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

描述(由申请人提供)： 该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)异常在糖尿病临床心血管疾病(CVD)、颈动脉IMT、心脏MRI和微血管(视网膜病变和肾病)并发症发病机制中的作用。从目前发现的碳水化合物和脂肪代谢产生氧化应激途径的分子足迹中产生的特定生物标记物将在一大批1型糖尿病(T1 DM)患者(DCCT/EDIC)中在基线和此后频繁间隔获得的样本中进行测量。这一队列及其血糖控制水平在25年期间得到了非常好的表征，并对糖尿病并发症及其已知危险因素进行了频繁而严格的检查，几乎没有损失进行随访。根据临床事件、颈动脉IMT和心脏MRI以及肾病和视网膜病变确定的关键生物标记物及其与心血管疾病的关系，以及这些生物标记物与血糖控制的可能关系，将导致新的、更具体的治疗方法和指南，以降低糖尿病并发症的风险。这些目标将通过两个具体目标来实现：目标1在DCCT/EDIC队列中，验证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。目的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，以及这种影响是否与慢性血糖控制(HbA1c)有关。 用于分析的生物标志物将包括氧化措施(异前列腺素、髓过氧化物酶和包括硝基酪氨酸在内的下游产品)以及可能改变其在动脉粥样硬化保护中的功能特征的高密度脂蛋白的修饰。还将测量包括ADMA、SDMA在内的NOS调制器。与DCCT/EDIC对照组相比，所有发生过DCCT/EDIC事件的DCCT/EDIC受试者中，这些标志物与心血管疾病(CVD)事件的关系(功率计算的初步分析)。在相关分析中，这些标记物对其他心血管指标(颈动脉内膜中层厚度和心脏MRI)以及对微血管并发症(糖尿病视网膜病变和临床肾病)的影响。相关分析将评估强化血糖控制与常规血糖控制(以及相关的HgbA1c水平)是否会影响生物标志物的水平。这些分析可能使我们深入了解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记物来调节。

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.