Increased oxidative stress and impaired antioxidant defense mechanisms are believed to be the important factors contributing to the pathogenesis and progression of diabetes mellitus. The products of lipid peroxidation and protein oxidation reactions were all found to be elevated significantly (p&lt / 0.05) in diabetic animals and supplementing the animals either individually or in combination, with two powerful antioxidants DL-&amp / #945 / -lipoic acid (LA) and vitamin C (VC) brought this increment toward the control values. Considering Cu-Zn SOD, CAT and GST-Mu, there was a significant decrease in all activities in diabetic group as compared with control animals. RT-PCR and Western blot analysis results demonstrated that this decrease in activity is regulated at the level of gene expression, as both mRNA and protein expressions were also suppressed for these enzymes. However, in diabetic animals both the mRNA expressions and the activities of two other antioxidant enzymes, namely Mn SOD and GPx, did not change, indicating that the control of activities of these two enzymes were not at the level of genes. Supplementing the diabetic animals with VC increased all CAT, Cu-Zn SOD, GPx, and GST-Mu activities without changing both mRNA and protein expressions suggesting the possible role of post-translational modifications. On the other hand, the effect of VC on Mn SOD was observed at mRNA levels reflecting a transcriptional regulation. Furthermore, supplementing the animals with LA increased the CAT, Cu-Zn SOD, Mn SOD and GPx activities in diabetic rats but different from VC, LA also increased mRNA of CAT and protein levels of CAT, Cu-Zn SOD and Mn SOD suggesting both transcriptional and translational regulation showed by LA. Combined application of antioxidants also increased the CAT, Cu-Zn SOD, Mn SOD and GPx activities toward the control values, but this time there were no statistically significant change in their mRNA expressions even though protein amounts of both CAT and GPx were augmented. That is, when given together, these antioxidants exert their effects mainly at the level of protein synthesis. As a conclusion, diabetes and the resulting oxidative stress coordinately regulate the activities of the antioxidant enzymes at different regulatory points. LA and VC, two powerful antioxidants affect all antioxidant enzyme activities at different levels of transcription and translation. The results indicated the presence of very intricate control mechanisms regulating the activities of antioxidant enzymes in order to prevent the damaging effects of oxidative stress.