LIPOPROTEINS AND OXIDATIVE STRESS

描述：(申请人提供) 糖尿病与冠状动脉疾病的风险增加有关， 脑血管和外周血管疾病，以及70%-80%的糖尿病 患者死于这些疾病。糖尿病也占到了几乎一半的 均为终末期肾病，是成人发病的最常见原因 西方世界的失明。流行病学研究表明，穷人 血糖控制、高血压、血脂异常(包括低密度脂蛋白)，以及 氧化应激是有贡献的，但血管的标志物和介体 糖尿病中的疾病还没有明确的确定。为了解决这个问题， 来自DCCT/EDIC(1型糖尿病，n=1,416)和一个新的退伍军人合作社的队列 研究(2型糖尿病，n=1700)将进行前瞻性研究。血脂异常， 包括定量和定性的脂蛋白异常，这可能 现在比以往任何时候都更详细地评估，可能会促进血管 损坏。核磁共振(核磁共振)脂蛋白图谱，载脂蛋白 A1、B、E和Lp(A)与脂蛋白相关的活性 对氧磷酶(PON)、卵磷脂胆固醇酰基转移酶(LCAT)和 测定血小板活化因子乙酰水解酶(PAFAH)。 氧化应激、炎症和同型半胱氨酸水平升高也可能 介导糖尿病血管内皮损伤和加速动脉粥样硬化。 自由基氧化产物和血浆中抗氧化剂储备，C反应 蛋白质和血清淀粉样蛋白A作为衡量炎症过程的指标， 同型半胱氨酸水平将在两个队列中进行测量。数据将是 与血管并发症的横断面和前瞻性相关， 胰岛素抵抗和干预，包括糖尿病管理 随机化组。相关研究，以解决潜在的机制 糖尿病中的血管损伤将被进行。血浆将与 体外纯化的酶及其对脂蛋白亚类的影响 核磁共振。低密度脂蛋白、高密度脂蛋白及其1型亚类的功能特征 并将确定2型糖尿病和对照受试者。低密度脂蛋白的作用 纤溶和血管紧张性内皮细胞调节剂亚类， 黏附分子、细胞内钙流量和基质结合 已评估。将对高密度脂蛋白亚组分进行潜在的抗动脉粥样硬化测试 功能，包括抑制细胞因子诱导的内皮细胞黏附 分子表达，防止低密度脂蛋白和细胞膜氧化，并断裂 膜中脂质氧化产物的减少。这些研究，在 与其他项目和核心的协作以及临床协调 这两项研究的中心，将使我们能够剖析复杂的机制 两种类型糖尿病的潜在血管疾病。我们的研究可能 为高危受试者的识别和治疗提供指导，以及 制定新的预防性或干预性战略的理由，这将改善 糖尿病患者的生命。

DESCRIPTION: (provided by applicant) Diabetes is associated with an increased risk of coronary artery disease, cerebrovascular, and peripheral vascular disease, and 70-80% of diabetic patients die of these conditions. Diabetes also accounts for almost half of all end stage renal disease, and is the most common cause of adult-onset blindness in the Western world. Epidemiologic studies suggest that poor glycemic control, hypertension, dyslipidemia (including low HDL), and oxidative stress are contributory, but markers and mediators of vascular disease in diabetes are not clearly established. To address this issue, cohorts from the DCCT/EDIC (Type 1 diabetes, n=1,416) and a new VA Cooperative Study (Type 2 diabetes, n=1,700) will be studied prospectively. Dyslipidemia, including quantitative and qualitative lipoprotein abnormalities, which can now be assessed in greater detail than ever before, may promote vascular damage. Nuclear Magnetic Resonance (NMR) lipoprotein profiles,apolipo-proteins A1, B, E, and Lp(a), and activities of the lipoprotein-related enzymes paraoxonase (PON), Lecithin Cholesterol Acyl Transferase (LCAT), and Platelet Activating Factor Acetyl Hydrolase (PAFAH) will be determined. Oxidative stress, inflammation, and elevated homocysteine levels may also mediate endothelial injury and accelerated atherosclerosis in diabetes. products of free radical oxidation and antioxidant reserves in plasma, C-reactive protein and serum amyloid A as measures of inflammatory processes, and homocysteine levels will be measured in both cohorts. Data will be related cross-sectionally and prospectively to vascular complication status, insulin resistance, and interventions, including diabetes management randomization groups. Related studies to address underlying mechanisms of vascular damage in diabetes will be conducted. Plasma will be incubated with purified enzymes in vitro and effects on lipoprotein subclasses determined by NMR. Functional characteristics of LDL, HDL, and their subclasses from Type 1 and Type 2 diabetic and control subjects will be determined. effects of LDL subclasses on endothelial cell modulators of fibrinolysis and vascular tone, adhesion molecules, intracellular calcium flux and matrix binding will be evaluated. HDL subfractions will be tested for potentially anti-atherogenic functions, including suppression of cytokin-induced endothelial cell adhesion molecule expression, prevention of LDL and cell membrane oxidation, and break down of lipid oxidation products in membranes. These studies, in collaboration with the other Projects and Cores and the Clinical Coordinating Centers of both studies, will enable us to dissect the complex mechanisms underlying vascular disease in both types of diabetes. Our studies may provide guidelines for identification and treatment of high-risk subjects, and rationale for new preventive or interventive strategies, which will improve the lives of people with diabetes.