Mechanisms by which exercise training ameliorates the metabolic syndrome

描述（由申请人提供）：在过去的二十年中，美国成人肥胖症的患病率翻了一番，糖尿病增加了50%以上。与肥胖和糖尿病相关的发病率可能很快就会超过与吸烟相关的发病率，如果不加以控制，美国公民的预期寿命将下降。这项申请是一个项目的继续，该项目旨在发现糖尿病高危人群无法充分享受运动训练的机制。这些研究的第一阶段评估了力量训练对代谢综合征受试者胰岛素反应性和肌肉适应性的影响。第二阶段将采用类似强度和持续时间的耐力训练。力量训练研究结果表明，刺激肌肉中线粒体生物合成比增加胰岛素反应性葡萄糖转运蛋白GLUT4的表达更重要。与对照组不同，经过训练的代谢综合征受试者并没有改善他们的胰岛素反应。在慢收缩（1型）肌纤维中，代谢综合征受试者主要激活哺乳动物雷帕霉素靶蛋白（mTOR）通路，而对照受试者主要激活AMP活化蛋白激酶（AMPK）通路。对照组受试者肌肉中的线粒体标记物增加了两倍。解释胰岛素作用缺乏改善的假设是代谢综合征患者对1型肌纤维AMPK途径的训练反应不足。预计耐力训练将在测量的关键参数中引起与对照组更大的差异，这将揭示线粒体生物发生中固有的减弱的反应，并为该机制提供重要线索。这种功能障碍可能与构成其骨骼肌的快速收缩（2型）纤维的比例较高以及尚未鉴定的mTOR通路与AMPK通路的抑制性串扰有关。这项建议的两个具体目标是：（1）将在患有代谢综合征的受试者和匹配的对照中量化与增强的胰岛素反应相关的腿部肌肉中的耐力训练驱动的适应，和（2）在糖尿病高风险的受试者中，我们将确定发生在快收缩和慢收缩中的基因表达的变化，肌肉纤维对同等能量消耗的耐力或力量训练的反应。胰岛素反应性的训练相关变化将用正葡萄糖钳夹测量。肌纤维特异性表达和关键细胞内通路的激活将通过训练前和训练后肌肉活检的免疫印迹和免疫组织化学研究进行评价。将通过激光捕获显微切割获得肌纤维类型样本，以使用Affyssin基因芯片组鉴定基因表达的主要变化。该项目的长期目标是找到2型糖尿病的遗传决定的风险因素，这些风险因素可以通过行为或药物干预来改善，从而可以在一部分可能发展这种疾病的人中预防临床糖尿病。 公共卫生相关性：该提案是寻求了解运动训练在预防代谢综合征患者糖尿病方面效果较差的原因的第二阶段。希望这些新信息将有助于设计更好的运动干预措施，并可能导致药物，使运动更有效。

DESCRIPTION (provided by applicant): In the past two decades there has been a doubling of the prevalence of obesity in adults and more than a 50% increase in diabetes in the United States. The morbidity associated with obesity and diabetes may soon exceed that associated with cigarette smoking, and if not checked, United States citizens' life expectancy will decline. This application is the continuation of a project aimed at discovering the mechanisms by which persons at high risk for diabetes fail to achieve the full benefit of exercise training. The first phase of these studies evaluated the impact of strength training on insulin responsiveness and muscle adaptation in subjects with the metabolic syndrome. The second phase will apply endurance training of similar intensity and duration. The strength training study results suggest that stimulation of mitochondrial biogenesis in muscle was more important than increased expression of the insulin-responsive glucose transporter, GLUT4. Unlike controls, trained metabolic syndrome subjects did not improve their insulin response. In slow-twitch (type 1) muscle fibers, metabolic syndrome subjects predominantly activated the mammalian target of rapamycin (mTOR) pathway, in contrast to control subjects who predominantly activated the AMP-activated protein kinase (AMPK) pathway. Mitochondrial markers increased twice as much in the control subjects' muscle. The hypothesis to explain the lack of improvement in insulin action is that persons with the metabolic syndrome have a deficient response to training in the type 1 muscle fiber AMPK pathway. It is anticipated that endurance training will induce a larger difference from controls in the key parameters measured, which will reveal the inherently diminished response in mitochondrial biogenesis and give important clues to the mechanism. This dysfunction may be related to a higher proportion of fast-twitch (type 2) fibers that make up their skeletal muscle and as yet unidentified inhibitory cross-talk from the mTOR pathway to the AMPK pathway. The two specific aims of this proposal are: (1) The endurance training-driven adaptations in leg muscle that are associated with enhanced insulin response will be quantified in subjects with the Metabolic Syndrome and matched controls, and (2) In subjects at high risk for diabetes, we will determine changes in gene expression that occur in fast-twitch and slow-twitch muscle fibers in response to endurance or strength training of equivalent energy expenditure. Training-related changes in insulin responsiveness will be measured with euglycemic clamps. Muscle fiber-specific expression and activation of key intracellular pathways will be evaluated by immunoblotting and immunohistochemical studies of pre- and post-training muscle biopsies. Muscle fiber type samples will be obtained by laser capture microdissection to identify major changes in gene expression with Affymetrix gene chip sets. The long term goal of this project is to find genetically-determined risk factors for type 2 diabetes that can be ameliorated by interventions, either behavioral or pharmacological, such that clinical diabetes can be prevented in a portion of those who would otherwise develop this disease. PUBLIC HEALTH RELEVANCE: This proposal is the second phase in a quest to understand the reasons why exercise training is less effective in preventing diabetes among persons with metabolic syndrome. The hope is that this new information will help design better exercise interventions and may lead to medications that may make exercise more effective.