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目的研究葛根素通过抑制钠-葡萄糖协同转运蛋白2(SGLT2)发挥促尿糖、降血糖作用。方法同源模建获得SGLT2蛋白虚拟结构,以达格列净为阳性药,与葛根素进行分子对接,考察其分子结合强弱;采用能稳定表达人SGLT2(h SGLT2)蛋白的中国仓鼠卵巢(CHO)细胞、以14C-甲基葡萄糖苷([14C]-AMG)为底物,评价葛根素体外抑制SGLT2的活性;以达格列净为阳性药,采用大鼠体内口服糖耐量试验(OGTT)和尿排泄糖试验(UGE)观察葛根素直接降血糖和促尿糖活性。结果分子对接得分显示,葛根素是SGLT2的底物,总体作用强度不及达格列净;体外实验显示,葛根素可较强抑制h SGLT2,最大效应为84%左右,半数抑制浓度(IC50)为0.40μmol/L;OGTT结果显示,葛根素10、30、60和120 mg/kg剂量的抑糖率分别为5.1%、6.5%、16%和22%,呈剂量相关性;在UGE实验中,随着葛根素剂量的增大,尿糖量增加,与模型组比较,30、60和120 mg/kg剂量组差异显著(P<0.05、0.01)。结论葛根素具有抑制h SGLT2、促尿糖降低血糖的药理活性,有可能作为一类新型结构的SGLT2抑制剂的先导化合物。
Objective To study the effect of puerarin on promoting urinary glucose and hypoglycemia by inhibiting sodium-glucose cotransporter 2 (SGLT2). Methods The hypothetical model of SGLT2 protein was obtained by homology modeling. Dapagliflozin was used as a positive drug, and puerarin was used as a docking molecule to investigate the molecular binding ability. The Chinese hamster ovary (h SGLT2) CHO) cells were treated with 14C-methylglucoside ([14C] -AMG) as substrate to evaluate the inhibitory effect of puerarin on the SGLT2 activity in vitro. Dapagliflozin was used as a positive drug and the oral glucose tolerance test (OGTT ) And urinary excretion glucose test (UGE) were used to observe the effects of puerarin on blood glucose and urinary glucose. Results The molecular docking score showed that puerarin was the substrate of SGLT2 and its overall effect intensity was less than that of dapagliflozin. In vitro experiments showed that puerarin could strongly inhibit h SGLT2 with a maximal effect of about 84% and an IC50 of 0.40μmol / L. The results of OGTT showed that the inhibition rates of puerarin at doses of 10, 30, 60 and 120 mg / kg were 5.1%, 6.5%, 16% and 22%, respectively. With the increase of puerarin dose, the amount of urine sugar increased, compared with the model group, 30,60 and 120 mg / kg dose group significant difference (P <0.05,0.01). CONCLUSION Puerarin has the pharmacological activity of inhibiting h SGLT2 and promoting blood glucose to promote urinary glucose, and may be used as a new class of leading compounds of SGLT2 inhibitors.