Vascular Metabolic Memory in Type 2 Diabetes

描述(申请人提供)：心血管疾病是2型糖尿病(T2 DM)发病率和死亡率的主要原因。然而，积极降低血糖是否减缓或防止动脉粥样硬化的发展还没有得到很好的证实，实施这一策略的临床试验也没有减少这一群体的心血管疾病(CVD)。最近的研究表明，T1 DM患者的强化降糖可能会减少动脉粥样硬化和心血管事件，但只有在强化治疗多年后才会发生。这些针对T1 DM的研究提出了一种非常重要的可能性，即代谢干预可能会对血管系统产生长期的好处，在干预停止多年后，创造出继续防止动脉粥样硬化的“血管代谢记忆”。这一假设如果属实，将对糖尿病的管理产生重大影响。然而，鉴于这两种形式的糖尿病之间的病理生理和代谢差异，以及可能调节T2 DM动脉粥样硬化和血管功能的其他心血管危险因素过多，在T2 DM患者中测试血管代谢记忆的概念是当务之急。目前的研究利用了一个独特的机会，即为期7年的VA糖尿病严格控制血糖和并发症试验(VADT)的结束，以及在VADT受试者中进行的一项亚临床动脉粥样硬化研究，以及VADT观察性后续研究的开始，以检验T2 DM患者“血管代谢记忆”的假设。我们将确定在VADT期间T2 DM的高强度降糖是否会对随后的动脉粥样硬化(血管代谢记忆)在多个血管床上的进展产生有利影响，以及这是否可以通过改善葡萄糖介导的损伤的直接和间接途径来部分解释。在参与VADT的460名受试者中，我们将在VADT完成后的5年内，使用冠状动脉和腹主动脉钙离子以及颈动脉内膜-中层厚度的测量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。我们还将利用VADT期间和之后的血糖控制、肾功能和新的危险因素的血清指标，探索降糖对“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末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，我们将探讨这一假说，即在VADT期间改善血糖控制将减少动脉粥样硬化程度与未来心血管事件之间的联系。公共卫生相关性：建议的研究利用了一项大型多中心研究中的特征良好的队列，研究地点位于美国各地，提供了一个相当具有代表性的多元化研究小组，代表美国最大的医疗保健系统中的T2 DM患者。这提供了一个难得的机会来确定葡萄糖在人类动脉粥样硬化形成中的具体作用，也许更重要的是，确定密集的降血糖努力是否可以转化为减缓多年的动脉粥样硬化进展。这不是一个微不足道的问题，因为T2 DM患者的动脉粥样硬化性疾病是发病率和死亡率的主要原因，强化的糖尿病治疗带来了巨大的财政和人力负担，并有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.