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

糖尿病运动不耐受的心血管机制和性别的作用

基本信息

批准号：
10579851
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579851
关键词：
Acute Address Aerobic Exercise Affect Algorithms Behavioral Blood Vessels Blood capillaries Blood flow Cardiac Cardiac rehabilitation Cardiovascular Diseases Cardiovascular system Cause of Death Clinical Closure by clamp Consumption Coupling Data Diabetes Mellitus Diagnosis Echocardiography Educational Intervention Erythrocytes Excess Mortality Exercise Functional disorder Glucose Clamp Goals Health Heart Heart Abnormalities Heterogeneity Image Imaging Device Impairment Individual Insulin Insulin Resistance Intervention Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Mediating Metabolism Modeling Muscle Muscle function Myocardial dysfunction Myocardium Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Oxygen Participant Pathologic Pathology Perfusion Persons Pharmacologic Substance Play Pulmonary Capillary Wedge Pressure Pulmonary Circulation Reporting Rest Rodent Model Role Sex Differences Skeletal Muscle Standardization System Testing Therapeutic Tissues Training Training Programs Vascular Diseases Veterans Woman Work base cardiometabolism cardiovascular risk factor exercise capacity exercise intolerance exercise training experimental study fitness heart function human subject imaging modality impaired capacity improved in vivo men military veteran mitochondrial dysfunction modifiable risk mortality non-diabetic novel pre-clinical response sex targeted treatment uptake young adult

项目摘要

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.

问题说明：2型糖尿病（T2D）影响24％的退伍军人，并且与心血管运动能力受损（CVEC），这很重要，因为 CVEC和过多的死亡率。该提议的目的是了解临床前的贡献心脏，血管功能障碍和骨骼肌灌注异常，导致男性CVEC受损和具有T2D的妇女，此外，还要使用运动训练来测试对干预的自适应反应揭示可修改的治疗靶标，以改善心脏代谢健康。总体假设：T2D中的CVEC受损是临床前心脏功能障碍的结果和骨骼肌灌注异常。运动训练将改善CVEC，并将揭示特定的这种病理的可逆治疗方面。具体目的：SA＃1：测试心脏功能的整合，大血管功能的假设，在T2D中，微血管功能受损，与CVEC损伤相关。理由：CVEC取决于从肺循环中协调的底物递送（例如O2）到工作组织（例如肌肉）。我们假设简历功能和净血流的整合不足和/或流动肌肉的流量分布导致CVEC减少。测量以检查简历效应迄今为止的糖尿病专注于心脏，血管和骨骼肌组织，但不同时 ne实验：常规终点（峰值O2消耗（VO2PEAK），静止超声心动图和胰岛素夹）和高级成像方式（4D流CV磁共振成像（MRI），2D PC- MRI和肌肉1H磁共振光谱（1H MRS）将用于构建系统性 CVEC病理变化的模型，在休息和运动过程中，有和没有T2D的男性和女性。成果：拟议的研究将对综合的简历全身功能采用全面的看法健康和T2D使用有和没有T2D的男性和女性使用基于MR的成像。 SA＃2：检验以下假设，即运动训练将引起特定的自适应反应综合的简历系统，肌肉灌注和代谢，其差异为T2D状态。理由：锻炼训练会影响心脏，大血管和微血管功能以及代谢通过改进集成的简历系统。新的试验数据表明，异常的肌肉氧化 T2D中体内的功能与补充O2急性归一化（与O2供应限制一致）和在肥胖的非糖尿病对照受试者中没有变化。在啮齿动物模型中已经报道了灌注异质性和T2D的人类受试者。在我们的实验室中开发的新建模算法表明灌注异质性可以解释DM模型中的O2提取受损。通过我们新颖的系统方法，我们将能够辨别系统反应的哪些方面通过培训来改进。实验：全部参与者将接受3个月的标准运动训练，以改善人们的适应性在有或没有糖尿病的情况下，然后重复测量AIM 1中描述的端点。结果：识别运动训练对综合简历系统和代谢的影响的差异有和没有T2D的男人和女人将揭示对运动的特定自适应反应。我们也会确定运动训练对骨骼肌灌注和O2提取的影响。对退伍军人的影响：T2D中的CVEC损害是CV整合不良的临床前标记在24％的退伍军人中被研究的功能，临床上很重要，并且存在于24％的退伍军人中。了解离散心脏和血管功能障碍以及骨骼肌灌注对CVEC损害的贡献以及对运动训练的反应将确定治疗目标。灌注异质性是定义的新因素 CVEC损伤可能具有行为或药物干预措施的目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired response to exercise intervention in the vasculature in metabolic syndrome.

DOI：
10.1177/1479164112459664
发表时间：
2013-05
期刊：
Diabetes & vascular disease research
影响因子：
2.4
作者：
Knaub LA;McCune S;Chicco AJ;Miller M;Moore RL;Birdsey N;Lloyd MI;Villarreal J;Keller AC;Watson PA;Reusch JE
通讯作者：
Reusch JE

Type 2 diabetes mellitus and exercise impairment.