Ginsenoside Rh2 mitigates hepatic gluconeogenesis by regulating Akt/FoxO1 pathway in type 2 diabetic mice

Hepatic glucose metabolic dysfunction is a core pathological feature of type 2 diabetes mellitus (T2DM), making interventions targeting hepatic glucose metabolism of significant clinical importance. Ginsenoside Rh2 (Rh2), a rare saponin from the roots of Panax ginseng, has been proven to improve metabolic disorders. Therefore, this study was designed to investigate the mechanisms of Rh2 for ameliorating T2DM-associated hepatic glucose metabolic disorders. We demonstrated that Rh2 (5 and 10 mg/kg) exerts significant hypoglycemic and hepatoprotective effects, evidenced by reduced fasting blood glucose (FBG) levels, improved oral glucose tolerance, alleviation of hepatic steatosis in high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM mouse model. Mechanistically, Rh2 activated the Akt/FoxO1 signaling pathway and inhibits hepatic gluconeogenesis and promoting glycogen synthesis. Genetic silencing experiments further confirmed the crucial role of Akt in Rh2-mediated hepatic glucose metabolism. Importantly, this study innovatively revealed that Rh2 regulates Akt expression by interfering with the binding of protein phosphatase 2A (PP2A) to p-Akt, thus reducing PP2A-mediated dephosphorylation of p-Akt and sustaining elevated levels of p-Akt to enhance Akt signaling. In conclusion, this work might provide a significant theoretical basis for developing novel T2DM therapies targeting Akt and PP2A, and also provides experimental evidence supporting the clinical transformation of Rh2.