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

1 型糖尿病并发症的生物标志物 (DCCT/EDIC)

• 批准号: 8019784
• 负责人: Stanley L Hazen
• 金额: $ 7.67万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-04 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019784
• 关键词: 3-nitrotyrosine; Acute; Affect; Albuminuria; Apolipoprotein A-I; Arginine; Atherosclerosis; Biochemical; Biological Markers; Blood Vessels; C-reactive protein; Carbohydrates; Cardiac; Cardiovascular Diseases; Cardiovascular system; Characteristics; Chronic; Clinical; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Enzymes; Epidemiology; Event; F2-Isoprostanes; Fibrinogen; Follow-Up Studies; General Population; Glucose; Glycosylated hemoglobin A; Goals; Guidelines; High Density Lipoproteins; Hydroxyl Radical; Hyperglycemia; Image; Inflammation; Insulin-Dependent Diabetes Mellitus; Intervention; Isoprostanes; Kidney Diseases; Lead; Link; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Medial; Mediating; Methods; Modeling; Modification; Molecular; Monitor; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peroxidases; Phenylalanine; Process; Production; Proteins; Reporting; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Site; Testing; Therapeutic; Thick; Tyrosine; Vascular Diseases; arm; base; cardiovascular disorder risk; cardiovascular risk factor; case control; cohort; conventional therapy; coronary artery calcification; design; diabetes control; experience; follow-up; glycemic control; indexing; inflammatory marker; inhibitor/antagonist; insight; lipid metabolism; macrovascular disease; molecular marker; nitration; nonhuman primate; oxidant stress; oxidation; prognostic; therapeutic target; type I diabetic; urinary

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.

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）并发症的发病机制中的作用。目前已确定的碳水化合物和脂质代谢产生氧化应激途径的分子足迹所产生的特定生物标志物，将在一大群 1 型糖尿病 (T1DM) 患者 (DCCT/EDIC) 的基线和此后频繁间隔获得的样本中进行测量。该队列及其血糖控制水平在 25 年的时间里得到了非常详细的描述和频繁而严格的糖尿病并发症及其已知危险因素的检查，几乎没有失访。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，应该会产生新的、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 2 个具体目标来实现： 目标 1 检验特定氧化途径与 DCCT/EDIC 队列中临床 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测量的影响，以及这种影响是否与长期血糖控制 (HbA1c) 相关。 用于分析的生物标志物将包括氧化测量（异前列烷、髓过氧化物酶和下游产物，包括硝基酪氨酸）以及 HDL 的修饰，这些修饰可能会改变其在动脉粥样硬化保护中的功能特征。 NOS 调制器包括 ADMA、SDMA 也将被测量。与 DCCT/EDIC 对照相比，所有发生过心血管疾病 (CVD) 事件的 DCCT/EDIC 受试者中这些标记物与心血管疾病 (CVD) 事件的关系（功效计算的初步分析）。在相关分析中，这些标志物对其他 CVD 指标（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明显肾病）的影响。相关分析将评估强化血糖控制与传统血糖控制（以及相关的 HgbA1c 水平）是否会影响生物标志物的水平。这些分析可以深入了解血糖控制对糖尿病并发症的影响是否是通过任何提出的生物标志物介导的。