Biomarkers of Vascular Disease Progression in Type 1 Diabetes Mellitus

描述（由申请人提供）：本研究的目的是阐明选定的生物标志物在预测1型糖尿病微血管和大血管并发症发展中的价值，并确定几种危险因素（其中一些是糖尿病特有的）是否可能相互作用以增加血管风险。我们将测量三类生物标志物：i.)内皮细胞功能障碍-可溶性ICAM-1， VCAM和E选择素；ii)炎症-白细胞介素-6、CRP和可溶性TNF受体；Iii .)纤溶和凝血系统-纤维蛋白原，纤溶酶原激活剂抑制剂-1和组织纤溶酶原激活剂。我们将在DCCT基线和结束阶段，以及EDIC阶段研究的3-5年和9-12年，从特征良好的1型糖尿病DCCT/EDIC队列中获得的样本中纵向分析这些生物标志物。我们假设炎症与内皮细胞/凝血/纤溶功能障碍之间的致病相互作用在很大程度上促进了糖尿病血管并发症的加速发展，并且上述生物标志物的选择性聚类可以预测并发症的高风险患者。此外，我们还假设，在DCCT研究的强化血糖控制组中，即使在DCCT关闭10年后，观察到的持续较低的并发症发生率是继发于我们建议测量的一种或多种生物标志物的持续血糖控制效果。我们将从三个方面来评估这一假设。目的1将确定任何生物标志物或生物标志物簇的浓度是否可以预测该队列中微血管或大血管并发症的发展，以及它们是预测一组精选并发症，所有血管并发症还是单一并发症。目的2将评估在研究的EDIC阶段，是否有任何生物标志物的水平与DCCT结束时测量的水平保持相似，可以解释在未来十年的随访中，在DCCT/EDIC研究的强化血糖控制组中观察到的并发症进展较慢，从而解释DCCT/EDIC研究小组假设的“代谢印记”现象。目的3将评估目的1中确定的一组新型生物标志物的价值，通过分析在进入DCCT试验时从未用于构建生物标志物风险算法的患者中收集的样本中的生物标志物来预测糖尿病并发症。

DESCRIPTION (provided by applicant): The goal of the proposed research is to elucidate the value of selected biomarkers in predicting the development of micro- and macro-vascular complications in Type 1 diabetes and to determine if several risk factors, some unique to diabetes, may interact to augment vascular risk. We will measure three classes of biomarkers: i.) endothelial cell dysfunction - soluble ICAM-1, VCAM, and E selectin; ii.) inflammation-interleukin-6, CRP, and soluble TNF ?receptors; iii.) fibrinolytic and clotting system - fibrinogen, plasminogen activator inhibitor-1 and tissue plasminogen activator. We will assay these biomarkers longitudinally in samples, obtained from the well characterized DCCT/EDIC cohort of type 1 diabetes, at the DCCT baseline and closeout phases, and in years 3-5 and 9-12 of the EDIC phase of the study. We hypothesize that the pathogenic interaction between inflammation and endothelial cell/clotting/fibrinolytic dysfunction greatly contributes to the accelerated development of vascular complications in diabetes, and that selective clustering of the above biomarkers will predict patients at high risk to develop complications. Furthermore, we also hypothesize that the persistent, lower rate of complications observed in patients enrolled in the intensive glycemic control arm of the DCCT study even 10 years after the close-out of the DCCT is secondary to the effect of sustained glycemic control in one or more of the biomarkers we propose to measure. We will evaluate this hypothesis in three aims. Aim 1 will determine if concentrations of any biomarker or cluster of biomarkers, will predict the development of micro- or macro-vascular complications in this cohort and whether they predict a select group of complications, all vascular complications, or a single complication. Aim 2 will assess if levels of any of the biomarkers studied that remain similar, during the EDIC phase of the study, to those measured at DCCT close-out can explain the slower progression of complications observed in patients enrolled in the intensive glycemic control arm of the DCCT/EDIC study over the next decade of follow-up and, therefore, explain the "metabolic imprint" phenomenon postulated by the DCCT/EDIC group of investigators. Aim 3 will assess the value of the panel of novel biomarkers identified in Aim 1 to predict diabetic complications by assaying these biomarkers in samples collected at entry into the DCCT trial from patients not used to construct the biomarker risk algorithm.