Abstract: Objective To study the changes of peripheral insulin resistance in highfatdiet rat models and the effect of Nacetylcystein intervention. Methods59 normal male SD rats aged 8 weeks were randomly divided into 3 groups:normal diet group(NC,n=20), high fat diet group(HF,n=20),and Nacetylcystein treated group (NAC,n=19, Nacetylcystein 300mg?kg-1?d-1 and on high fat diet). At the end of twenty weeks feeding, we determined fasting plasma insulin(Ins),glucose(Glu) and nitrotyrosine, malondialdehyde(MDA), reduced glutathione hormone(GSH). The glucose infusion rate(GIR)was measured by using euglycemic hyperinsulinemia clamp to evaluate the peripheral insulin resistance.The expressions of IRS1,IRS2 gene in muscle were detected by real time PCR. Results (1)The plasma insulin,glucose,nitrotyrosine and MDA concentrations were higher in HF group than in NC group,but GSH level in plasma was lower.NAC intervention could reverse these effects.(2)The GIR was decreased significantly in HF group as compared with NC group(5.25±1.2mg?min-1?kg-1 vs 13.56±1.7mg?min-1?kg-1)(P<0.01), NAC intervention can reverse these effect(9.28±1.5mg?min-1?kg-1vs 5.25±1.2 mg?min-1?kg-1)(P<0.01).(3)The gene expression of IRS1 was decreased by 52.1% in HF group, and the expressions of IRS2 was decreased by 43.5% (all P<0.01).In contrast, the expressions of IRS1,IRS2 in NAC group were reversed by 738% and 68.4% respectively as compared with HF group(P<0.01). ConclusionsAntioxidant therapy could increase the gene expression of insulin signal transduction molecules in muscle, which might relate with the antioxidant effects of NAC.