Exercise Dose-Response Effects in Prediabetes:Responses and Mechanisms

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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.