Role of Methionine Sulfoxide and Advanced Glycation Endproducts in Cardiovascular and Renal Complications of Type 2 Diabetes

甲硫氨酸亚砜和晚期糖基化终产物在 2 型糖尿病心血管和肾脏并发症中的作用

• 批准号: 10022163
• 负责人: Juraj Koska
• 金额: $ 10.61万
• 依托单位: ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022163
• 关键词: Advanced Glycosylation End Products; Atherosclerosis; Biological Assay; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Carotid Atherosclerotic Disease; Chemicals; Clinical Research; Complications of Diabetes Mellitus; Coronary; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Discrimination; Evaluation; Event; Future; Glomerular Filtration Rate; Glucose; Glycosylated hemoglobin A; Human; Hyperglycemia; Immunoassay; In Vitro; Individual; Kidney; Kidney Diseases; Link; Lipids; Long-Term Effects; Measures; Modeling; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Outcome; Participant; Pathology; Pathway interactions; Plasma; Proteins; Publications; Reaction; Reactive Oxygen Species; Renal function; Research; Risk; Risk Assessment; Risk Factors; Risk Marker; Role; Sampling; Spectrometry; Subgroup; Techniques; Testing; Veterans; cardiovascular disorder risk; cardiovascular risk factor; case control; cohort; epidemiology study; glycemic control; human data; improved; loss of function; macrovascular disease; methionine sulfoxide; novel; pre-clinical; predictive modeling; risk prediction model; sugar; treatment strategy

Abstract Oxidative end-products (OxPs) and advanced glycation end-products (AGEs) are long-lived reactive intermediates formed by reactions of reactive oxygen species and chemically reactive sugars with proteins, lipids and nucleic acids. Both are increased in diabetes and are believed to be important contributors to both micro- and macrovascular complications of diabetes. Several clinical and epidemiological studies indicated an association between selective individual AGE/OxPs in blood and cardiovascular risk. However, studies were often small, cross-sectional, used a single AGE or OxP or relatively inaccurate immunoassays, so convincing human data are lacking. A novel high-throughput LC-triple quadrupole approach has been recently developed to measure a panel of AGEs and OxPs concentrations in blood that is comprehensive, precise and can be readily applied to large sample numbers. Using this highly accurate technique, we demonstrated that several baseline plasma AGEs and OxPs (and combinations of them) from the panel were positively associated with long-term progression of coronary and carotid atherosclerosis and with incident CVD in a subset of participants of the Veterans Affairs Diabetes Trial (VADT). Specifically, we found a strong negative association between plasma levels of one of the OxPs, Methionine Sulfoxide (MetSO) and incident CVD events suggesting this unique OxP may offer, or reflect, protection against CVD. We observed many of the same CVD findings (including that for MetSO) in a small case- control subgroup of the Action to Control Cardiovascular Risk in Diabetes (ACCORD). None of the AGE/OxPs were related to concurrent hemoglobin A1c (HbA1c) levels but instead were associated with diabetes duration, consistent with long-term effects of hyperglycemia on these compounds. Furthermore, higher AGEs strongly predicted progression of diabetes kidney disease in our VADT subset, independently of glycemic control and other traditional risk factors of renal disease. These data were consistent previous small studies highlighting that several AGEs were related to renal pathology and its progression in type 2 diabetes. The present proposal builds on these findings and investigates the relationships of MetSO and AGEs and OxPs with diabetes complications diabetes complications in a case-cohort sample of the ACCORD trial. In Aim 1 we propose to validate an inverse relationship between MetSO and CVD. We will test whether baseline MetSO levels are associated with incident CVD events. We will also explore the relationship between individual AGEs or combined OxP/AGE scores and incident CVD, and whether a combined MetSO/AGE improve CVD risk prediction models. In Aim 2 we will determine whether AGEs are associated with incident diabetes kidney disease (DKD). We will explore whether individual AGEs or combined AGE scores would improve DKD prediction models. This first large scale and comprehensive evaluation will greatly expand our understanding of the relationships between AGE/OxPs and diabetes complications and their importance in humans, and potentially improve our risk assessment and discrimination models.

抽象的 氧化终产物 (OxP) 和晚期糖基化终产物 (AGE) 具有长寿命反应性 活性氧和化学活性糖与蛋白质、脂质反应​​形成的中间体 和核酸。两者在糖尿病中都会增加，并且被认为是这两种微生物的重要贡献者。 和糖尿病的大血管并发症。 多项临床和流行病学研究表明，选择性个体 AGE/OxP 之间存在关联。 血液和心血管风险。然而，研究通常是小型的、横断面的，使用单一的 AGE 或 OxP 或 免疫测定相对不准确，因此缺乏令人信服的人体数据。一种新型高通量 LC 三重 最近开发了四极方法来测量一组 AGE 和 OxP 浓度 全面、精确且可轻松应用于大量样本的血液。 使用这种高度准确的技术，我们证明了几种基线血浆 AGE 和 OxP（以及 它们的组合）与冠状动脉的长期进展呈正相关， 退伍军人事务部糖尿病试验的一部分参与者患有颈动脉粥样硬化和心血管疾病 （VADT）。具体来说，我们发现其中一种 OxP 的血浆水平之间存在很强的负相关性， 蛋氨酸亚硫酸 (MetSO) 和事件 CVD 事件表明这种独特的 OxP 可能提供或反映， 预防CVD。我们在一个小病例中观察到许多相同的 CVD 结果（包括 MetSO） - 控制糖尿病心血管风险行动（ACCORD）的控制亚组。没有 AGE/OxP 与并发血红蛋白 A1c (HbA1c) 水平相关，但与糖尿病持续时间相关， 与高血糖对这些化合物的长期影响一致。此外，较高的 AGE 强烈 在我们的 VADT 子集中预测糖尿病肾病的进展，独立于血糖控制和 肾脏疾病的其他传统危险因素。这些数据与之前的小型研究一致，强调 一些 AGE 与 2 型糖尿病的肾脏病理及其进展有关。 目前的提案以这些发现为基础，研究了 MetSO 与 AGE 和 OxP 的关系 糖尿病并发症 ACCORD 试验的病例队列样本中的糖尿病并发症。 在目标 1 中，我们建议验证 MetSO 和 CVD 之间的反比关系。我们将测试是否基线 MetSO 水平与突发的 CVD 事件相关。我们还将探讨个人之间的关系 AGE 或 OxP/AGE 综合评分与 CVD 事件，以及 MetSO/AGE 综合评分是否会改善 CVD 风险 预测模型。在目标 2 中，我们将确定 AGE 是否与糖尿病肾病发病相关 疾病（DKD）。我们将探讨单个 AGE 或组合 AGE 评分是否会改善 DKD 预测 模型。 这是第一次大规模、全面的评估，将极大地扩展我们对这些关系的理解 AGE/OxP 与糖尿病并发症及其对人类的重要性之间的关系，并可能改善我们的 风险评估和歧视模型。