Natural Triterpenoids Isolated from Akebia trifoliata Stem Explants Exert a Hypoglycemic Effect via α-Glucosidase Inhibition and Glucose Uptake Stimulation in Insulin-Resistant HepG2 Cells.

The inhibition of α-glucosidase activity is a prospective approach to attenuate postprandial hyperglycemia in the treatment of type 2 diabetes mellitus (T2DM). Herein, the inhibition of α-glucosidase by three compounds T -T of Akebia trifoliata stem, namely hederagenin (T ), 3-epiakebonoic acid (T ), and arjunolic acid (T ) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α-glucosidase. T -T showed the strongest inhibition with IC values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 μM, respectively, compared to the acarbose positive control (IC =106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T -T demonstrated competitive, mixed, and noncompetitive-type inhibition against α-glucosidase, respectively. The inhibition constant (K ) values were 21.21, 7.70, and 3.18 μM, respectively. Docking analysis determined that the interaction of ligands T -T and α-glucosidase was mainly forced by hydrogen bonds and hydrophobic interactions, which could result in improved binding to the active site of the target enzyme. The insulin resistant (IR)-HepG2 cell model used in this study (HepG2 cells exposed to 10  M insulin for 24 h) and glucose uptake assays showed that compounds T -T had no cytotoxicity with concentrations ranging from 6.25 to 25 μM and displayed significant stimulation of glucose uptake in IR-HepG2 cells. Thus, triterpenoids T -T showed dual therapeutic effects of α-glucosidase inhibition and glucose uptake stimulation and could be used as potential medicinal resources to investigate new antidiabetic agents for the prevention or treatment of diabetes.