Oxidative insults, antioxidative responses and type 1 diabetes complications

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DESCRIPTION (provided by applicant): The proposed study is based on an existing observational historical prospective study of childhood onset diabetes - the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. The focus is on oxidative stress and antioxidative defenses, the ultimate goal being to derive important background data which will be used to design an antioxidant trial in type 1 diabetes. The EDC is now in its 20th year of follow-up. Although a role for oxidative stress in diabetes complication incidence was proposed almost two decades ago, problems in the methods used to assess oxidative stress in vivo have prohibited definitive conclusions. Furthermore, despite the hypothesis that antioxidant vitamin supplementation could counteract oxidative stress, protecting against vascular disease, clinical trials results have generally not supported a protective effect of 1-tocopherol (the most active vitamin E form) supplementation on, especially, heart disease. Recent discoveries, however, may help shed light on the role of oxidative stress and antioxidant therapy in humans. On one hand, the ability to measure isoprostanes (IsoPs), currently considered the "gold standard" biomarker of oxidative stress, provides a better opportunity to understand this important pathway. Moreover, it has recently been proposed that antioxidant therapy may only be successful in those with specific Haptoglobin (Hp) genotypes. Hp, an acute phase protein, binds to free hemoglobin, inhibiting hemoglobin-induced oxidative tissue damage. As oxidative injury may contribute to the development of diabetes vascular complications, the Hp genotype could be a determinant of diabetic vascular disease risk. Our aim is to establish a profile of oxidative stress (urinary IsoPs) overtime among participants in the EDC study of type 1 diabetes. We further aim to assess whether the degree to which an individual is able to respond to oxidative stress (e.g. antioxidant intake/plasma levels and Hp genotype) modifies the risk associated with oxidative stress. Type 1 diabetes complications to be studied include proliferative retinopathy, confirmed distal symmetric polyneuropathy, overt nephropathy, and coronary artery disease. This proposal will entail: 1) the careful review of existing charts and more detailed documentation of antioxidant use, involving calling a number of participants for clarifications and details. Currently we have only documented use of vitamin supplements, lacking full information on dose and frequency of use; 2) the measurement of urinary IsoPs; and 3) the measurement of plasma 1-tocopherol from stored samples. Demonstrating that oxidative stress measures positively relate to the development of one or more of the proposed complications, and that plasma 1-tocopherol levels inversely relate to complications and/or modify the oxidative stress component would greatly strengthen the argument for a trial. Furthermore, examination of the oral dose/plasma level association for vitamin E intake/1-tocopherol levels will yield some data as to the appropriate dosage. Finally, the effects of Hp genotype on all of these outcomes will greatly influence the likely inclusion criteria for an intervention trial. PUBLIC HEALTH RELEVANCE: The significance of this proposal lies in the ability to provide, in a large type 1 diabetes cohort, evidence for: i) the role of oxidative stress in the pathogenesis of vascular disease, ii) the potential utility of antioxidant supplementation in decreasing levels of oxidative stress, and iii) the potential role of genetic susceptibility in both assessing disease risk and in identifying at risk populations with the potential to benefit from antioxidant treatment. Thus, this project may provide information for a relatively inexpensive regimen for the prevention of vascular complications among susceptible individuals with diabetes, improving their quality of life and reducing cost associated with the presence of complications.