Inhibition Mechanism of Mulberry Prenylated Flavonoids Sanggenone D/Kuwanon G Against α-Glucosidase and the Regulation of Glucose via GLUT4 Pathway

Background: Inhibition of α-glucosidase activity is recognized as an effective strategy for managing type 2 diabetes. Methods: The inhibitory mechanisms of two kinds of mulberry flavonoids, namely sanggenone D and kuwanon G, on α-glucosidase were investigated and the hypoglycemic pathways were explored in the current study. Results: The outcomes indicate that sanggenone D (IC50: 4.51 × 10−5 mol/L) and kuwanon G (IC50: 3.83 × 10−5 mol/L) inhibited α-glucosidase activity by non-competition/anti-competition mixed inhibition and competitive inhibition, respectively. Moreover, the secondary structure of α-glucosidase was altered by static quenching and exhibited a decrease in α-helix and β-antiparallel content, and an increase in β-sheet content. Furthermore, the interaction forces between sanggenone D/kuwanon G and α-glucosidase were hydrophobic interactions and hydrogen bonds, as evidenced by molecular docking. The binding affinity, stability, and binding energy aligned with the results of IC50. Notably, the cyclization in sanggenone D structure resulted in a decrease in the number of phenolic hydroxyl groups and thus a reduction in the formation of hydrogen bonds, which ultimately diminished the binding affinity of sanggenone D to α-glucosidase. In addition, Western blot analysis further indicated that sanggenone D and kuwanon G regulated glucose metabolism by activating the GLUT4 pathway. Conclusions: The results provided useful reference for the application of sanggenone D and kuwanon G in hypoglycemic functional components.