Vascular Metabolic Memory in Type 2 Diabetes

描述（由申请人提供）：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，目前还不清楚积极降低血糖是否会减缓或防止动脉粥样硬化的发展，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期糖尿病患者强化降糖可能会减少动脉粥样硬化和CVD事件，但只有在强化治疗多年后才会发生。这些针对T1型糖尿病的研究提出了一种非常重要的可能性，即代谢干预可能对脉管系统有长期益处，产生“血管代谢记忆”，在干预停止多年后继续防止动脉粥样硬化。这一假设如果成立，将对糖尿病的治疗产生重大影响。然而，鉴于这两种糖尿病之间的病理生理和代谢差异，以及可能调节T2 DM患者动脉粥样硬化和血管功能的大量其他CVD危险因素，有必要在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，即结束了7年的VA糖尿病试验（VADT）严格控制血糖和并发症，以及对一部分VADT受试者的亚临床动脉粥样硬化的伴随研究，以及开始VADT观察性随访研究，以检验T2 DM的“血管代谢记忆”假说。我们将确定VADT期间T2 DM的强化降糖是否会对多血管床的后续动脉粥样硬化进展（“血管代谢记忆”）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460名参加VADT的受试者中，我们将在VADT完成后的5年内，通过测量冠状动脉和腹主动脉钙以及颈动脉内膜-中膜增厚来测量动脉粥样硬化的进展。我们还将比较相同个体在VADT期间和之后血管钙的变化率。通过VADT期间和之后的血糖控制、肾功能和新危险因素的血清测量，我们还将探讨降血糖对“血管代谢记忆”的益处在多大程度上可以通过调节晚期糖基化终产物信号通路的成分或抑制肾脏疾病的发生和进展来解释。最后，我们将探讨在VADT期间改善血糖控制的时间将降低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：本研究在美国各地开展了一项大型、多中心的研究，利用了一个特征良好的队列，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相当代表性的T2糖尿病患者。这为确定葡萄糖在人类动脉粥样硬化发生中的具体作用提供了难得的机会，也许更重要的是，确定多年来强化降低葡萄糖的努力是否可以转化为减少动脉粥样硬化的进展。这不是一个微不足道的问题，因为T2 DM的动脉粥样硬化性疾病是发病率和死亡率的主要原因，强化糖尿病治疗既需要大量的财政和人力负担，又有可能发生更频繁和严重的低血糖。

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.