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

摘要 糖尿病前期(Pre-D)以糖化血红蛋白和血糖升高为特征，是一种临床 2型糖尿病(T2D)的先兆。Pre-D目前影响了约9000万美国人。Pre-D和T2D 与心血管疾病高度相关，并跻身全球五大死亡原因之列。锻炼 是管理的基石，在血糖低于 糖尿病阈值。然而，运动过程中的过度疲劳性(即运动引起的力量或 四肢肌肉的力量)限制了患有前D的人的运动能力。我们的实验室证明了 (1)在整个糖尿病谱系中，前D和T2D患者的四肢肌肉疲劳性比 由于肌肉内部机制的控制，以及(2)患有T2D的人的疲劳性与 运动肌肉的血流量减少。然而，尚不清楚患有Pre-D的人是否有血管受损 功能和氧气输送，导致疲劳性增加。我们的中心假设是 在运动中，血管功能会阻碍血液流动，阻碍随后向骨骼肌的氧气输送， 导致前驱-D患者四肢肌肉过度疲劳。这篇文章的一个独特和可翻译的方面 建议量化血管反应(大血管和微血管系统)对疲劳运动和 在血管树上的不同位置进行训练，包括在供血动脉(多普勒超声)， 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) 近红外光谱)和毛细血管密度(来自肌肉活组织检查)。目标1将确定血管功能障碍 是前D携带者过度疲劳性的一种机制。AIM 1.1将比较腿部血流量和骨骼 D前期、健康对照和运动性疲劳患者之间的肌肉氧合反应 T2D。将在年龄、性别、体重指数和体力活动水平上进行匹配，以确定疾病- 糖尿病相关的血管功能和疲劳性，而不是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和骨骼肌进行量化 动态疲劳性伸膝运动中的近红外光谱氧合。AIM 1.2将确定内皮细胞 Pre-D和T2D患者宏观和微观血管水平的血管功能。血流介导的扩张将 在活体中使用超声检查股动脉和从动脉中提取的小动脉 股外侧肌活组织检查。目标2是一项临床试验，将确定耐药性的有效性 运动训练结合血流限制改善老年高血压患者的疲劳性和血管功能 糖尿病。患有Pre-D和T2D的人将进行为期8周的单侧阻力训练，其中一条腿 在自由灌流条件下锻炼，另一条腿限制血流。因此，血液流动受限 并将以耐力训练为探针，进一步了解运动员疲劳的机制。 前D和T2D患者的血管树，并测试训练策略以改善这一人群的疲劳性。

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.