Targeting Microvascular Contributors to Impaired Functional Exercise Capacity in Diabetes

糖尿病（DM）缩短寿命，传统的心血管（CV）风险无法完全解释这种影响 因素功能性运动能力（FEC）是CV和全因死亡率的通用预测因子， 糖尿病患者的发病率下降。我们结合基础和临床研究的总体目标 该项目旨在了解和治疗糖尿病患者的FEC受损，以预防过早死亡。新 来自我们实验室的数据表明：氧气输送独特地限制了DM体内肌肉线粒体功能 肌肉血流分布的建模揭示了减少的流量和 毛细血管密度相对于不均匀流动分布的贡献较小（啮齿动物）; 靶向一氧化氮合酶/一氧化氮（NOS/NO）或胰高血糖素样肽1（GLP-1）影响FEC （跑步距离），并证明肌肉灌注（血流量，毛细血管密度和 血流分布）和氧消耗。 假设：微血管灌注异质性有助于糖尿病介导的肌肉 疲劳，肌肉VO 2减少和FEC受损，这些终点将在两次治疗后改善 改善肌肉血流分布的不同药物-GLP-1或亚硝酸盐。 SA #1：为了检验GLP-1和亚硝酸盐将预防或恢复高血糖症的假设- 介导的肌肉灌注异质性、肌肉疲劳和肌肉VO 2降低： 将采用诱导性高血糖小鼠模型来检查高血糖对肌肉的影响 灌注、肌肉疲劳和肌肉VO 2。第二组实验将测试GLP-I或GLP-II的能力。 亚硝酸盐通过不同的机制靶向eNOS/NO，以预防或恢复这些终点。SA #2：至 检查GLP-1或亚硝酸盐改善DM FEC和增强 运动训练：我们将确定GLP-1或亚硝酸盐对运动表现的影响， 没有高血糖和运动训练。这些实验将通过以下方式解决总体假设： 探索GLP-1或亚硝酸盐对FEC和运动训练反应的影响。SA#3：定义 GLP-1受体对肌肉灌注异质性和功能的重要性， 适应运动训练：已发表的和初步的数据表明，GLP-1可以增加 对运动训练的适应和试验数据表明，GLP-1受体拮抗剂干扰 适应性运动训练反应。这些研究将阐明内皮细胞GLP-1受体是否是 这是心脏代谢适应运动训练所必需的。这些研究对退伍军人的影响 人口：糖尿病降低预期寿命，在退伍军人中非常普遍。成功执行 这项研究计划将为可能急性改善功能的干预措施提供关键的临床前数据 增加身体活动对糖尿病患者心血管健康的影响。

Diabetes (DM) shortens lifespan, an impact that is not fully explained by traditional cardiovascular (CV) risk factors. Functional Exercise Capacity (FEC) is a universal predictor of CV and all-cause mortality and it is decreased in people with diabetes. The overall goal of our combined basic and clinical research program is to understand and treat impaired FEC in DM to prevent premature mortality. New data from our lab indicate that: Oxygen delivery uniquely limits in vivo muscle mitochondrial function in DM (human); Modeling of muscle blood flow distribution reveals that the contributions of reduced flow and capillary density were minor relative to the contributions of heterogeneous flow distribution (rodent) ; Targeting of nitric oxide synthase/nitric oxide (NOS/NO) or glucagon like peptide 1 (GLP-1) impacts FEC (running distance) and demonstrate a correlation between muscle perfusion (blood flow, capillary density and blood flow distribution) and oxygen consumption. Hypothesis: Microvascular perfusion heterogeneity contributes to diabetes mediated muscle fatigue, decreased muscle VO2 and impaired FEC and these endpoints will improve with two different agents that improve muscle blood flow distribution -GLP-1 or Nitrites. SA#1: To test the hypothesis that will GLP-1 and Nitrites will prevent or restore hyperglycemia- mediated muscle perfusion heterogeneity, muscle fatigue and decreased muscle VO2: This aim will employ a mouse model with inducible hyperglycemia to examine the impact of hyperglycemia on muscle perfusion, muscle fatigue and muscle VO2. The second set of experiments will test the ability of GLP-1 or Nitrites, targeting eNOS/NO by different mechanisms, to prevent or restore these endpoints. SA#2: To examine the ability of GLP-1 or Nitrites to improve DM FEC and to augment the impact of exercise training: We will determine the impact of GLP-1 or Nitrites on exercise performance with and without hyperglycemia and exercise training. These experiments will address the overall hypothesis by exploring the impact of GLP-1 or Nitrites on FEC and the exercise training response. SA#3: To define the importance of GLP-1 receptors for muscle perfusion heterogeneity and function and for the adaptation to exercise training: Published and preliminary data indicate that GLP-1 can augment adaptation to exercise training and pilot data demonstrate that the GLP-1 receptor antagonist interferes with the adaptive exercise training response. These studies will clarify whether endothelial cell GLP-1 receptors are required for cardiometabolic adaptation to exercise training. Impact of these studies on the Veteran Population: Diabetes decreases life expectancy and is highly prevalent in Veterans. Successful execution of this research program will provide critical preclinical data for interventions that may acutely improve function and increase the impact of physical activity on cardiovascular health in people with diabetes.