Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex

问题陈述：2型糖尿病(T2D)影响24%的退伍军人，与 心血管运动能力受损(CVEC)这一点很重要，因为 CVEC和超额死亡率。这项建议的目标是了解临床前研究的贡献 男性CVEC受损的心脏、血管功能障碍和骨骼肌灌注异常 以及患有T2D的女性，并进一步测试使用运动训练进行干预的适应性反应 揭示改善心脏代谢健康治疗的可修改靶点。 总体假设：T2D患者的CVEC受损是临床前心脏、血管功能障碍的结果 和骨骼肌灌注异常。运动训练将提高CVEC，并将揭示具体情况 这种病理的可逆治疗方面。 具体目标：SA#1：检验心脏功能、大血管功能、 T2D患者微血管功能受损，并与CVEC损伤相关。 原理：CVEC依赖于从肺循环协调输送底物(例如O2)- 作用于工作组织(如肌肉)。我们假设心血管功能和净血流量的结合不佳。 和/或流向工作肌肉的流量分配导致CVEC减小。检查CV效果的测量方法 到目前为止，糖尿病的研究主要集中在心脏、血管和骨骼肌组织，而不是同时发生。 确实如此。实验：常规终点(峰值耗氧量(VO2峰值)、静息超声心动图 和胰岛素夹)和高级成像方式(4D Flow CV磁共振成像(MRI)、2D PC- 将使用MRI和肌肉1H磁共振波谱(1H MRS)来构建系统的 静息和运动中有T2D和无T2D的男女CVEC病变模型。 结果：拟议的研究将采用综合心血管系统功能的全面观点 在有和没有T2D的男性和女性中使用基于MR的成像进行健康和T2D。 SA#2：检验运动训练将在大脑中引起特定适应性反应的假设 综合心血管系统、肌肉血流灌注和代谢，根据T2D状态的不同而不同。 理论基础：运动训练影响心脏、大血管和微血管的功能和代谢 通过完善整合的简历系统。新的试点数据表明，异常的肌肉氧化 补充氧气后，T2D的体内功能显著正常化(与氧气供应限制一致)和 在肥胖的非糖尿病对照组中没有变化。据报道，在啮齿动物模型中存在血流灌注的异质性。 以及接受T2D检查的人体受试者。我们实验室开发的新建模算法表明，血流灌注 异质性可以解释DM模型中氧摄取受损的原因。通过我们新颖的系统方法，我们将 能够辨别运动的系统反应的哪些方面随着训练而改善。实验：全部 参与者将接受为期3个月的标准化运动训练，以提高人们的健康水平 有和没有糖尿病，然后重复测量目标1中描述的终点。结果： 运动训练对老年人综合心血管系统和代谢影响的差异 患有和不患有T2D的男性和女性都会表现出对运动的特定适应性反应。我们还将 确定运动训练对骨骼肌血流和氧摄取的影响。 对退伍军人的影响：T2D的CVEC损害是CV整合不良的临床前标志 这一功能在24%的退伍军人中尚未得到充分研究，在临床上具有重要意义。了解离散型 心脏和血管功能障碍及骨骼肌灌注在血管内皮细胞损伤中的作用 对运动训练的反应将确定治疗的目标。血流灌注异质性是一个新的定义因素 行为干预或药物干预可能针对的血管内皮细胞损伤。

Statement of Problem: Type 2 Diabetes (T2D) affects 24% of Veterans and it is associated with impaired cardiovascular exercise capacity (CVEC) which is important because of a strong relationship between CVEC and excess mortality. The goal of this proposal is to understand the contribution of preclinical cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities to impaired CVEC in men and women with T2D and, further, to test the adaptive response to intervention using exercise training to reveal modifiable targets for therapy to improve cardiometabolic health. Overall Hypothesis: Impaired CVEC in T2D is the result of preclinical cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities. Exercise training will improve CVEC and will reveal specific reversible therapeutic aspects of this pathology. Specific Aims: SA#1: To test the hypothesis that the integration of cardiac function, macrovascular function, and microvascular function is impaired in T2D and correlates with CVEC impairment. Rationale: CVEC is dependent upon a coordinated delivery of substrate (E.g. O2) from the pulmonary circula- tion to the working tissue (e.g. muscle). We postulate that poor integration of CV function and net blood flow and/or flow distribution to working muscle results in diminished CVEC. Measurements to examine CV effects of diabetes to date have focused on cardiac, vascular and skeletal muscle tissues separately but not simulta- neously. Experiments: Conventional endpoints (peak O2 consumption (VO2peak), resting echocardiography and insulin clamp) and advanced imaging modalities (4D flow CV magnetic resonance imaging (MRI), 2D PC- MRI and muscle 1H magnetic resonance spectroscopy (1H MRS) will be employed to construct a systemic model of pathological changes in CVEC in men and women with and without T2D at rest and during exercise. Outcomes: The proposed studies will employ a comprehensive view of integrated CV systemic function in health and T2D using MR-based imaging in men and women with and without T2D. SA#2: To test the hypothesis that exercise training will elicit specific adaptive responses in the integrated CV system, muscle perfusion and metabolism with differences by T2D status. Rationale: Exercise training impacts cardiac, macrovascular and microvascular function and metabolism through improving the integrated CV system. New pilot data demonstrate that abnormal muscle oxidative function in vivo in T2D is acutely normalized with supplemental O2 (consistent with an O2 supply limitation) and unchanged in obese nondiabetic control subjects. Perfusion heterogeneity has been reported in rodent models and human subjects with T2D. New modeling algorithms, developed in our lab, indicate that perfusion heterogeneity can explain impaired O2 extraction in DM models. With our novel systematic approach, we will be able to discern which aspects of the systemic response to exercise improve with training. Experiments: All participants will undergo 3 months of standardized exercise training established to improve fitness in people with and without diabetes, followed by repeated measurement of endpoints described in Aim 1. Outcomes: Identification of differences in the effects of exercise training on the integrated CV system and metabolism in men and women with and without T2D will reveal specific adaptive responses to exercise. We will also determine the impact of exercise training on skeletal muscle perfusion and O2 extraction. Impact on Veterans: CVEC impairment in T2D is a preclinical marker of poor integration of CV function that is understudied, clinically important and present in 24% of Veterans. Understanding the discrete contributions of cardiac and vascular dysfunction and skeletal muscle perfusion to CVEC impairments and the response to exercise training will identify targets for therapy. Perfusion heterogeneity is a novel factor defining CVEC impairments that is potentially targetable with behavioral or pharmaceutical intervention.