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: 10577448
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577448
• 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; Persons; Physical activity; Positioning Attribute; Premature Mortality; Publishing; Reporting; Research; Rodent; Running; Skeletal Muscle; Testing; Tissues; Veterans; antagonist; 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; military veteran; 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) 会缩短寿命，这种影响无法用传统的心血管 (CV) 风险来完全解释 因素。功能运动能力 (FEC) 是心血管和全因死亡率的通用预测指标， 糖尿病患者减少。我们基础研究与临床研究相结合的总体目标 该计划的目的是了解和治疗 DM 中受损的 FEC，以防止过早死亡。新的 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 （人类）;肌肉血流分布的建模揭示了血流减少和血流减少的贡献 毛细血管密度相对于异质流分布（啮齿动物）的贡献较小； 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) 会影响 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）和耗氧量。 假设：微血管灌注异质性有助于糖尿病介导的肌肉 疲劳、肌肉摄氧量下降和 FEC 受损，这些终点将通过两种方法得到改善 改善肌肉血流分布的不同药物 - GLP-1 或亚硝酸盐。 SA#1：测试 GLP-1 和亚硝酸盐将预防或恢复高血糖的假设 - 介导的肌肉灌注异质性、肌肉疲劳和肌肉摄氧量下降：这一目标 将采用诱导高血糖的小鼠模型来检查高血糖对肌肉的影响 灌注、肌肉疲劳和肌肉摄氧量。第二组实验将测试GLP-1或 亚硝酸盐通过不同的机制针对 eNOS/NO，以预防或恢复这些端点。 SA#2：至 检查 GLP-1 或亚硝酸盐改善 DM FEC 并增强以下影响的能力 运动训练：我们将确定 GLP-1 或亚硝酸盐对运动表现的影响以及 无高血糖和运动训练。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 受体对于肌肉灌注异质性和功能的重要性以及 适应运动训练：已发表的数据和初步数据表明 GLP-1 可以增强 运动训练的适应和试点数据表明 GLP-1 受体拮抗剂会干扰 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需的。这些研究对退伍军人的影响 人群：糖尿病会缩短预期寿命，并且在退伍军人中非常流行。成功执行 该研究计划将为可能急剧改善功能的干预措施提供关键的临床前数据 并增加体力活动对糖尿病患者心血管健康的影响。

项目成果

Type 2 Diabetes - Controlling the Epidemic, Episode 2: After the Diagnosis - Making a Plan and Addressing Social Determinants of Health.

2 型糖尿病 - 控制流行病，第 2 集：诊断后 - 制定计划并解决健康的社会决定因素。

• DOI: 10.1056/nejmp2308232
• 发表时间: 2023
• 期刊: The New England journal of medicine
• 作者: Abel,EDale;Ingelfinger,JulieR;Kolko,Joshua;LinhalesBarker,Suyanna;Lopez,Dinora;Mejia,Mirna;Peek,Monica;Reusch,JaneEB;Rosen,CliffordJ
• 通讯作者: Rosen,CliffordJ

Sitagliptin improves diastolic cardiac function but not cardiorespiratory fitness in adults with type 2 diabetes.

• DOI: 10.1016/j.jdiacomp.2019.05.002
• 发表时间: 2019-08
• 期刊: Journal of diabetes and its complications
• 影响因子: 3
• 作者: R. Scalzo;D. Rafferty;I. Schauer;A. Huebschmann;M. Cree‐Green;J. Reusch;J. Regensteiner

SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain.

• DOI: 10.1038/s41598-018-35890-7
• 发表时间: 2018-12-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tyagi A;Nguyen CU;Chong T;Michel CR;Fritz KS;Reisdorph N;Knaub L;Reusch JEB;Pugazhenthi S
• 通讯作者: Pugazhenthi S

Type 2 Diabetes - Controlling the Epidemic, Episode 1: Understanding and Preventing Type 2 Diabetes.

2 型糖尿病 - 控制流行病，第 1 集：了解和预防 2 型糖尿病。

• DOI: 10.1056/nejmp2308230
• 发表时间: 2023
• 期刊: The New England journal of medicine
• 作者: Abel,EDale;Giffin,Jessica;Ingelfinger,JulieR;Peek,Monica;Reusch,JaneEB;Rosen,CliffordJ;Sagendorf,Amy;ThomasSr,Edwin
• 通讯作者: ThomasSr,Edwin

Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat.

• DOI: 10.1097/fjc.0000000000000170
• 发表时间: 2015-02
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Keller AC;Knaub LA;Miller MW;Birdsey N;Klemm DJ;Reusch JE
• 通讯作者: Reusch JE