HDL composition/function and cardiovascular risk in youths with diabetes

根据世界卫生组织的数据，有超过2亿的糖尿病患者，其中多达100万人 每年死于糖尿病的人数，预计到2030年将翻一番。重要的是，在那里 儿童和年轻人的糖尿病发病率已经大幅增加，新的 20岁前确诊的T2糖尿病患者占新发糖尿病病例的40%以上。 心血管疾病(CVD)在青年时期就开始发展，以动脉僵硬为特征。患有糖尿病的青年患者 动脉僵硬明显加快。导致这种显著加速的潜在机制 动脉硬化的机制还不是很清楚，目前的治疗方法疗效有限。其中一个 导致动脉僵硬的关键机制是NO减少介导的内皮功能障碍 可获得性和炎症增加。近年来，高密度脂蛋白(高密度脂蛋白)的功能、甾醇外排能力 被证明是独立于高密度脂蛋白胆固醇(高密度脂蛋白-C)的心血管事件和流行的有力预测因子 将研究范式从高密度脂蛋白胆固醇转变为高密度脂蛋白，作为衡量高密度脂蛋白抗动脉粥样硬化能力的指标。我们 有强有力的初步数据表明，在成年人中，高密度脂蛋白变得功能失调a)在T2D患者中，b)在 有内皮功能障碍的人和c)有T1D和心血管并发症的人。此外，我们 有初步数据表明，高密度脂蛋白中的特定蛋白质可以前瞻性地预测有患糖尿病风险的人 心血管事件。因此我们假设，高密度脂蛋白组成的改变和高密度脂蛋白功能的损害 青年糖尿病患者可能是导致动脉僵硬和动脉硬化增加的新的危险因素 在这一人群中发现了心血管风险。我们建议使用我们最先进的化验方法来研究 高密度脂蛋白的组成和功能是否与青年糖尿病患者动脉僵硬增加有关：第一， 我们将建立与健康对照的T1D或T2D青年的高密度脂蛋白组成和功能的变化 控制。然后，我们将在两个嵌套的互补研究中研究高密度脂蛋白在动脉硬化中的作用 搜索性研究。第一项研究将解决我们的高密度脂蛋白功能的新指标是否与 青年T2D患者的动脉僵硬。第二项研究将在患有T1D的年轻人中解决同样的问题。并行的 在Barbara Davis中心对患有T1D的青年进行的纵向研究中，我们将测试高密度脂蛋白指标的变化 与动脉僵硬的变化和基线高密度脂蛋白指标是否可以预测进展有关 动脉僵硬。总的来说，我们的研究具有在早期发现高密度脂蛋白功能的新角色的巨大潜力 动脉粥样硬化进展的阶段，并将促进我们对动脉生理学的理解 患有糖尿病的青少年僵硬和心血管风险增加。新的分子危险因素的识别 而与年轻人动脉僵硬相关的生物途径有可能识别新的生物标志物 和治疗目标，并有助于降低与糖尿病相关的心血管疾病死亡率，a 面对青少年糖尿病发病率迅速上升的关键研究领域。

According to the World Health Organization, there are over 200 million people with diabetes with up to 1 million deaths attributed to diabetes annually, and these numbers are expected to double by 2030. Importantly, there has been a major increase in the incidence of diabetes in children and young adults with the increase in newly diagnosed T2 diabetes reaching over 40% of the new diabetes cases before the age of 20. Cardiovascular disease (CVD) begins to develop already in youth, and is marked by arterial stiffness. In youth with diabetes the arterial stiffness is markedly accelerated. The underlying mechanisms leading to this marked acceleration of arterial stiffening are not well understood and the current treatments have only limited efficacy. One of the key mechanisms leading to the arterial stiffness is endothelial dysfunction mediated by decrease in NO availability and increased inflammation. Recently, high-density lipoprotein (HDL) function, sterol efflux capacity was shown to be a strong predictor of incident and prevalent CVD independent of HDL-cholesterol (HDL-C) shifting the paradigm from HDL-C to HDL function as the metric for the HDL anti-atherogenic capacity. We have strong preliminary data showing that in adults HDL becomes dysfunctional a) in people with T2D, b) in people with endothelial dysfunction and c) in people with T1D and cardiovascular complications. Moreover, we have preliminary data showing that specific proteins in HDL can prospectively predict people at risk for cardiovascular events. We therefore hypothesize that changes in HDL composition and impaired HDL function in youth with diabetes may be novel risk factors contributing to accelerated arterial stiffness and increased cardiovascular risk found in this population. We propose to use our state-of-the-art assays to investigate whether HDL composition and function associates with increased arterial stiffness in youth with diabetes: first, we will establish the changes in HDL composition and function in youth with T1D or T2D compared to healthy controls. We will then investigate the role of HDL in arterial stiffening in two complementary studies nested in SEARCH study. First study will address whether our novel metrics of HDL function associate with increased arterial stiffness in youth with T2D. Second study will address the same question in youth with T1D. In parallel in the longitudinal Barbara Davis Center study of youth with T1D we will test whether changes in HDL metrics associate with changes in arterial stiffness and whether the baseline HDL metrics can predict progression of arterial stiffness. Collectively, our studies have great potential to discover novel roles for HDL function in early stages of atherosclerosis progression, and, will advance our understanding of the physiology of the arterial stiffness and increased cardiovascular risk in youth with diabetes. Identification of novel molecular risk factors and biological pathways related to arterial stiffness in the youth has the potential to identify novel biomarkers and therapeutic targets, and contribute to the efforts to reduce the CVD mortality associated with diabetes, a critical area of research in the face of the rapidly increasing incidence of juvenile diabetes.