Lee_2025_Int.J.Biol.Macromol__149858

Glucagon-like peptide-1 (GLP-1) regulates insulin secretion; however, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP4). Synthetic DPP4 inhibitors are used to treat type 2 diabetes (T2D); however, safer alternatives are required owing to the side effects of these inhibitors. Given the well-documented health advantages of flavonoids, this study computationally screened flavonoid compounds (n = 241) and performed in vitro and in vivo studies to determine the potential of these compounds as natural DPP4 inhibitors. Ten compounds (isobavachalcone (IBC), spinosin, eupatilin, fisetin, glycitin, luteoloside, rhoifolin, isosilybin, ononin, and homoplantaginin) exhibited higher binding energies than the positive control, sitagliptin. IBC was the most potent inhibitor, with the highest binding energy and the lowest IC(50) value among the compounds tested. Furthermore, Caco-2 cells administered IBC exhibited reduced DPP4 mRNA and protein expression levels. IBC administered in vivo reduced high-fat diet (HFD)-induced hyperglycemia by increasing circulating GLP-1 and insulin levels more effectively than sitagliptin. Mice on the HFD exhibited an increase in DPP4 activity and expression, resulting in lower circulating GLP-1 and insulin levels, alongside decreased GLUT2 and GLUT4 expression in the liver and muscles, respectively. IBC treatment also reduced DPP4 expression and activity while increasing GLUT2 and GLUT4 expression in the respective tissues. Additionally, human skeletal muscle cells administered IBC also demonstrated increased cell proliferation and differentiation, indicating that IBC plays a role in myogenesis. Overall, IBC is a potent DPP4 inhibitor with potential for treating T2D, mitigating T2D-related muscle atrophy, and increasing circulating GLP-1 and insulin levels, thereby improving hyperglycemia conditions.