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

Abstract 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 1 – T 3 of Akebia trifoliata stem, namely hederagenin ( T 1 ), 3‐epiakebonoic acid ( T 2 ), and arjunolic acid ( T 3 ) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α‐glucosidase. T 1 – T 3 showed the strongest inhibition with IC 50 values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 μM, respectively, compared to the acarbose positive control (IC 50 =106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T 1 – T 3 demonstrated competitive, mixed, and noncompetitive‐type inhibition against α‐glucosidase, respectively. The inhibition constant ( K i ) values were 21.21, 7.70, and 3.18 μM, respectively. Docking analysis determined that the interaction of ligands T 1 – T 3 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 −7 M insulin for 24 h) and glucose uptake assays showed that compounds T 1 – T 3 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 1 – T 3 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.