Insulin sensitivity and fatty acid partitioning in skeletal muscle after exercise

 描述（由申请人提供）：运动是预防和治疗许多肥胖相关代谢并发症的关键组成部分，包括胰岛素抵抗和2型糖尿病。高强度间歇训练（HIIT），它交替短暂的高强度努力与短暂的恢复期，已被发现显着改善代谢健康的临床标志物（膳食耐量，24小时葡萄糖）。因此，HIIT可以被认为是“常规”锻炼的有效且省时的替代方案。重要的是，HIIT在肥胖和2型糖尿病患者中也被发现是安全和耐受性良好的。HIIT的运动刺激明显不同于常规运动，并能产生独特的适应。然而，HIIT诱导的代谢健康改善的机制仍然知之甚少。此外，HIIT的主要组成部分（间隔次数、运动时间、能量消耗）的变化可能导致非常不同的代谢结果，但尚未对这些参数的偏差进行系统评估。此外，虽然现有证据清楚地表明HIIT可以在几周到几周的训练后产生令人印象深刻的健康益处，但肥胖成年人坚持长期HIIT计划的能力/意愿尚不清楚。我们的总体目标是：1）在全身、组织和细胞水平上全面评估HIIT诱导的胰岛素抵抗改善的潜在机制，2）系统地评估对于改善肥胖成年人的代谢健康可能是最佳的HIIT的不同“剂量”的影响，和3）评估肥胖受试者坚持长期HIIT计划的能力/意愿。在具体目标#1中，我们将检查3个月HIIT（10 x 1分钟，约90%最大心率[HRmax]; 4天/周）对关键临床健康结局变化的影响（例如，胰岛素抵抗、24小时血糖控制、肝脏脂质蓄积、血脂谱）。我们还将比较HIIT与“常规”运动训练，包括在60-70%HRmax下进行45分钟的稳态运动（这代表了健康和健身的常见运动处方）。具体目标#2将确定胰岛素抵抗改善的潜在因素（例如，减少骨骼肌中的脂质积累，降低脂肪组织和骨骼肌中的巨噬细胞浸润和炎症标志物，和/或增强胰岛素信号传导）。具体目标#3将通过系统评价HIIT期间间隔次数、运动时间和能量消耗对胰岛素抵抗的影响来解决关于HIIT优化的重要临床/应用问题-我们还将评估糖耐量受损肥胖成人坚持HIIT计划长达1年的能力/意愿。这些研究的结果将大大扩展我们对HIIT对代谢健康影响的理解，并将为旨在最大限度地提高运动的关键代谢益处的计划设计提供非常有价值的信息。

 DESCRIPTION (provided by applicant): Exercise is a key component in the prevention and treatment of many obesity-related metabolic complications, including insulin resistance and type 2 diabetes. High intensity interval training (HIIT), which alternates brief high-intensity efforts ith brief recovery periods, has been found to markedly improve clinical markers of metabolic health (meal tolerance, 24h glucose). Therefore, HIIT may be considered an effective and time- efficient alternative to "conventional" exercise. Importantly, HIIT has also been found to be safe and well tolerated in obese and type 2 diabetic patients. The exercise stimulus of HIIT is obviously very different from conventional exercise, and can yield unique adaptions. However, mechanisms underlying HIIT-induced improvements in metabolic health remain poorly understood. In addition, variations in the main components of HIIT (# of intervals, exercise time, energy expended) may induce very different metabolic outcomes, yet a systematic assessment of deviations in these parameters has not been conducted. Furthermore, while available evidence clearly demonstrates HIIT can induce impressive health benefits after a few to several weeks of training, the ability/willingness of obese adults to adhere to a long-term HIIT program is not known. Our overall objectives are to: 1) comprehensively assess putative mechanisms underlying HIIT-induced improvements in insulin resistance at the whole-body, tissue, and cellular levels, 2) systematically evaluate the impact of different "doses" of HIIT that may be optimal for improving metabolic health in obese adults, and 3) assess the ability/willingness of obese subjects to adhere to long-term HIIT programs. In Specific Aim #1, we will examine the effects of 3 months of HIIT (10 x 1min at ~90%maximal heart rate [HRmax]; 4d/wk) on changes in key clinical health outcomes (e.g., insulin resistance, 24h glucose control, hepatic lipid accumulation, blood lipid profile) in obese adults with impaired glucose tolerance. We will also compare HIIT with "conventional" exercise-training involving steady-state exercise for 45 min at 60-70%HRmax (which represents a common exercise prescription for health and fitness). Specific Aim #2 will determine factors underlying the improvements in insulin resistance (e.g., reduced lipid accumulation in skeletal muscle, lower macrophage infiltration and markers of inflammation in adipose tissue and skeletal muscle, and/or enhanced insulin signaling). Specific Aim #3 will address important clinical/applied issues regarding the optimization of HIIT by systematically evaluating the effects of the number of intervals, exercise time, and energy expended during HIIT on insulin resistance - and we will also assess the ability/willingness of obese adults with impaired glucose tolerance to adhere to HIIT programs for up to 1 year. Findings from these studies will greatly expand our understanding about the effects of HIIT on metabolic health, and will provide tremendously valuable information for the design of programs aimed at maximizing key metabolic benefits of exercise.