Vascular Metabolic Memory in Type 2 Diabetes

描述（由申请方提供）：心血管疾病是2型糖尿病（T2 DM）发病和死亡的主要原因。然而，积极降低血糖是否会减缓或预防动脉粥样硬化的发展并没有得到很好的证实，实施这种策略的临床试验并没有减少这组个体的心血管疾病（CVD）。最近的研究表明，T1 DM患者强化降糖可能会减少动脉粥样硬化和CVD事件，但仅在强化治疗后多年。T1 DM的这些研究提出了非常重要的可能性，即代谢干预可能对血管系统具有长期益处，产生“血管代谢记忆”，在干预停止后数年继续保护免受动脉粥样硬化。如果这一假设是正确的，那么它对糖尿病的管理具有重大意义。然而，鉴于这两种形式的糖尿病之间的病理生理学和代谢差异以及可能调节T2 DM中动脉粥样硬化和血管功能的其他CVD风险因素过多，必须在T2 DM患者中测试血管代谢记忆的概念。目前的研究利用了一个独特的机会，结束了为期7年的VA糖尿病试验（VADT）的严格血糖控制和并发症，并在一个亚组的VADT受试者的亚临床动脉粥样硬化的伴随研究，以及VADT观察性随访研究的开始，以测试T2 DM的“血管代谢记忆”的假设。我们将确定VADT期间T2 DM患者的强化降糖是否会对多血管床中动脉粥样硬化（“血管代谢记忆”）的后续进展产生有利影响，以及这是否可以部分解释为葡萄糖介导的损伤的直接和间接途径的改善。在参与VADT的460例受试者中，我们将在完成VADT后的5年期间使用冠状动脉和腹主动脉钙以及颈动脉内膜中层增厚的测量来测量动脉粥样硬化的进展。我们还将比较VADT期间和之后相同个体之间血管钙的变化率。在VADT期间和之后，使用血糖控制、肾功能和新风险因素的血清测量，我们还将探索在何种程度上可以通过调节晚期糖基化终产物信号通路的组分或抑制肾脏疾病的发展和进展来解释降糖对“血管代谢记忆”的益处。最后，我们将探讨VADT期间改善血糖控制的时期将减少动脉粥样硬化程度与未来CVD事件之间的联系的假设。公共卫生相关性：拟议的研究利用了一项大型多中心研究中的一个特征良好的队列，该研究的研究中心位于美国各地，提供了一个多样化的研究小组，在全国最大的医疗保健系统中具有T2 DM患者的代表性。这为确定葡萄糖在人类动脉粥样硬化形成中的具体作用提供了难得的机会，也许更重要的是，确定多年来降低葡萄糖的密集努力是否可以转化为减少动脉粥样硬化进展。这不是一个微不足道的问题，因为T2 DM中的动脉粥样硬化疾病是发病率和死亡率的主要原因，强化糖尿病治疗带来了巨大的经济和人力负担，并可能导致更频繁和更严重的低血糖。

DESCRIPTION (provided by applicant): Cardiovascular disease is major cause of morbidity and mortality in type 2 diabetes (T2 DM). However, it is not well-established whether aggressively lowering glucose slows or prevents development of atherosclerosis and clinical trials implementing this strategy have not reduced cardiovascular disease (CVD) in this group of individuals. Recent studies suggest that intensive glucose lowering in T1 DM may reduce atherosclerosis and CVD events, but only many years after the period of intensive therapy. These studies in T1 DM raise the very important possibility that metabolic interventions may have long- term benefits on the vasculature, creating "vascular metabolic memory" that continues to protect against atherosclerosis years after the intervention is discontinued. This hypothesis, if true, has major implications for management of diabetes. However, given the pathophysiologic and metabolic differences between these two forms of diabetes and the plethora of other CVD risk factors that may modulate atherosclerosis and vascular function in T2 DM, it is imperative that the concept of vascular metabolic memory be tested in persons with T2 DM. The current study takes advantage of a unique opportunity, the ending of both the 7-year VA Diabetes Trial (VADT) of tight glycemic control and complications, and an accompanying study of subclinical atherosclerosis in a subset of VADT subjects, and the beginning of the VADT observational follow-up study to test the hypothesis of "vascular metabolic memory" in T2 DM. We will determine if intensive glucose lowering in T2 DM during the VADT will have favorable effects on subsequent progression of atherosclerosis ("vascular metabolic memory") in multiple vascular beds and whether this can be partly explained by improvements in direct and indirect pathways of glucose-mediated injury. In 460 subjects who participated in the VADT, we will measure progression of atherosclerosis using both measures of coronary and abdominal aortic calcium and carotid intima-media thickening during a 5-year period after the completion of the VADT. We will also compare the rates of change in vascular calcium between the same individuals during and after the VADT. Using serum measures of glycemic control, renal function and novel risk factors during and after the VADT, we will also explore to what extent the benefit of glucose lowering has on "vascular metabolic memory" can be explained by modulating components of the advanced glycation endproduct signaling pathway, or inhibiting development and progression of renal disease. Finally, we will explore the hypothesis that the period of improved glucose control during the VADT will reduce the link between extent of atherosclerosis and future CVD events. PUBLIC HEALTH RELEVANCE: The proposed study takes advantage of a well characterized cohort within a large, multicenter study with sites located throughout the U.S., providing a diverse study group that is quite representative of individuals with T2 DM within the largest healthcare system in the nation. This provides a rare opportunity to determine the specific role of glucose in human atherogenesis, and perhaps more importantly, to determine whether intensive efforts to lower glucose may translate into reduced atherosclerosis progression over many years. This is not a trivial question, as atherosclerotic disease in T2 DM is the primary cause of morbidity and mortality, and intensive diabetes treatment carries both a substantial financial and manpower burden and a potential for more frequent and severe hypoglycemia.