HDL composition/function and cardiovascular risk in youths with diabetes

青少年糖尿病患者的 HDL 组成/功能和心血管风险

• 批准号: 10318179
• 负责人: Tomas Vaisar
• 金额: $ 63.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318179
• 关键词: Acceleration; Accounting; Address; Adult; Age; Antiatherogenic; Area; Atherosclerosis; Attenuated; Biological; Biological Assay; Biological Availability; Biology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Childhood diabetes; Cholesterol; Cohort Studies; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Early treatment; Elasticity; Endothelial Cells; Endothelium; Event; Failure; Functional disorder; Future; General Population; Genetic study; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Impairment; Incidence; Inflammation; Insulin-Dependent Diabetes Mellitus; Lead; Link; Lipids; Mediating; Molecular; Newly Diagnosed; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathway interactions; Persons; Physiology; Population; Prediabetes syndrome; Prevalence; Production; Property; Prospective Studies; Proteins; Race; Reporting; Research; Risk; Risk Factors; Role; Sterols; Stress; Testing; Therapeutic Intervention; Uncertainty; World Health Organization; Youth; arterial stiffness; atheroprotective; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; cohort; endothelial dysfunction; epidemiology study; follow up assessment; improved; mortality; new therapeutic target; novel; novel marker; particle; prospective; protective effect; sex; type I and type II diabetes; young adult

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.

据世界卫生组织统计，全球有超过2亿糖尿病患者， 每年死于糖尿病的人数都在增加，预计到2030年这一数字将翻一番。重要的是 儿童和年轻人糖尿病发病率的主要增加， 在20岁之前诊断的T2糖尿病达到新糖尿病病例的40%以上。心血管 心血管疾病（CVD）在年轻时就已经开始发展，并且以动脉僵硬为标志。在青年糖尿病患者 动脉硬化明显加速。导致这种显著加速的潜在机制 动脉硬化的机制还没有很好的理解，目前的治疗方法只有有限的疗效。之一 导致动脉硬化的关键机制是由NO减少介导的内皮功能障碍 可用性和炎症增加。最近，高密度脂蛋白（HDL）功能，固醇流出能力 被证明是独立于HDL-胆固醇（HDL-C）的CVD事件和流行的强预测因子 将范例从HDL-C转移到HDL功能作为HDL抗动脉粥样硬化能力的度量。我们 有强有力的初步数据表明，成人中的HDL变得功能失调a）T2 D患者，B） 患有内皮功能障碍的人和c）患有T1 D和心血管并发症的人。而且我们 有初步数据显示，HDL中的特定蛋白质可以前瞻性地预测人们有患 心血管事件。因此，我们假设HDL成分的变化和HDL功能的受损 在青年糖尿病患者中，可能是导致动脉硬化加速和 心血管疾病的风险在这个人群中。我们打算用最先进的检测方法来研究 高密度脂蛋白的组成和功能是否与青年糖尿病患者动脉硬化增加有关：首先， 我们将确定与健康人相比，患有T1 D或T2 D的年轻人HDL组成和功能的变化。 对照然后，我们将在两项补充研究中研究HDL在动脉硬化中的作用， 仔细研究。第一项研究将解决我们的HDL功能的新指标是否与增加的 2型糖尿病青年患者的动脉硬化。第二项研究将在T1 D青年中解决同样的问题。并行 在芭芭拉戴维斯中心对T1 D青年的纵向研究中，我们将测试HDL指标的变化是否 与动脉硬度的变化以及基线HDL指标是否可以预测动脉硬化的进展有关。 动脉僵硬。总的来说，我们的研究有很大的潜力发现HDL功能在早期糖尿病中的新作用。 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， 僵硬和心血管风险增加。新分子危险因素的鉴定 与年轻人动脉僵硬度相关的生物学途径有可能发现新的生物标志物 和治疗目标，并有助于努力降低与糖尿病相关的心血管疾病死亡率， 面对青少年糖尿病发病率的迅速增加，这是一个关键的研究领域。

项目成果

Sex differences in the associations of HDL particle concentration and cholesterol efflux capacity with incident coronary artery disease in type 1 diabetes: The RETRO HDLc cohort study.

• DOI: 10.1016/j.jacl.2024.01.004
• 发表时间: 2024-01
• 期刊: Journal of clinical lipidology
• 影响因子: 4.4
• 作者: T. Costacou;Rachel G. Miller;K. Bornfeldt;Jay W. Heinecke;Trevor J. Orchard;T. Vaisar

Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.

APOA1 的 C 末端翻转可促进小 HDL 依赖于 ABCA1 的胆固醇流出。

• DOI: 10.1161/circulationaha.123.065959
• 发表时间: 2024
• 期刊: Circulation
• 影响因子: 37.8
• 作者: He,Yi;Pavanello,Chiara;Hutchins,PatrickM;Tang,Chongren;Pourmousa,Mohsen;Vaisar,Tomas;Song,HyunD;Pastor,RichardW;Remaley,AlanT;Goldberg,IraJ;Costacou,Tina;SeanDavidson,W;Bornfeldt,KarinE;Calabresi,Laura;Segrest,JereP;H
• 通讯作者: H

Does small HDL's function improve when lipid-lowering alters its composition?

当降脂改变其组成时，小HDL的功能是否会改善？

• DOI: 10.1016/j.jlr.2024.100505
• 发表时间: 2024
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Heinecke,JayW;Vaisar,Tomas;Bornfeldt,KarinE
• 通讯作者: Bornfeldt,KarinE