Oxidative insults, antioxidative responses and type 1 diabetes complications

描述（由申请人提供）：拟议的研究是基于现有的儿童发病糖尿病的观察性历史前瞻性研究-匹兹堡糖尿病并发症流行病学（EDC）研究。重点是氧化应激和抗氧化防御，最终目标是获得重要的背景数据，用于设计1型糖尿病的抗氧化试验。《经济发展公约》现已进入其后续行动的第20个年头。虽然氧化应激在糖尿病并发症发生率中的作用在近20年前被提出，但用于评估体内氧化应激的方法存在问题，因此无法得出明确的结论。此外，尽管假设补充抗氧化维生素可以抵消氧化应激，防止血管疾病，但临床试验结果通常不支持补充1-生育酚（最活跃的维生素E形式）对心脏病的保护作用。然而，最近的发现可能有助于阐明氧化应激和抗氧化治疗在人类中的作用。一方面，测量异前列腺素（IsoPs）的能力，目前被认为是氧化应激的“金标准”生物标志物，为理解这一重要途径提供了更好的机会。此外，最近有人提出，抗氧化治疗可能仅对具有特定的触珠蛋白（Hp）基因型的患者有效。Hp是一种急性期蛋白，与游离血红蛋白结合，抑制血红蛋白诱导的氧化性组织损伤。由于氧化损伤可能导致糖尿病血管并发症的发生，因此Hp基因型可能是糖尿病血管疾病风险的决定因素。我们的目的是建立1型糖尿病EDC研究参与者的氧化应激（尿IsoPs）随时间变化的概况。我们进一步旨在评估个体对氧化应激的反应程度（例如抗氧化剂摄入量/血浆水平和Hp基因型）是否能改变与氧化应激相关的风险。研究的1型糖尿病并发症包括增生性视网膜病变、确诊的远端对称多神经病变、显性肾病和冠状动脉疾病。该提案将需要：1)仔细审查现有的图表和更详细的抗氧化剂使用文件，包括打电话给一些参与者澄清和细节。目前我们只记录了维生素补充剂的使用情况，缺乏关于剂量和使用频率的完整信息；2)尿IsoPs测定；3)储存样品中血浆1-生育酚的测定。证明氧化应激测量与一种或多种并发症的发生呈正相关，血浆1-生育酚水平与并发症和/或改变氧化应激成分呈负相关，将极大地加强试验的论证。此外，检查口服剂量/血浆水平与维生素E摄入量/1-生育酚水平的关系将得到一些关于适当剂量的数据。最后，Hp基因型对所有这些结果的影响将极大地影响干预试验的可能纳入标准。公共卫生相关性：该建议的意义在于能够在一个大型1型糖尿病队列中提供以下证据：1)氧化应激在血管疾病发病机制中的作用，2)补充抗氧化剂在降低氧化应激水平中的潜在效用，以及3)遗传易感性在评估疾病风险和识别有可能从抗氧化治疗中获益的高危人群中的潜在作用。因此，该项目可能为预防易感糖尿病患者血管并发症的相对廉价的治疗方案提供信息，提高他们的生活质量，减少与并发症相关的费用。

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.