Biomarkers of Vascular Disease Progression in Type 1 Diabetes Mellitus

描述(申请人提供)：拟议研究的目标是阐明选定的生物标记物在预测1型糖尿病微血管和大血管并发症的发展中的价值，并确定几个风险因素，其中一些是糖尿病独有的，是否可能相互作用而增加血管风险。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、血管细胞黏附分子和E选择素；炎症--白介素6、C反应蛋白和可溶性肿瘤坏死因子受体；纤溶和凝血系统-纤维蛋白原、纤溶酶原激活物抑制物-1和组织纤溶酶原激活物。我们将在DCCT基线和收尾阶段，以及研究的第3-5年和第9-12年的EDIC阶段，纵向测定从1型糖尿病患者的DCCT/EDIC队列中获得的样本中的这些生物标志物。我们假设炎症和内皮细胞/凝血/纤溶功能障碍之间的致病相互作用极大地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集将预测高危患者发生并发症。此外，我们还假设，在DCCT研究的强化血糖控制组的患者中，即使在DCCT关闭10年后，观察到的持续较低的并发症发生率也次于我们建议测量的一个或多个生物标记物的持续血糖控制的效果。我们将从三个方面对这一假设进行评估。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将预测该队列中微血管或大血管并发症的发展，以及它们是否预测选定的一组并发症、所有血管并发症或单一并发症。目标2将评估在研究的EDIC阶段与DCCT关闭时测量的生物标记物中的任何一个的水平是否能够解释在DCCT/EDIC研究的强化血糖控制分支登记的患者在接下来的十年中观察到的并发症进展较慢的原因，并因此解释DCCT/EDIC研究小组假设的“代谢印记”现象。AIM 3将评估AIM 1中确定的一组新生物标记物对预测糖尿病并发症的价值，方法是在进入DCCT试验时收集的未用于构建生物标记物风险算法的患者的样本中分析这些生物标记物。

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.