基于LXR/FXR调控SGLT1/2-GLUT2介导葡萄糖转运的黄芪降糖机制与药效物质基础研究

本课题聚焦中药降糖机制与药效物质基础前沿科学问题，选择黄芪为研究对象，以葡萄糖等为生物标志物，以核受体LXR、FXR和转运体SGLT1、SGLT2、GLUT2为靶点，采用细胞药动学和代谢组学前沿方法技术，构建人LXR、FXR、SGLT1、SGLT2、GLUT2基因转染MDCKⅡ、HEK293细胞及基因敲除T2DM小鼠模型，从分子、亚细胞、细胞及动物水平，研究黄芪及其组分是否通过LXR、FXR调控SGLT1、SGLT2、GLUT2介导的葡萄糖转运发挥降糖作用；考察黄芪多组分对葡萄糖转运多靶点、多通路协同调控作用；采用“中药化学指纹-药代标示物-生物标志物-药效靶标”四维模式，从药动学和代谢组学独特视角，从核受体和转运体调控角度，研究阐释黄芪降糖分子机制与药效物质基础。本研究对于揭示中药降糖机制与药效物质基础具有重要理论价值和临床意义，为降糖药研发、临床应用及糖尿病治疗提供科学依据和技术支撑。

The project focuses on the frontier scientific issues of the mechanism and pharmacodynamic material basis of traditional Chinese medicine (TCM) for prevention and treatment of diabetes. Astragali Radix (AR) was chosen as the research object. Glucose and so on was chosen as the biomarkers of diabetes. The nuclear receptors LXR, FXR and the transporters SGLT1, SGLT2, GLUT2 were selected as drug targets. The frontier methods and techniques of cellular pharmacokinetics and metabonomics, human LXR, FXR, SGLT1, SGLT2 and GLUT2 gene transfected MDCKII and HEK293 cell models, and the gene knockout T2DM mice, were used to explore the hypoglycemic effect of AR and its components based on LXR, FXR-regulated SGLT1, SGLT2, GLUT2-mediated glucose transport at the molecular, subcellular, cellular and animal levels, respectively. The effect of synergistic regulation from multiple components of AR on glucose transport based on multi-targets and multi-pathways was also observed. Using the four-dimensional research model “chemical fingerprint of TCM-pharmacokinetic markers-biomarkers-drug targets”, the molecular mechanism and pharmacodynamic material basis of AR decreasing blood glucose level were investigated and interpreted from the perspective of regulation of nuclear receptors and transporters. The research will demonstrate important theoretical value and clinical significance in disclosing the molecular mechanism and pharmacodynamic material basis of TCM in preventing and treating diabetes, and provide scientific evidence and technical support for research, development and reasonable application of hypoglycemic drugs as well as diabetes therapy.