Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes

项目概要 这个两个地点提案的目标是确定是否以及通过什么方式抵抗胰岛素，其形式为 胰岛素对微血管灌注的调节受损，导致功能运动能力（FEC）下降 2 型糖尿病 (T2D)。我们两个研究小组的数据表明，心肌和骨骼肌 T2D 患者存在的微血管功能障碍导致心肌和骨骼肌受限 与功能运动能力受损相关的氧合和功能（CV 和全功能的主要预测因子） 导致死亡）。胰岛素作用是 T2D 中 FEC 损伤的有效预测因子。确切的关系 胰岛素作用、心脏和肌肉功能障碍、心脏和骨骼肌灌注和减少之间的关系 T2D 中的 FEC 仍不清楚。在这里，我们建议通过定义受损者的角色来解决这一知识差距 T2D 患者胰岛素介导的心脏和骨骼肌灌注和运动表现。 假设：T2D 中胰岛素介导的肌肉灌注减少有助于发展 心脏和骨骼肌功能障碍以及随后的运动能力受损。我们进一步 假设运动训练减弱胰岛素抵抗并恢复胰岛素介导的灌注 骨骼和心肌，从而提高运动表现。具体目标 1：测试 胰岛素介导的心脏灌注受损限制运动表现的假设 通过其对 T2D 患者心脏功能的影响。我们将研究胰岛素之间的关系 介导的心脏灌注、心脏功能的其他测量以及静息和运动时的 VO2 峰值 患有和不患有 T2D 的受试者。鉴于糖尿病结局和运动障碍存在性别差异 由于缺乏对性别差异的机制洞察，我们将分析性别差异的所有参数 三个目标的探索性基础。具体目标 2：检验胰岛素介导功能受损的假设 骨骼肌灌注通过影响人体氧化能力来限制运动表现 与 T2D。我们将研究胰岛素介导的骨骼肌灌注之间的关系；肌肉 氧合、骨骼肌线粒体功能和体内骨骼肌氧化通量；和 VO2 峰值 患有和不患有 T2D 的受试者。具体目标 3：检验 FEC 改进的假设 运动训练之后通过对 T2D 心脏和肌肉功能的作用来进行。这些 实验将测试通过运动训练观察到的 VO2peak 的改善是否与 胰岛素介导的灌注、心脏和骨骼肌功能的改善以及 T2D 对 这些变化。了解微血管疾病在糖尿病介导的运动障碍中的作用 可能提供新的干预目标，以提高人们的运动能力、功能状态和寿命 患有糖尿病。我们两个小组将共同利用互补的理论背景和研究 方法采用协同方法来解决为改善 T2D 健康而提出的创新假设。

Project Summary The goal of this two-site proposal is to determine whether and by what means insulin resistance, in the form of impaired insulin regulation of microvascular perfusion, leads to decreased functional exercise capacity (FEC) in type 2 diabetes (T2D). Data from our two research teams suggest that the cardiac and skeletal muscle microvascular dysfunction present in people with T2D contributes to limitations in cardiac and skeletal muscle oxygenation and function associated with impaired function exercise capacity (a major predictor of CV and all- cause mortality). Insulin action is a potent predictor of the FEC impairment in T2D. The exact relationship between insulin action, cardiac and muscle dysfunction, cardiac and skeletal muscle perfusion and decreased FEC in T2D remains unclear. Here we propose to address this gap in knowledge by defining the roles of impaired insulin-mediated cardiac and skeletal muscle perfusion and exercise performance in people with T2D. Hypothesis: Decreased insulin-mediated muscle perfusion found in T2D contributes to the development of cardiac and skeletal muscle dysfunction and subsequent impairment in exercise capacity. We further hypothesize that exercise training attenuates insulin resistance and restores insulin-mediated perfusion to the skeletal and cardiac muscle, leading to improved exercise performance. Specific Aim 1: To test the hypothesis that impairment in insulin-mediated cardiac perfusion limits exercise performance through its effect on cardiac function in people with T2D. We will examine the relationship between insulin- mediated cardiac perfusion, other measures of cardiac function, and VO2 peak at rest and with exercise in subjects with and without T2D. Given that there is a sex disparity in diabetes outcomes and exercise impairment with a lack of mechanistic insights on sex differences, we will analyze all parameters for differences by sex on an exploratory basis in the three aims. Specific Aim 2: To test the hypothesis that impaired insulin-mediated skeletal muscle perfusion limits exercise performance through its effect on oxidative capacity in people with T2D. We will examine the relationship between insulin-mediated skeletal muscle perfusion; muscle oxygenation, skeletal muscle mitochondrial function and in vivo skeletal muscle oxidative flux; and VO2 peak in subjects with and without T2D. Specific Aim 3: To test the hypothesis that the improvement in FEC subsequent to exercise training operates via action on cardiac and muscle function in T2D. These experiments will test whether the improvements in VO2peak observed with exercise training correlate with improvements in insulin-mediated perfusion, cardiac and skeletal muscle function and the impact of T2D on these changes. Understanding the role of microvascular disease in the diabetes-mediated exercise impairment may offer novel targets for intervention to improve exercise capacity, functional status and longevity in people with diabetes. Together, our two groups will employ complementary theoretical backgrounds and research methods in a synergistic approach to address the innovative hypothesis posed to improve health in T2D.