Compound C(Shahid Beheshti University)

Type 2 diabetes mellitus (T2DM) has become a leading cause of chronic liver disease worldwide. Farrerol has been demonstrated to ameliorate multiple metabolic disorders. However, the role of farrerol in hepatic insulin resistance (IR) in T2DM, as well as the underlying mechanism, remain unclear. The present study aims to elucidate these issues. A rat model of T2DM was used to evaluate the effect of farrerol on IR in vivo. BRL 3 A cells were stimulated with palmitic acid to obtain an in vitro model of IR to further determine the role and mechanism of farrerol in hepatic IR. The involvement of the AMPK pathway was investigated using a selective and ATP-competitive AMPK inhibitor Compound C and specific siRNA targeting AMPKα1. The present study demonstrated that farrerol administration reduced HOMA-IR index, ameliorated dyslipidemia, and regulated glucose tolerance in diabetic rats. Additionally, farrerol administration alleviated hepatic damage, inflammation and oxidative stress accompanied by restored the AMPKα1/mTOR/SREBP-1 pathway in the liver of diabetic rats. Furthermore, in an in vitro model, farrerol enhanced glucose uptake, inhibited lipid accumulation, restored the membrane translocation of GLUT-2, suppressed inflammation and oxidative stress, and regulated the AMPKα1/mTOR/SREBP-1 pathway in palmitic acid-induced BRL 3 A cells. However, incubation with AMPK inhibitor or AMPKα1 knockdown reversed the protective effects of farrerol in vitro. Our findings demonstrate that farrerol ameliorates hepatic IR and associated metabolic dysfunctions by regulating the AMPKα1/mTOR/SREBP-1 pathway. Farrerol may be a promising therapeutic target for the treatment of IR in T2DM.