Flavonoid Derivatives Isolated from <i>Hypericum monogynum</i> Ameliorate Insulin Resistance via Modulation of IRS-1/PI3K/Akt/FOXO1 Pathway in HepG2 Cells

In this study, two high-content flavonoid derivatives [3-8 biapigenin (HM 104) and quercetin-3-<i>O</i>-β-<i>d</i>-galactopyranoside (HM 111)] were obtained through the bioactivity-guided isolation of antidiabetic compounds from <i>Hypericum monogynum</i> flowers. HM 104 and HM 111 exhibited good glucose consumption in fatty acid-induced insulin-resistant HepG2 cells. Moreover, both active compounds enhanced glucose uptake by restoring the expression of key regulators of glucose metabolism, including insulin receptor substrate 1, phosphoinositide 3-kinase, protein kinase B, and glucose transporter type 4, and by mitigating the expression of forkhead box O1 and the factors involved in gluconeogenesis. They upregulate the phosphorylation of glycogen synthase kinase-3β, which may affect glycogen synthesis. Furthermore, the production of reactive oxygen species was decreased by the two compounds. This study provides novel mechanistic insights into the protective effects of flavonoid derivatives isolated from <i>H. monogynum</i> flowers in preventing and managing insulin resistance and associated metabolic disorders.