Mechanism‐based antioxidant therapies promise to prevent diabetic complications?

Intensive blood glucose control can prevent the initiation and progression of diabetic complications. However, the impacts of intensive therapy against diabetic complications might be limited, because of difficulty in maintaining blood glucose concentrations close to the normal range or other unknown reasons. Thus, another approach based on the elucidation of mechanisms of diabetic complications might be required to prevent the progression of the complications. Production of reactive oxygen species (ROS) and lipid peroxidation are increased in diabetic patients, especially in those with poor glycemic control. Oxidative stress can be crucial for the development of diabetic vascular complications. Thus, there is interest in determining whether antioxidant therapy can complement intensive blood glucose control. In fact, a large number of studies evaluating the efficacy of antioxidants have been carried out. However, the efficacy of these antioxidantbased therapies is still uncertain in relation to preventing diabetic complications in clinical practice. Certainly, a number of experimental studies suggest that some natural antioxidants, such as a-tocopherol (vitamin E), ascorbate (vitamin C), coenzyme Q (CoQ), taurine, glutathione or a lipoic acid, showed beneficial effects on diabetic complications. However, the results from large, long-term clinical trials using a-tocopherol were disappointing. Among the various antioxidantbased therapies, only a-lipoic acid might be somewhat useful in preventing diabetic complications. Meta-analysis has provided evidence that intravenous treatment with 600 mg/day a-lipoic acid over 3 weeks significantly improves both positive neuropathic symptoms and neuropathic deficits in diabetic patients with symptomatic polyneuropathy. a-Lipoic acid is approved in Germany as an agent for the treatment of diabetic neuropathy. The effectiveness of natural antioxidants in preventing diabetic complications is still uncertain. Therefore, new strategies for controlling oxidative stress, such as development of new mechanism-based antioxidants, will be required to prevent diabetic complications. In addition, to develop these agents, we should investigate the mechanisms that underlie the association between diabetes and oxidative stress. There are several potential mechanisms by which hyperglycemia can lead to oxidative stress: