Regulation of Glutathione S Transferase Mu with type 1 diabetes and its regulation with antioxidants

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Objective: Increased oxidative stress is now related with the pathogenesis and the chronic complications associated with the disease, diabetes mellitus. While roles of oxidative stress in diabetic complications are widely studied, the molecular mechanisms playing role in the regulations of detoxification enzymes in the presence of antioxidants have not been clearly established because of the complexity of the pathways. Methods: Diabetes was induced by single dose streptozotocin application and rats were treated with 50mg/kg antioxidants DL-alpha-lipoic acid (LA), vitamin C (VC) and combination of both for three weeks. Lipid peroxidation, protein oxidation and reduced glutathione levels were measured and Glutathione S-Transferase Mu (GST-Mu) isozyme activity was determined by using enzyme specific substrate. mRNA and protein expressions were evaluated by RT-PCR and western blot methods respectively. Results: In diabetic animals the products of lipid peroxidation and protein oxidation reactions were all found to be elevated significantly (p<0.05) and supplementing the animals either individually or in combination with two powerful antioxidants restored this effect. GST-Mu activities were also significantly decreased in diabetic group compared to controls and RT-PCR and Western blot analysis results showed that this decrease in activity is regulated at the level of gene expression, as both mRNA and protein expressions were suppressed. All antioxidant treatments did not reverse the effect of diabetes at the gene expression level and interestingly protein expressions were further suppressed indicating a post-translational regulation by antioxidants. Conclusion: Presence of oxidative stress and the effects of antioxidants in diabetic rats were confirmed and it was found that diabetes leads to GST-Mu to be down regulated at mRNA expression levels. Future post-translational modification studies will help to determine the mechanism or combination of mechanisms underlying the damaging effects of oxidative stress observed in streptozotocin induced diabetic rats.