Gentiopicroside Alleviates Type 2 Diabetes Mellitus by Ameliorating Hepatic Oxidative Stress via Activation of the <scp>PI3K</scp> / <scp>AKT</scp> /Nrf2 Signaling Pathway

Gentiopicroside (GPS), derived from Gentiana manshurica, exhibits multiple pharmacological activities, such as anti-inflammatory and antioxidant effects, but its role and mechanisms in treating type 2 diabetes mellitus (T2DM) remain unclear. This study explored GPS's therapeutic effects and underlying mechanisms in vitro and in vivo. In a T2DM mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ), the results demonstrated that GPS significantly relieved diabetic symptoms, corrected oral glucose tolerance impairment, enhanced insulin sensitivity, and ameliorated lipid metabolism disorders. GPS also increased the activities of antioxidant enzymes, elevated the levels of antioxidant substances, reduced malondialdehyde (MDA) in serum and liver, and ameliorated hepatic insulin resistance (IR). In palmitic acid (PA)-induced HepG2 cells, GPS dramatically inhibited PA-induced cytotoxicity and oxidative stress by increasing glutathione (GSH) levels and superoxide dismutase (SOD) activities while lowering malondialdehyde (MDA) levels, and reversed PA-induced IR. Mechanistically, GPS regulated protein expression in the PI3K/AKT/Nrf2 pathway and promoted Nrf2 nuclear translocation in both models. More importantly, further studies revealed that LY294002 (a PI3K inhibitor) or ML385 (an Nrf2 inhibitor) suppressed the protective effects of GPS against PA-induced hepatic oxidative damage. In conclusion, GPS alleviates hepatic oxidative damage, IR and delays the progression of T2DM through activating the PI3K/AKT/Nrf2 signaling pathway, providing an important foundation for further development and utilization of GPS. However, this study still has limitations including the lack of a positive control drug and insufficient exploration of the relevant molecular mechanisms, and will further improve the research and explore the clinical potential of GPS in the future.