Mechanisms of Fatigability and the Protective Effects of Exercise in People with Diabetes

糖尿病患者的疲劳机制和运动的保护作用

• 批准号: 10705020
• 负责人: SANDRA K HUNTER
• 金额: $ 61.63万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705020
• 关键词: Acetylcholine; Adult; Affect; Age; American; Arteries; Attenuated; Biological Availability; Biopsy; Blood Vessels; Blood capillaries; Blood flow; Body mass index; Cardiovascular Diseases; Clinical; Clinical Trials; Coupled; Couples; Dependence; Diabetes Mellitus; Disease; Doppler Ultrasonography; Educational Intervention; Elderly; Endothelium; Exercise; Extensor; Fatigue; Glucose; Glycosylated Hemoglobin; Goals; Human; Impairment; Individual; Insulin; Intervention; Knee; Knowledge; Laboratories; Leg; Limb structure; Lower Extremity; Measures; Mediating; Muscle; Near-Infrared Spectroscopy; Neuropathy; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oxygen; Participant; Performance; Perfusion; Persons; Physical Exercise; Physical Function; Physical activity; Plasma; Population; Prediabetes syndrome; Prevalence; Site; Skeletal Muscle; Testing; Training; Trees; Ultrasonography; Vascular Diseases; Vascular Endothelium; Video Microscopy; arteriole; clinically significant; density; diabetes control; diabetic; diet and exercise; effectiveness evaluation; exercise program; exercise training; femoral artery; improved; in vivo; mortality; novel; prevent; protective effect; resistance exercise; response; sex; skeletal muscle metabolism; vastus lateralis; young adult

ABSTRACT Pre-diabetes (Pre-D) is characterized by elevated glycated hemoglobin and plasma glucose and is a clinical precursor to type 2 diabetes mellitus (T2D). Pre-D currently affects ~90 million Americans. Both Pre-D and T2D are highly associated with cardiovascular disease and among the top five causes of mortality worldwide. Exercise is the cornerstone of management and is most efficacious during the Pre-D stage when glycemia is below the diabetic threshold. However, excessive fatigability during exercise (i.e., exercise induced reductions in force or power of the limb muscles) limits exercise performance in people with Pre-D. Our laboratory demonstrated that (1) across the diabetic spectrum, people with Pre-D and T2D have greater fatigability of limb muscles than controls due to mechanisms within the muscle, and (2) fatigability in people with T2D was associated with a reduced blood flow to the exercising muscle. It is unknown, however, if people with Pre-D have impaired vascular function and oxygen delivery that leads to an increased fatigability. Our central hypothesis is that impaired vascular function impedes blood flow and blunts subsequent oxygen delivery to skeletal muscle during exercise, resulting in excessive fatigability of limb muscles in people with Pre-D. A unique and translational aspect of this proposal is the quantification of the vascular responses (macro- and micro-vasculature) to fatiguing exercise and exercising training at different sites along the vascular tree, including, in feed arteries (doppler ultrasonography), isolated skeletal muscle arterioles (extracted from muscle biopsy), capillary perfusion (near infrared spectroscopy, NIRS) and capillary density (from muscle biopsies). Aim 1 will determine if vascular dysfunction is a mechanism for excessive fatigability in people with Pre-D. Aim 1.1 will compare leg blood flow and skeletal muscle oxygenation in response to dynamic fatiguing exercise between people with Pre-D, healthy controls and T2D. Groups will be matched for age, sex, body mass index and physical activity levels to determine disease- related vascular function and fatigability rather than inactivity-related changes across the diabetic spectrum. Skeletal muscle blood flow through the femoral artery will be quantified with ultrasonography and skeletal muscle oxygenation with NIRS during a dynamic fatiguing knee extension exercise. Aim 1.2 will determine endothelial vascular function at macro- and micro-vascular levels in people with Pre-D and T2D. Flow-mediated dilation will be assessed in vivo in the femoral artery using ultrasonography and in isolated arterioles extracted from the vastus lateralis muscle biopsies. Aim 2 is a clinical trial that will determine the effectiveness of resistance exercise training coupled with blood flow restriction to improve fatigability and vascular function in people with diabetes. People with Pre-D and T2D will perform 8 weeks of unilateral resistance training in which one leg is exercised with freely perfused conditions and the other leg with blood flow restriction. Thus, blood flow restriction and resistance training will be used as a probe to further understand the mechanisms of fatigability along the vascular tree in people with Pre-D and T2D, and test training strategies to improve fatigability in this population.

抽象的 糖尿病前期（Pre-D）以糖化血红蛋白和血浆葡萄糖升高为特征，是一种临床常见疾病。 2 型糖尿病 (T2D) 的先兆。 Pre-D 目前影响约 9000 万美国人。 Pre-D 和 T2D 与心血管疾病高度相关，是全球前五位死因之一。锻炼 是管理的基石，在血糖低于正常值的 Pre-D 阶段最为有效。 糖尿病阈值。然而，运动过程中过度疲劳（即运动导致力量或体力下降） 肢体肌肉的力量）限制了 Pre-D 患者的运动表现。我们的实验室证明 (1) 在整个糖尿病谱系中，患有 Pre-D 和 T2D 的人比患有 Pre-D 和 T2D 的人具有更高的肢体肌肉疲劳性 由于肌肉内部机制的控制，(2) T2D 患者的疲劳性与 流向运动肌肉的血流量减少。然而，尚不清楚 Pre-D 患者的血管是否受损 功能和氧气输送，导致疲劳性增加。我们的中心假设是受损 血管功能会阻碍血液流动并减弱运动过程中随后向骨骼肌的氧气输送， 导致 Pre-D 患者肢体肌肉过度疲劳。其独特且可转化的方面 该提案是对疲劳运动的血管反应（宏观和微观血管）进行量化， 在血管树的不同部位进行训练，包括供血动脉（多普勒超声检查）， 分离的骨骼肌小动脉（从肌肉活检中提取），毛细血管灌注（近红外 光谱、NIRS）和毛细血管密度（来自肌肉活检）。目标 1 将确定是否存在血管功能障碍 是 Pre-D 患者过度疲劳的一种机制。目标 1.1 将比较腿部血流量和骨骼血流量 Pre-D 人群、健康对照组和 T2D。各组将根据年龄、性别、体重指数和体力活动水平进行匹配，以确定疾病- 相关的血管功能和疲劳性，而不是整个糖尿病谱系中与不活动相关的变化。 通过股动脉的骨骼肌血流量将通过超声检查和骨骼肌进行量化 在动态疲劳膝关节伸展运动中使用 NIRS 进行氧合。目标 1.2 将确定内皮细胞 Pre-D 和 T2D 患者的大血管和微血管水平的血管功能。血流介导的扩张将 使用超声检查对股动脉和从股动脉中提取的分离小动脉进行体内评估 股外侧肌活检。目标 2 是一项临床试验，将确定耐药性的有效性 运动训练与血流限制相结合，可改善患有以下疾病的人的疲劳性和血管功能 糖尿病。 Pre-D 和 T2D 患者将进行 8 周的单侧阻力训练，其中一条腿 在自由灌注条件下锻炼，另一条腿血流限制。因此，血流限制 阻力训练将作为进一步了解疲劳机制的探针 研究 Pre-D 和 T2D 人群的血管树，并测试改善该人群疲劳性的训练策略。