Biomarkers for Complications in Type 1 Diabetes (DCCT/EDIC)

描述（由申请人提供）： 本项目的总体目标是确定氧化应激与相关炎症和一氧化氮合酶（NOS）异常在临床心血管疾病（CVD）、颈动脉IMT、心脏MRI和糖尿病微血管（视网膜病变和肾病）并发症发病机制中的作用。将在一个大型1型糖尿病（T1 DM）患者队列（DCCT/EDIC）的基线和此后频繁间隔时采集的样本中，测量由目前已确定的碳水化合物和脂质代谢产生氧化应激的途径的分子足迹产生的特异性生物标志物。该队列及其血糖控制水平在25年的时间内得到了非常好的表征，并经常和严格地检查糖尿病并发症及其已知的风险因素，随访损失很小。通过临床事件、颈动脉IMT和心脏MRI以及肾病和视网膜病变确定关键生物标志物及其与CVD的关系，以及这些生物标志物与血糖控制的可能关系，应导致新的和更具体的治疗方法和指南，以降低糖尿病并发症的风险。这些目标将通过2个具体目标来实现：目标1检验DCCT/EDIC队列中特定氧化途径与临床CVD、颈动脉IMT、心脏MRI和微血管并发症风险增加相关的假设。目标2.确定DCCT期间强化治疗与常规治疗对氧化应激指标的影响，以及该影响是否与慢性血糖控制（HbA 1c）相关。 用于分析的生物标志物将包括氧化的测量（异前列腺素、髓过氧化物酶和下游产物，包括硝基酪氨酸）以及可能改变其在动脉粥样硬化保护中的功能特征的HDL的修饰。NOS的调制剂包括ADMA、SDMA也将被测量。与DCCT/EDIC对照相比，所有发生事件的DCCT/EDIC受试者中这些标志物中的每一种与心血管疾病（CVD）事件的关系（把握度计算的主要分析）。在相关分析中，这些标志物对CVD的其他测量（颈动脉内膜中层厚度和心脏MRI）以及微血管并发症（糖尿病视网膜病变和显性肾病）的影响。相关分析将评估强化与常规血糖控制（以及相关的HgbA 1c水平）是否影响生物标志物的水平。这些分析可能会提供洞察血糖控制对糖尿病并发症的影响是否通过任何拟议的生物标志物介导。

DESCRIPTION (provided by applicant): The overall goal of this project is to determine the role of oxidative stress with associated inflammation and abnormalities in nitric oxide synthase (NOS) in the pathogenesis of clinical cardiovascular disease (CVD), carotid IMT, cardiac MRI and microvascular (retinopathy and nephropathy) complications of diabetes. Specific biomarkers arising from the molecular footprints of currently identified pathways producing oxidative stress from carbohydrate and lipid metabolism will be measured in samples obtained at baseline and frequent intervals thereafter in a large cohort of patients (DCCT/EDIC) with type 1 diabetes (T1DM). This cohort and their level of glycemic control has been exceedingly well characterized and examined frequently and rigorously for diabetic complications and their known risk factors over a 25 year period with little loss to follow-up. The identification of key biomarkers and their relationship CVD as determined by clinical events, carotid IMT and cardiac MRI as well as, nephropathy and retinopathy as well as possible relationships of these biomarkers to glycemic control should lead to new and more specific therapeutic methods and guidelines for reducing the risk of diabetic complications. These goals will be accomplished through 2 specific aims: Aim 1 To test the hypothesis that specific oxidative pathways are associated with increased risk for clinical CVD, carotid IMT, cardiac MRI and microvascular complications in the DCCT/EDIC cohort. Aim 2. To determine the effect of intensive versus conventional treatment during the DCCT on measures of oxidative stress and whether this effect is related to chronic glycemic control (HbA1c). Biomarkers for analysis will include measures of oxidation (Isoprostanes, myeloperoxidase and downstream products including nitrotyrosine) as well as modifications of HDL that may alter its functional characteristics in atherosclerosis protection. Modulators of NOS including ADMA, SDMA will also be measured. The relationship of each of these markers to cardiovascular disease (CVD) events (primary analyses for power calculations) in all DCCT/EDIC subjects who have had an event compared to DCCT/EDIC controls. In related analyses, the effects of these markers on other measures of CVD (carotid intimal medial thickness and cardiac MRI) as well as on microvascular complications (diabetic retinopathy and overt nephropathy). Related analyses will evaluate whether intensive vs. conventional glycemic control (and associated levels of HgbA1c) affect the levels of the biomarkers. These analyses may give insights into whether the effects of glycemic control on the complications of diabetes are mediated through any of the proposed biomarkers.