具类胰岛素效应的钒化合物对胰岛素信号路径干预的化学基础

项目名称： 具类胰岛素效应的钒化合物对胰岛素信号路径干预的化学基础

项目编号： No.20871008

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： 杨晓改

作者单位： 北京大学

项目金额： 35万元

中文摘要： 本项目以钒化合物对胰岛素信号路径的干预调节为主线，利用金属物种生物效应的相似/相异性规律，结合钒化合物在医药中的潜在应用，探索其可能的作用机制，主要进展如下:（1）研究结果表明,除PI3K/Akt通路外，钒化合物还可通过Akt非依赖的路径发挥抑制脂解的作用；而MAPK/ERK通路的激活在此效应中不起关键作用。（2）结果显示，尽管所研究的钒化合物均能提高脂肪细胞的活性氧(ROS)水平，且ROS参与了钒化合物对胰岛素信号通路的激活，但主要体现在ROS对糖代谢通路的影响上；对于胰岛素抵抗的3T3L1脂肪细胞，钒化合物诱导产生的ROS对其所激活的Akt活性以及糖代谢信号通路中的关键调节蛋白的活性均无显著影响。（3）本项目的研究还表明钒化合物对正常与肿瘤肝细胞具有一定的选择性，而这种选择性基于钒化合物在不同细胞中所诱导的ROS水平的异同。同时结果还显示钒化合物在胞外和胞内的作用机制存在差异性。本研究结果将对阐明钒化合物的类胰岛素效应以及进一步研发利用具糖尿病防治作用的新型钒化合物提供依据，也为钒化合物同时发挥抗肿瘤以及抗糖尿病效应的可能性提供了理论基础。

中文关键词： 钒化合物；胰岛素信号路径；糖尿病；抗脂解效应；相似/相异性规律

英文摘要： This project explored the underlying mechanisms of vanadium compounds on their antidiabetic effect with their intervention and regulation in insulin signaling pathway as a main clue. In light of similarity/dissimilarity rules of metal species and considering the potential applications of vanadium compounds in medicine, three major progresses have been achieved:（1）The results demonstrate that activation of PI3K/Akt pathway contributed to the inhibition of lipolysis by vanadium compounds and at the same time the Akt-independent pathway is also indicated to play a part in this process. However, MAPK/ERK pathway activation is not involved. (2) The present study show that reactive oxygen species(ROS) may not play a major role in the inhibition of lipolysis of vanadium compounds. Although all the vanadium compounds studied lead to an increase of ROS level in the normal 3T3L1 adipocytes and ROS is involved in the activation of signaling pathways, it is found that ROS is mainly associated with the intervention on the glucose metabolism pathways. Moreover, in insulin-resistant 3T3L1 adipocytes, the elevation of ROS level induced by vanadium compounds exert no remarkable effect either on the Akt activity or on the activities of key modulators in the signaling pathways of glucose metabolism. (3) It is also found that the selectivity of vanadium compounds against human hepatoma cells for their differential induction of ROS level in different cell types. Additionally, the results indicate that extracellular vanadium compounds may exert the same biological effects by different mechanisms from that on the intracellular side. The current results will lead to elucidate the mechanism underlying the insulin-mimetic effect of vanadium compounds and to provide theoretical basis for further development and application of new vanadium compounds in prevention and treatment of diabetes as well as to provide the foundation for their possible therapeutical value in the treatment of diabetes with cancer.

英文关键词： Vanadium compounds;insulin signaling pathway;diabetes;antilipolysis;similarity/dissimilarity