Targeting Microvascular Contributors to Impaired Functional Exercise Capacity in Diabetes

针对糖尿病患者功能运动能力受损的微血管贡献者

• 批准号: 9898228
• 负责人: JANE E REUSCH
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898228
• 关键词: Activities of Daily Living; Acute; Address; Animals; Basic Science; Blood capillaries; Blood flow; Cardiovascular system; Clinical Research; Data; Diabetes Mellitus; Endothelial Cells; Endothelium; Exercise; GCG gene; GLP-I receptor; Goals; Heterogeneity; Human; Hyperglycemia; Impairment; Insulin-Dependent Diabetes Mellitus; Intervention; Life Expectancy; Link; Longevity; Measures; Mediating; Microvascular Dysfunction; Minor; Modeling; Mus; Muscle; Muscle Fatigue; Muscle Mitochondria; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Non-Insulin-Dependent Diabetes Mellitus; Oxygen; Oxygen Consumption; Performance; Perfusion; Physical activity; Population; Positioning Attribute; Premature Mortality; Publishing; Reporting; Research; Rodent; Running; Skeletal Muscle; Testing; Tissues; Veterans; base; cardiometabolism; cardiovascular health; cardiovascular risk factor; density; exercise capacity; exercise training; experimental study; functional disability; glucagon-like peptide; glucagon-like peptide 1; healthspan; impaired capacity; improved; improved functioning; in vivo; mortality; mouse model; oxygen transport; pre-clinical; prevent; programs; response; uptake; young adult

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.

糖尿病(DM)缩短寿命，这种影响不能用传统的心血管(CV)风险完全解释 各种因素。功能性运动能力(FEC)是心血管疾病和全因死亡率的普遍预测指标，它是 在糖尿病患者中减少。我们基础研究和临床研究相结合的总体目标 该计划旨在了解和治疗糖尿病患者的FEC受损，以防止过早死亡。新的 来自我们实验室的数据表明：氧气输送在体内唯一地限制了糖尿病患者肌肉线粒体的功能 (人体)；肌肉血流分布的模拟显示，减少的流量和 毛细血管密度相对不均匀血流分布的贡献较小(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)对FEC的影响 (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)和耗氧量。 假说：微血管灌注的异质性有助于糖尿病介导的肌肉 疲劳、肌肉VO2下降和FEC受损，这些终点将在两个月后改善 改善肌肉血流分布的不同制剂--GLP-1或亚硝酸盐。 SA#1：为了验证GLP-1和亚硝酸盐将预防或恢复高血糖的假设- 调节肌肉灌注的异质性、肌肉疲劳和降低肌肉VO2：这一目标 将使用可诱导高血糖的小鼠模型来检查高血糖对肌肉的影响 血液灌流、肌肉疲劳和肌肉VO2。第二组实验将测试GLP-1或 通过不同的机制靶向eNOS/NO的亚硝酸盐，以防止或恢复这些终点。SA#2：TO 检查GLP-1或亚硝酸盐改善DM FEC的能力，并增强 运动训练：我们将确定GLP-1或亚硝酸盐对运动成绩的影响 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 探讨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 运动训练适应：已发表的和初步的数据表明，GLP-1可以增强 对运动训练的适应和飞行员数据表明，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 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：糖尿病降低了预期寿命，在退伍军人中非常普遍。成功执行 这项研究计划将为可能显著改善功能的干预措施提供关键的临床前数据 增加运动对糖尿病患者心血管健康的影响。