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，美国成年人肥胖患病率翻了一番，糖尿病患病率增加了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会下降。该应用程序是一个项目的延续，旨在发现糖尿病高危人群未能充分受益于运动训练的机制。这些研究的第一阶段评估了力量训练对代谢综合征患者胰岛素反应性和肌肉适应的影响。第二阶段将进行类似强度和持续时间的耐力训练。力量训练的研究结果表明，刺激肌肉中的线粒体生物生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。在慢抽搐（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）途径，而对照组受试者主要激活amp激活的蛋白激酶（AMPK）途径。对照组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通路的训练反应不足。预计耐力训练将诱导与对照组相比在关键参数测量上产生更大的差异，这将揭示线粒体生物发生中固有的减少反应，并为其机制提供重要线索。这种功能障碍可能与组成骨骼肌的快速抽搐（2型）纤维比例较高以及mTOR途径与AMPK途径之间尚未确定的抑制性串扰有关。该提案的两个具体目标是：(1)在代谢综合征受试者和匹配对照中，与胰岛素反应增强相关的耐力训练驱动的腿部肌肉适应将被量化；(2)在糖尿病高风险受试者中，我们将确定在耐力或同等能量消耗的力量训练中，快肌纤维和慢肌纤维中基因表达的变化。训练相关的胰岛素反应性变化将用血糖钳测量。肌肉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估。肌肉纤维类型样本将通过激光捕获显微解剖获得，用Affymetrix基因芯片组确定基因表达的主要变化。这个项目的长期目标是找到基因决定的2型糖尿病的危险因素，这些因素可以通过行为或药物干预来改善，这样就可以预防一部分本来会患这种疾病的人患上临床糖尿病。

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.