Abstract: HepG₂ cells were pre-incubated with insulin (Ins 0,1,0.1,0.01 μmol/L) and dexamethasone (Dex 0,3,0.3,0.03 μmol/L) alone or together for 24 h to induce insulin resistance(IR)in vitro,the resistant level was estimated by glucose consumption,the optimal model of insulin resitance was chosen,and at the same time its lasting time of resistance was determined.In order to investigate the effects and mechanisms of mifepristone on insulin-resistant HepG₂cells induced by insulin and dexamethasone,mifepristone and pioglitazone were administered 24 h after the optimal model of insulin-resistant HepG₂ cells was established.The glucose consumption,intracellular concentrations of glucose,glycogen,ATP,and free fatty acid (FFA) in each group were detected.The expression of InsR-mRNA and GR-mRNA was detected by semi-quantitative reverse transcription and polymerase chain reaction (SqRT-PCR).Results revealed that pretreatment with insulin (0.1 μmol/L) and dexamethasone (0.3 μmol/L) for 24 h caused optimal insulin resistance of HepG₂ cells which lasted for 36 h.Compared with control group,the glucose consumption,intracellular glucose,glycogen,ATP contents and the level of InsR-mRNA in model cells decreased while FFAs concentrations and GR-mRNA increased.However,the tendency of insulin- resistant HepG₂ cells was obviously attenuated by pioglitazone at the concentration of 0.2 mmol/L and mifepristone at 200 μmol/L and 20 μmol/L while mifepristone at 2 μmol/L had no effect on insulin-resistant cells.The findings indicated that mifepristone at 200 μmol/L and 20 μmol/L improved the insulin resistance via modulating intracellular glucolipid metabolism and the expression of InsR-mRNA and GR-mRNA.