、SIRT1基因转染等分子生物学技术，从细胞水平揭示SIRT1下调在高糖或高脂培养IEC增殖和血管新生功能受损中的关键作用及信号途径；进一步应用共培养系统研究SIRT1高表达的IEC对高糖或高脂培养胰岛α细胞和β细胞功能的改善作用及分子机制；并以SIRT1激动剂干预糖尿病前期OLETF大鼠，体内验证SIRT1的保护作用；以从胰岛微环境角度揭示α细胞及β细胞功能紊乱的机制，并为糖尿病前期的干预提供新的靶点。

中文关键词： 胰岛微环境；2型糖尿病；内皮细胞；SIRT1；胰岛β细胞

英文摘要： Islet endothelial cells (IEC) play important roles in beta cell growth, differentiation and insulin secretion. The number of IEC is found decreased in type 2 diabetes. In our former research, we found that the islet of OLETF rats in pre-diabetic phase is hypoxia, which infers that the number of IEC is already decreased in pre-diabetes, and can not meet the needs of beta cell proliferation in the control of normal plasma glucose. SIRT1 is an important regulator of endothelial cell proliferation and angiogenesis in hypoxia. But in our research, we found the expression of SIRT1 is decreased in pre-diabetic situation. So we hypotheses that, the decreased expression or activity of SIRT1 may play key roles in the low level of IEC proliferation and angiogenesis, which may inturn lead to abnormal function of beta cell and alpha cell. So, in this research, we will carry out both in vivo and in vitro study to analyze the roles of SIRT1 in the promotion of IEC proliferation and angiogenesis in pre-diabetes by siRNA technique, SIRT1 gene transfection and other bio-molecular techniques. Later, we will construct co-culture system to study the direct effects of SIRT1 high expressing IEC on beta cell and alpha cell proliferation and secreting function. Our results will be helpful in the understanding of the mechanism of abnorma

英文关键词： Islet microenvironment；Type 2 diabetes mellitus；Endothelial cells；SIRT1；Islet beta cells