Ginsenoside Rf improves glucose metabolism via the IRS/PI3K/Akt and PPARα/PGC1α signaling pathways in insulin-resistant AML12 cells.

BACKGROUND: Insulin resistance (IR) is a key component of type 2 diabetes mellitus and other metabolic disorders. Persistent hyperglycemia impairs insulin signaling and mitochondrial function, thereby contributing to IR progression. Ginsenoside Rf (G-Rf), a bioactive component of Panax ginseng (ginseng), possesses various pharmacological properties. However, its role in glucose metabolism under IR conditions remains largely unexplored. METHODS: High-glucose and insulin treatment was used to induce IR in AML12 hepatocytes. G-Rf cytotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays. Glucose metabolism was evaluated by measuring glucose consumption and Glut2 expression. Western blot analysis and real-time quantitative polymerase chain reaction were used to analyze the key proteins in the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways. Mitochondrial function was assessed through mitochondrial DNA (mtDNA) quantification and intracellular adenosine triphosphate (ATP) measurements. In parallel, liquid chromatography–mass spectrometry (LC–MS) analysis was conducted to quantify the G-Rf content in mature and sprouted ginseng. RESULTS: No cytotoxicity was observed at G-Rf concentrations up to 10 µM. G-Rf treatment significantly improved glucose uptake and Glut2 expression in IR-AML12 cells and restored IRS1 phosphorylation, PI3K expression, and activation of downstream Akt/GSK-3β signaling, promoting glycogen synthesis. Moreover, it upregulated PPARα and PGC1α expression and increased mtDNA content and ATP production, indicating improved mitochondrial function. LC–MS/MS analysis revealed that mature and sprouted ginseng contained G-Rf, with higher concentrations in underground parts. Importantly, substantial G-Rf levels were found in the edible aerial parts of sprouted ginseng. CONCLUSION: G-Rf improves glucose metabolism in IR hepatocytes by activating the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways and enhancing mitochondrial function. Thus, G-Rf is a promising candidate for the dietary or therapeutic management of IR. Furthermore, sprouted ginseng may serve as a sustainable source of G-Rf, supporting its application as a functional food. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-025-05091-7.