Mechanisms by which exercise training ameliorates the metabolic syndrome

描述(申请人提供)：在过去的二十年里，美国成年人的肥胖率翻了一番，糖尿病的发病率增加了50%以上。与肥胖和糖尿病相关的发病率可能很快就会超过吸烟，如果不加以控制，美国公民的预期寿命将会下降。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实现运动训练的全部好处的机制。这些研究的第一阶段评估了力量训练对患有代谢综合征的受试者的胰岛素反应和肌肉适应的影响。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，刺激肌肉中线粒体的生物生成比增加胰岛素反应性葡萄糖转运体GLUT4的表达更重要。与对照组不同，受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。在慢抽动(1型)肌肉纤维中，代谢综合征受试者主要激活哺乳动物雷帕霉素(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。对照组受试者肌肉中线粒体标志物的增加是对照组的两倍。解释胰岛素作用缺乏改善的假设是，患有代谢综合征的人对1型肌肉纤维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上与对照组产生更大的差异，这将揭示线粒体生物发生过程中固有的反应减弱，并为机制提供重要线索。这种功能障碍可能与组成骨骼肌的较高比例的快抽动(2型)纤维以及从mTOR通路到AMPK通路的未知抑制串扰有关。这项建议的两个具体目标是：(1)与胰岛素反应增强相关的腿部肌肉耐力训练驱动的适应将在代谢综合征受试者和匹配对照组中进行量化，以及(2)在糖尿病高危受试者中，我们将确定快抽动和慢抽动肌肉纤维在同等能量消耗的耐力或力量训练中发生的基因表达变化。与训练相关的胰岛素反应性变化将通过正常血糖钳来测量。肌肉纤维特异性表达和关键细胞内通路的激活将通过免疫印迹和免疫组织化学研究训练前和训练后的肌肉活检来评估。肌肉纤维类型的样本将通过激光捕获显微切割获得，以利用Affymetrix基因芯片组识别基因表达的主要变化。这个项目的长期目标是找到2型糖尿病的基因决定的风险因素，这些因素可以通过行为或药物干预来改善，这样就可以在一部分本来会发展成这种疾病的人中预防临床糖尿病。 与公共健康相关：这项建议是寻求了解运动训练在代谢综合征患者中预防糖尿病效果较差的原因的第二阶段。人们希望这些新信息将有助于设计更好的运动干预措施，并可能导致可能使运动更有效的药物的出现。

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.