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)为预防糖尿病前期患者的2型糖尿病(T2 DM)建立了一种“黄金标准”疗法，即改变包括饮食、锻炼和减肥在内的生活方式。尽管这项研究在预防2型糖尿病方面取得了进展，但仍然存在以下重要问题：1)运动计划在多大程度上起到了作用；2)糖尿病前期患者的最佳/最低运动量和运动强度是多少；以及3)运动训练在防止糖尿病前期受试者发展为T2 DM方面可能有哪些具体的生理益处。采用对照、随机设计，我们建议比较三个为期六个月的运动训练计划对糖尿病前期患者血糖控制措施和机制的影响，并通过与包含DPP组成部分但持续时间短得多的六个月临床生活方式干预(CLI)进行比较，评估这三个仅运动干预措施的总体有效性。研究人群将包括空腹血糖受损的糖尿病前期患者(IFG-空腹血糖100-125 mg/dl)，有或没有糖耐量受损-IGT。所有受试者将被随机分为以下运动训练或生活方式干预组之一，为期六个月：1)小剂量/中强度：150分钟/周的中等强度运动，2)大剂量/中强度：300分钟/周的中等强度运动，3)大剂量/大强度：200分钟/周的大强度运动(热量等于高剂量，即上述第二组)，4)临床生活方式干预(饮食、锻炼和减肥)：150分钟/周的中等强度运动(与第一组相同)加饮食，还有6%的减肥目标。目的1.确定不同量和强度的纯运动干预措施对血糖控制措施的有效性：空腹血糖、口服葡萄糖耐量和胰岛素敏感性。目的2.确定不同运动量和强度对继发性糖尿病和心脏代谢重要危险因素的影响。目的3.探讨不同运动量和强度对血糖控制机制的影响：a)肝脏葡萄糖的产生；b)异位脂肪的分布和数量；c)骨骼肌线粒体功能障碍--通过对股外侧肌活检标本的代谢组学表现来评估；d)IVGTT和OGTT中葡萄糖和非酯化脂肪酸动力学的决定因素。与公共健康相关：这是一项在人类糖尿病发展道路上进行的运动研究，解决了三个问题。首先，与包括节食和专心减肥的临床生活方式计划相比，单独的锻炼计划如何？其次，步行项目和慢跑项目一样好还是更好？第三，运动带来的益处是如何产生的？这些问题的答案应该会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.