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）缩短了寿命，这种影响未完全由传统心血管（CV）风险解释 因素。功能运动能力（FEC）是简历和全因死亡率的普遍预测指标，这是 糖尿病患者减少。我们组合基础和临床研究的总体目标 计划是理解和治疗DM中FEC受损的情况，以防止过早死亡。新的 来自我们实验室的数据表明：氧递送在DM中的体内肌肉线粒体功能中唯一地限制 （人类）;肌肉血流分布的建模表明，流量减少和 毛细血管密度相对于异质流量分布（啮齿动物）的贡献而言是较小的。 一氧化氮合酶/一氧化氮（NOS/NO）或胰高血糖素（如肽1（GLP-1））的靶向FEC （跑步距离）并证明肌肉灌注（血流，毛细血管密度和 血流分布）和消耗氧。 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VO2减少和FEC受损，这些终点将有两个 改善肌肉血流分布的不同药物-GLP -1或亚硝酸盐。 SA＃1：测试将GLP-1和亚硝酸盐的假设可以预防或恢复高血糖 - 介导的肌肉灌注异质性，肌肉疲劳和肌肉降低VO2：这个目标 将采用具有诱导高血糖的小鼠模型检查高血糖对肌肉的影响 灌注，肌肉疲劳和肌肉VO2。第二组实验将测试GLP-1或 亚硝酸盐（通过不同的机制靶向eNOS/NO）预防或恢复这些终点。 SA＃2：到 检查GLP-1或亚硝酸盐改善DM FEC的能力并增强的影响 锻炼训练：我们将确定GLP-1或亚硝酸盐对使用和 没有高血糖和运动训练。这些实验将通过 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受体对肌肉灌注异质性和功能的重要性以及 适应运动培训：已发布和初步数据表明GLP-1可以增加 适应运动训练和试验数据表明，GLP-1受体拮抗剂会干扰 自适应运动训练反应。这些研究将阐明内皮细胞GLP-1受体是否是 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：糖尿病会降低预期寿命，并且在退伍军人中非常普遍。成功执行 该研究计划将为干预措施提供关键的临床前数据，这些数据可能会急性提高功能 并增加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