Vascular Metabolic Memory in Type 2 Diabetes

2 型糖尿病的血管代谢记忆

• 批准号: 8241031
• 负责人: Peter D Reaven
• 金额: $ 60.3万
• 依托单位: ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241031
• 关键词: Abdomen; Accounting; Advanced Glycosylation End Products; Albumins; Atherosclerosis; Blood Vessels; Calcium; Cardiovascular Diseases; Clinical; Clinical Trials; Coronary; Creatinine; Cystatins; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease; Event; Future; Glucose; Glycosylated hemoglobin A; Health; Healthcare Systems; Human; Human Resources; Hypoglycemia; Individual; Injury; Insulin-Dependent Diabetes Mellitus; Intensive Care; Intervention; Kidney; Kidney Diseases; Light; Link; Long-Term Effects; Longitudinal Studies; Measures; Mediating; Memory; Metabolic; Modification; Morbidity - disease rate; Multicenter Studies; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Persons; Phase; Publications; Renal function; Reporting; Risk Factors; Role; Scanning; Scheme; Serum; Signal Pathway; Site; Testing; Thick; Translating; active method; arm; atherogenesis; blood glucose regulation; cardiovascular disorder risk; cohort; diabetes management; follow-up; glycemic control; improved; intima media; mortality; novel; novel therapeutics; post gamma-globulins; prevent; receptor for advanced glycation endproducts; standard care; vascular bed

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.

描述（由申请人提供）：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。但是，尚不确定是积极降低葡萄糖的速度还是防止动脉粥样硬化的发展和实施这种策略的临床试验的发展尚未降低这组个体的心血管疾病（CVD）。最近的研究表明，T1 DM中的密集葡萄糖降低可能会减少动脉粥样硬化和CVD事件，但在强化治疗期间只有很多年。这些在T1 DM中的研究提出了非常重要的可能性，即代谢干预措施可能会对脉管系统具有长期的益处，从而产生“血管代谢记忆”，从而在干预后几年中继续预防动脉粥样硬化。该假设（如果为true）对糖尿病的管理具有重大影响。但是，鉴于这两种形式的糖尿病与其他CVD危险因素之间的病理生理和代谢差异可能会调节T2 DM中的动脉粥样硬化和血管功能，因此必须在T2 DM 。当前的研究利用了一个独特的机会，紧密的血糖控制和并发症的7年VA糖尿病试验（VADT）的结束，以及随附的VADT受试者中亚临床动脉粥样硬化的研究，以及vADT受试者的开始的开始VADT观察性随访研究，以检验T2 DM中“血管代谢记忆”的假设。我们将确定在VADT期间T2 DM中的密集葡萄糖是否会对多个血管性床的随后进展（“血管代谢记忆”）产生有利的影响介导的伤害。在参与VADT的460名受试者中，我们将使用冠状动脉和腹主动脉钙和颈动脉内膜膜增厚的冠状动脉和腹部主动脉钙的测量来测量动脉粥样硬化的进展。我们还将比较VADT期间和之后同一个体之间血管钙的变化率。使用血清血糖控制，肾功能和新的危险因素的血清测量值，我们还将通过调节高级糖化糖化末端产生信号传导的组件来解释降低葡萄糖对“血管代谢记忆”的益处的程度。途径，或抑制肾脏疾病的发展和进展。最后，我们将探讨以下假设：VADT期间改善葡萄糖控制的时期将减少动脉粥样硬化范围与未来CVD事件之间的联系。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具有良好特征的人群，该研究与美国各地的地点相关，提供了一个多元化的研究小组，该小组非常代表了全国最大的医疗保健系统中T2 DM的人。这提供了一个难得的机会来确定葡萄糖在人动脉粥样硬化中的特定作用，也许更重要的是，确定降低葡萄糖的强化努力是否可以转化为多年来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中的动脉粥样硬化疾病是发病率和死亡率的主要原因，而密集的糖尿病治疗既承担着巨大的财务和人力负担，也带来了更频繁和更严重的低血糖症的潜力。