Luteolin from Lonicera japonica Thunb. restores GLUT4-mediated glucose uptake via PI3K/Akt signaling in insulin resistance

Insulin resistance is a key pathological feature of metabolic disorders, closely associated with impaired insulin signaling and reduced GLUT4-mediated glucose uptake in adipose tissue. Luteolin, a flavonoid from Lonicera japonica Thunb., has been reported to exhibit various metabolic regulatory effects, but its direct role in restoring GLUT4-dependent glucose uptake under insulin-resistant conditions remains insufficiently elucidated. This study aimed to investigate whether luteolin restores GLUT4-mediated glucose uptake and to elucidate the underlying PI3K/Akt-dependent mechanism in obesity-related insulin resistance. Network pharmacology and molecular docking analyses identified luteolin as a candidate compound targeting insulin resistance pathways. Differentiated 3T3-L1 adipocytes and high-fat diet-induced insulin-resistant mouse models were used and glucose uptake, insulin signaling protein phosphorylation and GLUT4 translocation were analyzed by biochemical assays, Western blotting, immunofluorescence and flow cytometry. Network analysis revealed strong associations between L. japonica-related targets and insulin resistance pathways, including PI3K/Akt signaling. In vitro and in vivo experiments demonstrated that luteolin enhanced glucose uptake and promoted GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes, accompanied by increased phosphorylation of IRS, PI3K, Akt and AS160. These effects were abolished by wortmannin, which suppressed both GLUT4 translocation and glucose uptake, indicating a PI3K-dependent mechanism. In addition, luteolin improved metabolic parameters and restored insulin signaling under insulin-resistant conditions in vivo. Collectively, these findings suggest that luteolin from L. japonica improves insulin signaling associated with GLUT4-mediated glucose uptake through a PI3K/Akt-dependent mechanism.