Decoding the functional code of Tuo tea: From untargeted metabolomic profiling to multi-target anti-diabetic mechanisms via liver-pancreas metabolic crosstalk.

Type 2 diabetes mellitus (T2DM) is a growing global health challenge marked by insulin resistance and limited therapeutic options. Tuo tea (CT), a fermented dark tea from Southwest China with reputed hypoglycemic benefits, has unclear bioactive components and mechanisms. Here, we investigated the effects of Tuo tea on insulin resistance using a high-fat/high-sucrose and streptozotocin-induced T2DM mouse model, and explored its multi-organ mechanisms through an integrated strategy combining untargeted metabolomics, network pharmacology, molecular docking, and cellular validation. Tuo tea intervention significantly ameliorated hyperglycemia, insulin resistance, and dyslipidemia, while concurrently alleviating hepatic steatosis and pancreatic islet damage. Integrated analysis identified 548 bioactive constituents and pinpointed FXR, KEAP1, and NF-κB as pivotal targets. Molecular docking prioritized 1,2,6-tri-O-galloyl-β-d-glucopyranose (1,2,6-TGGP) as a key phytopharmacological molecule, which was further validated to enhance glucose metabolism and boost antioxidant capacity in insulin-resistant HepG2 cells, acting through modulation of the FXR/SHP, KEAP1/Nrf2, and NF-κB pathways. These findings demonstrate that Tuo tea alleviates insulin resistance by orchestrating liver-pancreas crosstalk via multi-target mechanisms that mitigate oxidative stress and inflammation, with 1,2,6-TGGP identified as a highly active compound. This study establishes a systematic pharmacological foundation for Tuo tea as a dietary intervention strategy for T2DM.