天然化合物牛蒡子苷元调控胰岛功能及其分子机制研究

项目名称： 天然化合物牛蒡子苷元调控胰岛功能及其分子机制研究

项目编号： No.81202570

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 黄素玲

作者单位： 中国科学院上海药物研究所

项目金额： 23万元

中文摘要： 2型糖尿病是严重威胁人类健康的重大疾病，胰岛素抵抗和胰岛功能衰竭是其主要的病理基础，从天然产物中寻找多功能或多靶点的抗糖尿病活性先导活性化合物是糖尿病新药研发的重要手段。我们前期研究发现，天然产物单体牛蒡子苷元具有显著的抗糖尿病活性，该作用与其激活AMPK、增强骨骼肌和肝脏的胰岛素敏感性相关。同时，牛蒡子苷元还可抑制高糖和高脂所诱导的INS-1E胰岛细胞凋亡，并明显增加INS-1E胰岛细胞中胰岛素基因表达关键转录因子mRNA水平，因此，牛蒡子苷元可能具有胰岛素增敏和胰岛功能保护双重作用。本项目将系统研究牛蒡子苷元对胰岛功能的保护及其分子机制，重点观察牛蒡子苷元对糖脂毒性或活性氧干预下胰岛细胞凋亡及增殖的影响，并深入探讨AMPK、内质网应激和氧化应激等信号通路在牛蒡子苷元调控胰岛细胞功能中的作用，为该化合物及其类似物发展成为一种具有全新作用机理的抗糖尿病新药提供物质基础和理论依据。

中文关键词： 牛蒡子苷元；INS-1E细胞；细胞凋亡；ZDF大鼠；beta细胞功能

英文摘要： Type 2 diabetes is a major serious disease threatening the human health. It is pathologically based on insulin resistance and islet failure. Looking for multi-functional or multi-target anti-diabetic lead compounds from natural products is an important method to develop new anti-diabetic drugs. Our previous study showed that the natural product arctigenin exerted significant anti-diabetic activity through activating AMPK and enhancing insulin sensitivity in skeletal muscle and liver. Meanwhile, arctigenin inhibited the apoptosis induced by high glucose or high fatty aicd in INS-1E pancreatic islet cell. And moreover, arctigenin significantly increased the mRNA levels of key transcription factor related in insulin gene expression in the INS-1E pancreatic islet cells. The protective effects and molecular mechanism of arctigenin on islet function will be studied in this project. We will observe the effects of arctigenin on islet cell apoptosis and proliferation intervented by glycolipid toxic or reactive oxygen species, and investigate its regulation on AMPK, endoplasmic reticulum stress and oxidative stress signaling pathway. The completion of this project will provide the material basis and theoretical basis for developing arctigenin and its analogues to be new anti-diabetes drugs with novel mechanism.

英文关键词： arctigenin；INS-1E cells；cell apoptosis；ZDF rat；β-cell function