Apolipoproteins and the complications of Type 1 diabetes

描述(由申请人提供)： 目的：利用DCCT/EDIC样本，确定基于载脂蛋白的血浆脂蛋白亚类与1型糖尿病血管并发症(视网膜病变、肾病、颈动脉内膜增厚)的横断面和前瞻性相关性。确定对降脂药物和胰岛素增敏药物的反应。开发临床适用的分析方法，以预测并发症风险和治疗反应。理论基础：血脂异常(定量和定性)与1型糖尿病的微血管和大血管并发症有关。尽管基于载脂蛋白的脂蛋白亚类水平在非糖尿病和2型糖尿病人群中与血管疾病有关，但从未在1型受试者中进行过研究，也没有与并发症状态或其他脂蛋白特征相关。在1型糖尿病受试者中，载脂蛋白定义的亚类对潜在治疗的反应尚不清楚。假设：基于载脂蛋白的血浆脂蛋白亚类分布与1型糖尿病的血管并发症相关，并可能决定其易感性。研究计划：第一阶段(R21)：确定100名易发生并发症的DCCT/EDIC受试者和100名不耐受并发症的DCCT/EDIC受试者的载脂蛋白亚类分布；确定与这三种并发症中的每一种并发症的关系，选择临床检测发展感兴趣的亚类。第二阶段(R33)：在当地招募的1型患者中，使用阿托伐他汀、非诺贝特、尼卡潘和罗格列酮进行干预并确定疗效。开发临床适用的分析方法。方法：DCCT/EDIC的储存样本已在我们的实验室建立，并建立了所有载脂蛋白亚类测定和脂蛋白-细胞相互作用研究的方法。这项研究汇集了一个独特的人群(DCCT/EDIC)和一个从未在1型糖尿病中使用过的脂蛋白的重要描述符，目的是预防和治疗并发症

DESCRIPTION (provided by applicant): Objectives: Determine cross-sectional and prospective associations of apolipoprotein-based plasma lipoprotein subclasses to vascular complications of Type 1 diabetes (retinopathy, nephropathy, carotid intimal thickening) using DCCT/EDIC samples. To define responses to lipid-lowering and insulin sensitizing drugs. To develop clinically applicable assays to predict complication risk and response to treatment. Rationale: Dyslipidemia (quantitative and qualitative) is implicated in micro- and macro-vascular complications of Type 1 diabetes. Although apolipoprotein-based lipoprotein subclass levels are implicated in vascular disease in non-diabetic and Type 2 diabetic populations, they have never been studied in Type 1 subjects, nor related to complication status or to other lipoprotein characteristics. Responses of apolipoprotein-defined subclasses to potential treatments in Type 1 diabetic subjects are unknown. Hypotheses: Apolipoprotein-based plasma lipoprotein subclass profiles are associated with, and may determine susceptibility to, vascular complications of Type 1 diabetes. Research Plan: First (R21) phase: determine apolipoprotein subclass profiles in 100 complication-prone and 100 complication-resistant DCCT/EDIC subjects; define associations with each of the three complications, select subclasses of interest for clinical assay development. Second (R33) phase: in locally-recruited Type 1 patients, intervene with atorvastatin, fenofibrate, Niaspan, and rosiglitazone and define effects. Develop clinically applicable assays. Methods: Stored samples from DCCT/EDIC are already in hand, and all methods for apolipoprotein subclass determination and for lipoprotein-cell interaction studies are established in our laboratories. The study brings together a unique population (DCCT/EDIC) with an important descriptor of lipoproteins never used in Type 1 diabetes, with the goal of preventing and treating complications