Identification of bioactive antidiabetic compounds from Teucrium polium L. enhancing glucose uptake in HepG2 cells

The global rise in diabetes prevalence has intensified the search for more effective glucose-lowering agents derived from natural sources. Teucrium polium L. (Lamiaceae), referred to as “golden germander,” has been traditionally used for centuries in Middle Eastern and Mediterranean regions as a medicinal plant for treating of diabetes and other metabolic disorders. Although its antihyperglycemic properties have been previously reported in ethnobotanical and pharmacological studies, the specific bioactive components responsible for its antidiabetic properties remain inadequately characterized. The total ethanol/water (70:30) extract of Teucrium polium aerial parts was extracted sequentially using organic solvents ( n -hexane, ethyl acetate, and chloroform). The glucose uptake potential of each fraction was evaluated in HepG2 cells using the fluorescent glucose analogue 2-NBDG. The most active extract (ethyl acetate) underwent bioassay-guided purification involving column chromatography and preparative high-performance liquid chromatography. Purified compounds were identified using high-resolution tandem mass spectrometry. The resazurin assay was employed to assess cell viability. The ethyl acetate extract demonstrated significant glucose uptake activity (∼76 % efficacy relative to metformin positive control) without notable cytotoxicity. Bioassay-guided purification resulted in the identification of eight active compounds: Teupolin XII, Forsythoside H, Crisiliol, Cynaroside, Cosmosioside, Cirsilineol, 24-Methylenecycloartanol, and Moretenyl acetate. All purified compounds significantly enhanced glucose uptake (>70 %) and displayed minimal cytotoxic effects (>90 % cell viability at effective concentrations). The results highlight the capacity of Teucrium polium to yield bioactive compounds with therapeutic potential for diabetes, particularly by enhancing glucose uptake in HepG2 cells. • Ethyl acetate extract of Teucrium polium enhances glucose uptake in HepG2 cells. • Bioassay-guided purification identified eight active antidiabetic compounds. • All isolated compounds significantly increased glucose uptake (>70 % activity). • Compounds showed low cytotoxicity, maintaining > 90 % HepG2 cell viability. • Study supports Teucrium polium as a source of safe, multi-target antidiabetic agents.