Longitudinal Assessment of LDL Immune Complexes and Type 1 Diabetes Complications

描述（由申请人提供）：本申请响应PAR-09-247：主要正在进行的临床研究的辅助研究，以推进NIDDK使命内的科学兴趣领域（R01）。此外，拟议的研究不仅利用了糖尿病控制和并发症试验/糖尿病干预和并发症流行病学（DCCT/EDIC）研究的既定基础设施，而且还建立了先前支持的NIH资助的项目资助（P01 HL55782），题为“糖尿病血管疾病的标志物和机制”，该项目于2008年终止。简而言之，我们建议完成二次数据分析，研究520名DCCT/EDIC参与者的LDL免疫复合物（IC）测量与微血管和大血管并发症的流行病学，这些生物标志物在22年的四个时间点测量。初步数据表明，与LDL-胆固醇水平、血红蛋白A1c和白蛋白排泄率等已知危险因素相比，oxLDL-IC和AGE-LDL-IC是1型糖尿病动脉粥样硬化的更强预测因子。然而，对纵向数据的适当分析是必不可少的。提出的纵向研究将使我们能够确定哪种LDL-IC修饰在预测糖尿病并发症的发展中最重要，并可能使我们揭示预防并发症发展的可能机制。该研究的目的1是确定葡萄糖控制、降脂治疗或血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARBs）治疗是否会导致LDL-IC水平降低，这些药物已知可以降低脂质和/或氧化应激。该研究的目的2是验证ox-LDL、AGE-LDL和MDA-LDL免疫复合物预测1型糖尿病患者微血管和大血管疾病结局的假设；确定这些新的风险因素相对于已确定的风险因素的歧视性力量；识别能够预测目标结果的生物标志物组；并确定严格的血糖控制、降脂治疗或ACE抑制剂或arb治疗是否会改变基线LDL-IC水平与疾病结局之间的关系。1型糖尿病是一种慢性衰弱性疾病，最终导致并发症，导致主要发病率和死亡率。如果特异性LDL-IC在1型糖尿病并发症的发生中起着关键作用，那么特异性LDL-IC不仅可以作为未来疾病风险的生物标志物，而且了解它们在疾病途径中的作用可能为治疗开发提供一种机制。

DESCRIPTION (provided by applicant): This application is responsive to PAR-09-247: Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK (R01). Moreover, the proposed study not only capitalizes on the established infrastructure of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, but builds of off a previously supported NIH funded Program Project Grant (P01 HL55782) entitled "Markers and Mechanisms of Vascular Disease in Diabetes" that terminated in 2008. In brief, we propose to complete secondary data analysis to study the epidemiology of LDL immune complex (IC) measurements in relation to micro- and macro-vascular complications in 520 DCCT/EDIC participants with these biomarkers measured at four time points spanning 22 years. Preliminary data suggest that oxLDL-IC and AGE-LDL-IC are stronger predictors of atherosclerosis in type 1 diabetes than established risk factors including LDL cholesterol levels, hemoglobin A1c and albumin excretion rate. However, proper analysis of the longitudinal data is essential. The longitudinal studies proposed will allow us to determine which LDL-IC modifications are the most important in predicting development of complications in diabetes and may allow us to uncover possible mechanisms through which the development of complications could be prevented. Aim 1 of the proposed study is to determine whether glucose control, lipid lowering therapy or treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which are known to decrease lipids and/or oxidative stress, leads to a decrease in LDL-IC levels. Aim 2 of the proposed study is to test the hypothesis that ox-LDL, AGE-LDL and MDA-LDL immune complexes predict micro- and macro-vascular disease outcomes in individuals with type 1 diabetes; to determine the discriminatory power of these novel risk factors relative to established risk factors; to identify biomarker panels able to predict outcomes of interest; and to determine whether tight glucose control, lipid lowering therapy or treatment with ACE inhibitors or ARBs modifies the relationship between baseline LDL-IC levels and disease outcomes. Type 1 diabetes is a chronic debilitating disease which ultimately results in complications which cause major morbidity and mortality. If specific LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development. PUBLIC HEALTH RELEVANCE: LDL immune complexes (IC) are new biomarkers which may predict complications in patients with type 1 diabetes. Therefore, using data on these biomarkers previously collected as part of a large ongoing study on individuals with type 1 diabetes we propose to determine whether specific LDL immune complexes are associated with common complications in individuals with type 1 diabetes including heart disease, peripheral vascular disease, renal disease and eye disease. If LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development.