Exercise training, CACs, and vascular function in older veterans with IGT

描述(由申请人提供)： 超重、糖耐量受损(IGT)的老年退伍军人患2型糖尿病及其大血管和微血管并发症的风险增加。循环血管生成细胞(CAC)动员受损和CAC功能降低可能参与IGT血管并发症的发生，因为CAC参与了血管生成和血管维持。这项研究测试了这样一种假设，即6个月的有氧运动(AEX)训练将通过提高血管生成生长因子水平和减少炎症和CAC氧化应激来改善患有IGT的老年退伍军人的CAC动员和功能，并且CAC的改善将转化为更好的血管功能和胰岛素敏感性。这将通过两个目标在患有IGT和正常糖耐量(NGT)的老年退伍军人中进行测试。目的1：确定AEX训练对年龄和体重指数匹配的老年IGT和NGT退伍军人CAC动员和功能的影响。A)我们将评估急性运动后循环和骨骼肌血管生成生长因子水平(VEGF和SDF-1)以及CAC动员，以确定IGT患者与NGT患者相比，这些水平是否降低，以及AEX训练后两组患者的CAC动员水平是否增加。B)我们将使用老年IGT和NGT患者的血清和新鲜分离的CACs来测量体外CAC管形成，以确定炎症细胞因子(�循环C反应蛋白、IL-6和肿瘤坏死因子�)和/或CAC中的氧化应激(�超氧化物、�NOX2和�SOD-1)是否损害IGT和NGT患者的CAC管形成，以及6个月的AEX+WL是否增加了这两组患者的CAC管形成。目的：通过测量6个月AEX训练前后骨骼肌毛细血管密度、肱动脉内皮细胞反应性、微血管血流量和胰岛素敏感性，确定AEX训练对老年退伍军人CAC动员和功能的影响是否转化为体内血管功能和胰岛素敏感性。我们将招募32名久坐不动、超重肥胖(BMI 25-35 kg/m2)的IGT退伍军人和32名性别、年龄和BMI匹配的NGT退伍军人，他们将接受为期6个月的AEX培训。在干预前后，受试者将接受a)急性运动试验以评估CAC动员和血管生成生长因子水平，b)采血以评估CAC功能，c)骨骼肌取样以测量毛细血管密度和血管生长因子表达，d)血管测试以评估内皮血管反应性和微血管血流，e)高胰岛素-正常血糖钳夹以测量胰岛素敏感性，以及f)心肺适合性测试和身体成分测定。ANOVA模型将被用来确定基线时IGT与NGT的CAC动员和功能异常，以及两组AEX训练后的变化。回归分析将确定CAC动员和功能的变化是否与骨骼肌毛细血管密度和内皮血管反应性的改善有关，以及血管结果的改善是否与胰岛素敏感性的增加有关。这项面向患者的转化性研究计划使用创新的方法来研究IGT和NGT老年患者CAC动员和功能的调节机制，并将这些发现转化为与临床相关的血管功能和胰岛素敏感性测量。目前，胰岛素抵抗引起的大血管和微血管并发症(如视网膜病变、肾病和神经病变)导致退伍军人医疗保健费用高昂，并严重影响老年人的生活质量。我们乐观地认为，这项研究将为退伍军人管理局改善胰岛素抵抗老年退伍军人的血管健康提供治疗和规划方向。这可能会减少IGT向2型糖尿病及其相关血管并发症的进展，降低与治疗这些心血管疾病并发症相关的医疗成本，并改善我国退伍军人的健康。

DESCRIPTION (provided by applicant): Overweight, older Veterans with impaired glucose tolerance (IGT) are at increased risk for type 2 diabetes and its macro- and microvascular complications. Impaired circulating angiogenic cell (CAC) mobilization and reduced CAC function may contribute to the development of vascular complications in IGT because CACs participate in angiogenesis and vascular maintenance. This study tests the hypothesis that 6-month aerobic exercise (AEX) training will improve CAC mobilization and function in older Veterans with IGT by increasing angiogenic growth factor levels and reducing inflammation and CAC oxidative stress, and that the improvements in CACs will translate to better vascular function and insulin sensitivity. This will be tested in older Veterans with IGT and normal glucose tolerance (NGT) through two aims. Aim 1: Determine the effects of AEX training on CAC mobilization and function in age and BMI- matched older Veterans with IGT and NGT. A) We will assess circulating and skeletal muscle angiogenic growth factor levels (VEGF and SDF-1) and CAC mobilization in response to an acute bout of exercise to determine whether these are reduced in subjects with IGT vs. NGT, and whether these increase after AEX training in both groups. B) We will measure ex vivo CAC tube formation using serum and freshly-isolated CACs from older subjects with IGT and NGT to determine whether inflammatory cytokines (�circulating CRP, IL-6 and TNF�) and/or oxidative stress in CACs (�superoxide, �Nox2, and �SOD-1) impair CAC tube formation in IGT vs. NGT, and whether 6-month AEX+WL increases CAC tube formation in both groups. Aim 2: Determine whether AEX training-induced effects on CAC mobilization and function translate to in vivo vascular function and insulin sensitivity in older Veterans by measuring skeletal muscle capillary density, brachial artery endothelial reactivity, microvascular blood flow, and insulin sensitivity before and after 6-month AEX training. We will enroll 32 sedentary, overweight-obese (BMI 25-35kg/m2) older (50-75 years) Veterans with IGT and 32 sex-, age-, and BMI-matched Veterans with NGT who will undergo 6-month AEX training. Before and after the intervention, subjects will undergo a) acute exercise tests to assess CAC mobilization and angiogenic growth factor levels, b) blood sampling to assess CAC function, c) skeletal muscle sampling to measure capillary density and angiogenic growth factor expression, d) vascular testing to assess endothelial vasoreactivity and microvascular blood flow, e) hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, and f) cardiorespiratory fitness testing and determination of body composition. ANOVA models will be used to determine abnormalities in CAC mobilization and function in IGT vs. NGT at baseline, as well as changes with AEX training in both groups. Regression analyses will determine whether changes in CAC mobilization and function are associated with improvements in skeletal muscle capillary density and endothelial vasoreactivity, and whether improvements in vascular outcomes are associated with increases in insulin sensitivity. This patient-oriented translational research proposal uses innovative approaches to study mechanisms regulating CAC mobilization and function in older subjects with IGT and NGT, and translate these findings to clinically-relevant measures of vascular function and insulin sensitivity. Currently, the macro- and microvascular complications (e.g., retinopathy, nephropathy and neuropathy) of insulin resistance result in substantial VA health care costs and significantly impair the quality of life of older Veterans. We are optimistic that tis study will provide VA with therapeutic and programmatic directions to improve vascular health in insulin resistant older Veterans. This may reduce the progression of IGT to type 2 diabetes and its associated vascular complications, lower medical costs related to treatment of these cardiovascular disease complications, and improve the health of our Nation's Veterans.