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

摘要 糖尿病前期（Pre-D）的特征在于糖化血红蛋白和血浆葡萄糖升高，并且是一种临床表现。 2型糖尿病（T2 D）的先兆。Pre-D目前影响约9000万美国人。Pre-D和T2 D 与心血管疾病高度相关，是全球五大死亡原因之一。行使 是管理的基石，在Pre-D阶段最有效，此时， 糖尿病阈值然而，运动期间的过度疲劳（即，运动引起的武力减少或 四肢肌肉的力量）限制了Pre-D患者的运动表现。我们的实验室证明， (1)在整个糖尿病谱中，Pre-D和T2 D患者的肢体肌肉疲劳性高于 由于肌肉内的机制，以及（2）T2 D患者的疲劳与 减少了流向运动肌肉的血液。然而，尚不清楚Pre-D患者是否有血管受损， 功能和氧气输送，导致疲劳性增加。我们的核心假设是 血管功能阻碍了血流并使随后在运动过程中向骨骼肌的氧气输送变钝， 导致Pre-D患者肢体肌肉过度疲劳。一个独特的和翻译的方面， 建议是量化血管反应（宏观和微观血管）疲劳运动和 在沿着血管树的沿着不同部位进行锻炼，包括，在供血动脉中（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 光谱学，NIRS）和毛细血管密度（来自肌肉活检）。目标1将确定血管功能障碍 是导致Pre-D患者过度疲劳的机制目的1.1将比较腿部血流量和骨骼血流量。 肌肉氧合反应的人与前D，健康对照和动态疲劳运动之间的 2型糖尿病各组将根据年龄、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，而不是整个糖尿病谱的不活动相关的变化。 通过股动脉的骨骼肌血流量将用超声和骨骼肌定量 在动态疲劳性膝关节伸展运动期间，使用NIRS进行氧合。目标1.2将确定内皮 Pre-D和T2 D患者在大血管和微血管水平的血管功能。血流介导的扩张将 在体内使用超声检查在股动脉中和在从动脉中提取的分离的小动脉中进行评估。 股外侧肌活检。目标2是一项临床试验，将确定抵抗的有效性 运动训练结合血流限制，以改善疲劳和血管功能， 糖尿病患有Pre-D和T2 D的人将进行8周的单侧阻力训练，其中一条腿 自由灌注条件下锻炼，另一条腿血流受限。因此，血流限制 和抗阻训练将被用作进一步了解疲劳机制的探针， 血管树的人与Pre-D和T2 D，并测试训练策略，以改善这一人群的疲劳。

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.