Exercise Dose-Response Effects in Prediabetes: Responses and Mechanisms

描述（由申请人提供）：具有里程碑意义的糖尿病预防计划（DPP）已经建立了预防糖尿病前期2型糖尿病（T2 DM）的“金标准”疗法，即，生活方式的改变，包括饮食，锻炼和减肥。尽管本研究在预防T2 DM方面取得了进展，但仍存在以下重要问题：1）运动计划在多大程度上发挥了作用; 2）糖尿病前期患者的最佳/最低运动量和运动强度是什么; 3）运动训练在预防糖尿病前期受试者进展为T2 DM方面可能具有哪些特定的生理学益处。采用对照、随机设计，我们建议比较三种为期六个月的运动训练方案（包括不同运动量和强度）对糖尿病前期患者血糖控制措施和机制的影响，并通过将这三种仅运动干预与六个月的临床生活方式干预（CLI）进行比较，评估其总体有效性包含DPP的组成部分，但持续时间要短得多。研究人群将包括空腹血糖受损（IFG-空腹血糖100-125 mg/dl）、伴或不伴糖耐量受损-IGT的糖尿病前期患者。所有受试者将被随机分配到以下运动训练或生活方式干预组中的一个，持续六个月：1）低剂量/中等强度：150分钟/周的中等强度运动，2）高剂量/中等强度：300分钟/周的中等强度运动，3）高剂量/剧烈强度：200分钟/周的剧烈强度运动（热量等于高剂量，即，4）临床生活方式干预（饮食、运动和减肥）：150分钟/周的中等强度运动（与第1组相同）加饮食，以及6%的减肥目标。目标1.确定不同运动量和强度的单纯运动干预对血糖控制指标的有效性：空腹血糖、口服葡萄糖耐量和胰岛素敏感性。目标2.确定不同量和强度的运动对重要的继发性糖尿病和心脏代谢危险因素的影响。目标3。确定不同量和强度的运动对血糖控制机制的影响：a）肝脏葡萄糖生成; B）异位脂肪分布和量; c）骨骼肌线粒体功能障碍-通过对股外侧肌肌肉活检样本进行代谢组学性能评价; d）IVGTT和OGTT期间葡萄糖和非酯化脂肪酸动力学的决定因素。公共卫生相关性：这是一项在人类受试者中进行的运动研究，旨在解决三个问题。首先，与包括饮食和专门减肥的临床生活方式计划相比，单独的锻炼计划如何比较？第二，步行计划，以及大量的步行计划，与慢跑计划一样好还是更好？第三，运动带来的好处是如何累积的？这些问题的答案应该对糖尿病的预防和治疗产生影响。

DESCRIPTION (provided by applicant): The landmark Diabetes Prevention Program (DPP) has established a "gold standard" therapy for prevention of type 2 diabetes (T2DM) in prediabetics, i.e., lifestyle changes that include diet, exercise and weight loss. Despite the advances to the prevention of T2DM that this study provides, there remain important questions about 1) how much of the effect was due to the exercise program; 2) what is the optimal/minimal exercise amount and exercise intensity for prediabetics; and 3) what might be the specific physiologic benefits underlying exercise training in preventing the progression to T2DM in prediabetic subjects. Using a controlled, randomized design, we propose to compare the effects of three six-month exercise-training programs involving different amounts and intensities of exercise on measures and mechanisms of glucose control in prediabetics, and to evaluate the overall effectiveness of these three exercise-only interventions by comparing them to a six-month clinical lifestyle intervention (CLI) that contains the components of the DPP but which is of much shorter duration. The study population will consist of prediabetics with impaired fasting glucose (IFG-fasting plasma glucose 100-125 mg/dl), with or without impaired glucose tolerance-IGT. All subjects will be randomized to one of the following exercise training or lifestyle intervention groups for six months: 1) Low-Dose/Moderate-Intensity: 150 min/wk of moderate intensity exercise, 2) High-Dose/Moderate-Intensity: 300 min/wk of moderate intensity exercise, 3) High-Dose/Vigorous-Intensity: 200 min/wk of vigorous intensity exercise (amount calorically equal to High-Dose, i.e., Group 2 above), 4) Clinical Lifestyle Intervention (diet, exercise & weight loss): 150 min/wk of moderate intensity exercise (same as Group 1) plus diet, and a 6% weight loss goal. Aim 1. To determine the effectiveness of exercise only interventions differing in amount and intensity on measures of glucose control: fasting plasma glucose, oral glucose tolerance, and insulin sensitivity. Aim 2. To determine the effects of different amounts and intensities of exercise on important secondary diabetic and cardiometabolic risk factors. Aim 3. To determine the effects of different amounts and intensities of exercise on mechanisms of glucose control: a) hepatic glucose production; b) ectopic fat distribution and amount, c) mitochondrial dysfunction in skeletal muscle - evaluated via the performance of metabolomics on muscle biopsy samples from the vastus lateralis d) determinants of glucose and nonesterified fatty acid kinetics during an IVGTT and OGTT. PUBLIC HEALTH RELEVANCE: This is an exercise study in human subjects on the path to developing diabetes that addresses three questions. First, compared to a clinical lifestyle program that includes diet and dedicated weight loss, how does an exercise program alone compare? Second, is a walking program, and lots of it, as good or better than a jogging program? Third, how do the exercise-induced benefits accrue? The answers to these questions should have an impact on the prevention and treatment of diabetes.