目的 研究何首乌中2，3，5，4'-四羟基二苯乙烯-2-β-D-葡萄糖苷（简称二苯乙烯氧苷，TSG）降血糖的靶点以及体内外抑制钠-葡萄糖协同转运蛋白2（SGLT2）和α-葡萄糖苷酶的活性。方法 采用分子对接法考察TSG与糖尿病相关靶点的结合强弱，糖尿病相关靶点结构取自蛋白质数据库或文献；采用荧光标记的脱氧葡萄糖（1-NBDG）和4-硝基苯基-α-D-葡萄糖苷（PNPG）作为底物对TSG进行体外抑制SGLT2和α-葡萄糖苷酶活性测试，采用大鼠口服糖耐量实验及促尿糖实验对TSG进行体内活性测试。结果 TSG与SGLT2和α-葡萄糖苷酶的分子对接得分分别为-9.35和-5.44，接近阳性对照的-9.79和-5.58，表明TSG可能对SGLT2和α-葡萄糖苷酶的具有抑制作用；体外实验显示，TSG在浓度为10 μmol/L时对SGLT的抑制率为21.6%，在100 μmol/L对α-葡萄糖苷酶的抑制率达32.5%，大鼠体内实验显示TSG在120 mg/kg时血糖抑制率为（9.3±1.0）%，尿糖量为（435.5±84.0）mg/kg，体现出一定的降血糖作用。结论 TSG体外具有抑制SGLT2和α-葡萄糖苷酶活性，体内具有较弱的降血糖和促尿糖活性，有可能作为一类具有双靶点抑制作用的降血糖药物的先导化合物。

Objective To study the mechanism that TSG can reduce plasma glucose level by inhibiting sodium-dependent glucose cotransporters 2 (SGLT2) and α-glucosidase in vitro and in vivo. Methods Molecular docking method was used to study the binding affinities of TSG and diabetes related targets. The structures of targets were taken from Protein Data Bank or references. 1-NBDG and PNPG were used as the substrates for the inhibition assays of TSG against SGLT2 and α-glucosidase respectively in vitro. The antihyperglycemic activity of TSG was operated by oral glucose tolerance test (OGTT) and urinary glucose excretion (UGE) test in rats. Results TSG was identified as the inhibitors of SGLT2 with the docking score of -9.35 less than -9.79 of dapagliflozin as the positive control and α-glucosidase with the docking score of -5.44 compared to -5.58 of acarbose as the positive control. TSG showed the inhibitory rate of 21.6% at the dose of 10 μmol/L against SGLT2 and 32.5% at the dose of 100 μmol/L in vitro test. Compared with model group, the group of 120 mg/kg dose had significant difference (P < 0.05) but the overall effect was not as strong as dapagliflozin in OGTT and UGE test. The result of rat in vivo test showed that glucose inhibition rate of TSG (120 mg/kg) was (9.3 ±1.0)%, urinary glucose content was (435.5 ±84.0) mg/kg, which showed certain hypoglycemic effect. Conclusion TSG exhibited antiglycemic activity through inhibiting SGLT2 and α-glucosidase, which was considered to be a new lead compound of dual target inhibitors.

陕西省教育厅专项科研项目（18JK0224）；陕西中医药大学学科创新团队（2019-YL13）