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; 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（前D）的特征是糖化的血红蛋白和血浆葡萄糖升高，是临床 2型糖尿病的前体（T2D）。目前，前D会影响约9000万美国人。前D和T2D 与心血管疾病高度相关，是全球死亡率的前五名。锻炼 是管理的基石，在D前阶段是血糖以下时最有效的 糖尿病阈值。但是，运动过程中过度疲劳性（即运动诱导的有效减少或 肢体肌肉的力量）限制了前D患者的运动表现。我们的实验室证明了 （1）在整个糖尿病光谱中，前D和T2D的人的肢体肌肉的疲劳性比 由于肌肉内的机制而引起的控制，以及（2）T2D患者的疲劳性与 减少了运动肌肉的血液流动。但是，如果患有前的人有损害血管，这是未知的 功能和氧递送导致疲劳性增加。我们的中心假设是受损 血管功能阻碍了运动过程中随后将氧气递送至骨骼肌的血液流动， 导致肢体肌肉过度疲劳性肌肉的疲劳性。这是一个独特而翻译的方面 提案是对疲劳运动的血管反应（宏观和微脉管系统）的定量 在沿着血管树的不同地点进行训练，包括在饲料动脉（多普勒超声检查）中， 孤立的骨骼肌动脉（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）。 AIM 1将确定是否血管功能障碍 是预先使用前患者过度疲劳性的机制。 AIM 1.1将比较腿部血流和骨骼 肌肉氧合响应于患有D，健康对照和健康对照的人之间的动态疲劳运动和 T2D。小组将与年龄，性别，体重指数和体育活动水平相匹配，以确定疾病 - 相关的血管功能和疲劳性，而不是与糖尿病光谱的无效变化。 骨骼肌血液流过股动脉，将用超声和骨骼肌肉进行定量 在动态疲劳的膝盖伸展运动中，用NIR氧合氧合。 AIM 1.2将确定内皮 前D和T2D患者的宏观和微血管水平的血管功能。流介导的扩张会 使用超声检查和从股动脉中进行体内评估 巨大的外侧肌肉活检。 AIM 2是一项临床试验，它将确定电阻的有效性 运动训练以及血流限制，以改善患有患者的疲劳性和血管功能 糖尿病。患有D前和T2D的人将进行8周的单方面抵抗训练，其中一条腿是 以自由灌注的疾病和另一只腿进行血流限制进行运动。因此，血流限制 阻力训练将被用作进一步了解沿着疲劳性机制的探针 患有前D和T2D的人的血管树以及改善该人群疲劳性的测试培训策略。