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

• 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
• 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

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.

问题陈述：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）这一点很重要，因为两者之间存在密切关系 CVEC 和超额死亡率。该提案的目标是了解临床前研究的贡献 心脏、血管功能障碍和骨骼肌灌注异常导致男性 CVEC 受损 以及患有 T2D 的女性，并进一步通过运动训练来测试对干预措施的适应性反应 揭示改善心脏代谢健康的可修改治疗目标。 总体假设：2型糖尿病中 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 并揭示具体的 这种病理学的可逆治疗方面。 具体目标：SA#1：检验心脏功能、大血管功能、 T2D 患者的微血管功能受损，并与 CVEC 受损相关。 基本原理：CVEC 依赖于肺循环底物（例如 O2）的协调输送 作用于工作组织（例如肌肉）。我们假设 CV 功能和净血流量整合不佳 和/或流向工作肌肉的流量分布导致 CVEC 减少。检查 CV 效应的测量 迄今为止，对糖尿病的研究主要集中在心脏、血管和骨骼肌组织上，而不是同时关注。 神经兮兮地。实验：常规终点（峰值耗氧量 (VO2peak)、静息超声心动图 和胰岛素钳）和先进的成像方式（4D 血流 CV 磁共振成像 (MRI)、2D PC- MRI 和肌肉 1H 磁共振波谱 (1H MRS) 将用于构建系统性 患有或不患有 T2D 的男性和女性在休息和运动期间 CVEC 的病理变化模型。 结果：拟议的研究将采用综合 CV 系统功能的全面观点 使用基于 MR 的成像对患有和不患有 T2D 的男性和女性进行健康和 T2D 治疗。 SA#2：检验运动训练会在身体中引发特定适应性反应的假设 综合 CV 系统、肌肉灌注和代谢，因 T2D 状态而异。 理由：运动训练影响心脏、大血管和微血管的功能和新陈代谢 通过改进综合简历系统。新的试点数据表明异常的肌肉氧化 通过补充 O2（与 O2 供应限制一致），T2D 体内功能急剧正常化，并且 在肥胖的非糖尿病对照受试者中没有变化。啮齿动物模型中已报道灌注异质性 以及患有 T2D 的人类受试者。我们实验室开发的新建模算法表明灌注 异质性可以解释 DM 模型中 O2 提取受损的原因。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，旨在提高人们的健康水平 患有或不患有糖尿病，然后重复测量目标 1 中描述的终点。结果： 识别运动训练对综合心血管系统和新陈代谢影响的差异 患有或未患有 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灌注和氧气提取的影响。 对退伍军人的影响：T2D 中的 CVEC 损伤是 CV 整合不良的临床前标志 该功能尚未得到充分研究，具有临床重要性，并且存在于 24% 的退伍军人中。理解离散 心脏和血管功能障碍以及骨骼肌灌注对 CVEC 损伤的影响以及 对运动训练的反应将确定治疗目标。灌注异质性是一个新的定义因素 可以通过行为或药物干预来针对 CVEC 损伤。

项目成果

Type 2 diabetes mellitus and exercise impairment.

• DOI: 10.1007/s11154-012-9234-4
• 发表时间: 2013-03
• 期刊: Reviews in endocrine & metabolic disorders
• 影响因子: 8.2
• 作者: Reusch JE;Bridenstine M;Regensteiner JG
• 通讯作者: Regensteiner JG

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