Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes

项目摘要 这项两点提案的目标是确定胰岛素抵抗是否以及以什么形式存在 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功能受限 氧合和功能与功能运动能力受损有关(心血管疾病和ALL的主要预测指标) 导致死亡)。胰岛素作用是T2D患者FEC受损的有效预测因子。确切的关系 胰岛素作用、心脏和肌肉功能障碍、心肌和骨骼肌灌注量减少 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缺口 胰岛素介导的心肌和骨骼肌灌注与T2D患者的运动能力。 假设：在T2D患者中发现胰岛素介导的肌肉灌注量减少有助于T2D的发展 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 运动训练可减轻胰岛素抵抗并恢复胰岛素介导的血流灌注的假说 对骨骼肌和心肌有益，从而提高运动成绩。具体目标1：测试 胰岛素介导的心脏灌流障碍限制运动能力的假说 通过其对T2D患者心脏功能的影响。我们将研究胰岛素与- 中介性心脏灌注，心功能的其他测量，以及安静和运动时的VO2峰值 有和没有T2D的受试者。考虑到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械性见解，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：检验胰岛素介导受损的假说 骨骼肌灌注通过影响人体的氧化能力来限制运动能力 使用T2D。我们将研究胰岛素介导的骨骼肌灌注和肌肉之间的关系 氧合作用、骨骼肌线粒体功能和体内骨骼肌氧化通量；VO2峰值 有和没有T2D的受试者。具体目标3：检验FEC的改善 运动后，T2D训练通过对心脏和肌肉功能的作用而起作用。这些 实验将测试在运动训练中观察到的VO2峰值的改善是否与 胰岛素介导的血流灌注、心肌和骨骼肌功能的改善以及T2D对 这些变化。了解微血管病变在糖尿病运动损伤中的作用 可能为改善人们的运动能力、机能状态和寿命提供新的干预目标 患有糖尿病。我们两个小组将共同采用互补的理论背景和研究 方法以协同的方法解决在T2D中提出的改善健康的创新假说。

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.