Conclusion and Future Directions

The onset and progression of diabetes-related atherosclerosis is likely to involve a wide range of pathogenic mechanisms, including oxidative stress, which as suggested by Brownlee, may have a central role stemming from hyperglycemia hyper-glycemia-induced O2- production by mitochondria. Research has increased our understanding of oxidative stress in general and in diabetes, and its contribution to atherosclerosis and diabetic vascular complications. Well-validated and standardized assays of oxidative stress and damage are urgently needed. Samples for analysis must be collected and stored appropriately to avoid ex vivo oxidation, an obvious point, but one that can be difficult to achieve in large multicenter clinical trials. Knowledge of oxidative stress-related gene polymorphisms may facilitate identification and treatment of high complication risk diabetic patients and drug choice. Well-tolerated and effective drugs targeting appropriate oxidative stress pathways in appropriate compartments are required.

The relationship of oxidative stress stress-related markers to macrovascular events in both Type 1 and in Type 2 diabetes, levels defining high risk and treatment goals, and response to appropriate interventions requires much further study. Further biochemical, cell culture, animal, and human studies are required to elucidate underlying mechanisms of oxidative damage and to design and test effective treatments. Longer -term observational and intervention studies in well-characterized Type 1 and in Type 2 diabetic patients, focusing on macrovascular end-points and including measures of oxidative stress and damage are required. Surrogate measures of macrovascular damage will facilitate such studies, but knowledge of their relationship to clinical events and survival is vital.

Until such data and more specific guidelines and antioxidant drugs are available, aggressive management of diabetes according to currently accepted guidelines for lifestyle, glycemia, blood pressure, and dyslipidemia265 dyslipidemia264 should be continued for the prevention of macrovascular disease. These have proven successful, although atherosclerosis and the related microvascular complications still remain major causes of morbidity and premature mortality in this increasingly common condition. As diabetes complications are multi-factorial in origin, it is appropriate that a multi-faceted approach to prevention and treatment should be taken, and in the future, this may include new antioxidant therapies guided by measures of oxidative stress.

Acknowledgements The authors thank our colleagues for input into discussed research from the authors' laboratories, including: Professors James Best, George Jerums, Bruce Kemp, Timothy Lyons, John Baynes, Suzanne Thorpe, Maria Lopes-Virella, and W. Tim Garvey, and Drs Rick Klein, Deanna Cheek, Peter Hoffman, Christine Winterbourn, George Kalogerakis, Arthur Baker, Craig Nelson, Andrew Wilson, Kevin Croft, Trevor Mori, Andrzej Januszewski, Jasmine Chung, SQ Chan, and also Ms. Connie Karschimkus and Jade Woon, and Mr. George Dragicevic. Grant support for the research was provided by the Australian National Heart Foundation, VicHealth, the Juvenile Diabetes Research Foundation, Diabetes Australia Research Trust, the American Diabetes Association Lions SightFirst Diabetic Retinopathy Research Program, National Health and Medical Research Council, and the Ophthalmic Research Institute of Australia.

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