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

摘要 氧化终产物（OxPs）和晚期糖基化终产物（AGEs）是一种长寿命的反应性糖基化终产物。 由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。两者在糖尿病中均增加，并且被认为是微- 和糖尿病的大血管并发症。 几项临床和流行病学研究表明，选择性个体AGE/OxPs在 血液和心血管风险。然而，研究往往是小规模的，横断面的，使用单一的年龄或OxP或 相对不准确的免疫测定，因此缺乏令人信服的人体数据。一种新型的高通量LC-三联体 四极杆方法最近被开发用于测量一组AGEs和OxPs浓度， 血液分析是全面的，精确的，可以很容易地应用于大量的样本。 使用这种高度精确的技术，我们证明了几种基线血浆AGEs和OxPs（和 他们的组合）与冠状动脉的长期进展呈正相关， 在退伍军人事务部糖尿病试验的一部分参与者中， （VADT）。具体地说，我们发现一种OxPs的血浆水平之间存在强烈的负相关， 甲基亚砜（MetSO）和意外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）的对照亚组。没有AGE/OxPs 与同时发生的血红蛋白A1c（HbA1c）水平相关，但与糖尿病病程相关， 这与高血糖症对这些化合物的长期影响一致。此外，较高的AGEs强烈 在我们的VADT亚组中，预测糖尿病肾病进展，与血糖控制无关， 肾脏疾病的其他传统风险因素。这些数据与先前的小型研究一致， 几种AGEs与2型糖尿病的肾脏病理及其进展有关。 本建议建立在这些发现和调查的MetSO和AGEs和OxPs的关系 ACCORD试验中糖尿病并发症的病例队列样本。 在目标1中，我们提出验证MetSO和CVD之间的反比关系。我们将测试基线是否 MetSO水平与CVD事件有关。我们还将探索个人之间的关系 AGEs或合并OxP/AGE评分与CVD事件，以及合并MetSO/AGE是否可改善CVD风险 预测模型在目标2中，我们将确定AGEs是否与糖尿病肾病相关 疾病（DKD）。我们将探讨单个AGE或合并AGE评分是否能改善DKD预测 模型 这是第一次大规模和全面的评估，将大大扩大我们对这些关系的理解。 AGE/OxPs与糖尿病并发症之间的关系及其在人类中的重要性，并可能改善我们的 风险评估和识别模型。

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.