ABSTRACT
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.
ABSTRACT
Objective To study that puerarin can prevent the renal glucose reabsorbtion process and promote urinary glucose excretion by inhibiting sodium-dependent glucose cotransporters 2 (SGLT2) to reduce plasma glucose in diabetes rats.Methods Molecular docking was carried out on puerarin and the obtained SGLT2 complexes through homology modeling method with dapagliflozin as positive control.Chinese hamster ovary (CHO) cells stably expressing human SGLT2 and [14C]-MethylD-glucopyranoside ([14C]-AMG) as the substrate were used in vitro for the transport assays and IC50 for SGLT2.The antihyperglycemic activity ofpuerarin was operated by oral glucose tolerance test (OGTT) and urinary glucose excretion (UGE) test in rats.Results Puerarin was identified as the substrate of SGLT2 through molecular docking,but the overall effect was not as strong asdapagliflozin.In vitro experiments showed that puerarin can strongly inhibit hSGLT2,the maximum effect was about 84％ with the half inhibitory concentration (IC50) of 0.40 mol/L.OGTT results showed that glucose inhibition rates of puerarin 10,30,60 and 120 mg/kg doses were 5.1％,6.5％,16％,and 22％ respectively,in a dose-dependent manner.In the UGE experiment,the urine sugar increased with the increase of puerarin dose.Compared with model group,the 30,60,and 120 mg/kg dose groups had significant difference (P ＜ 0.05 and 0.01).Conclusion Puerarin exhibited antiglycemic activity through inhibiting SGLT2 and was considered to be a new lead compound of SGLT2 inhibitors.