Mechanisms by which strength training ameliorates the Metabolic Syndrome

描述(由申请人提供)：生活方式的改变可以有力地阻止2型糖尿病的发展，也是治疗这种疾病的基石。有氧运动和阻力运动都能改善糖尿病、血糖控制和胰岛素抵抗。这两种运动似乎对不同类型的肌肉纤维产生了影响--红色代表耐力，白色代表力量。与耐力运动训练的效果相似，力量训练会增加肌肉葡萄糖转运蛋白4(GLUT4)，但相比之下，线粒体数量并不增加。我们假设(1)糖尿病前期患者的力量训练可能通过不同于耐力训练诱导的线粒体生物发生的新机制有效地逆转胰岛素抵抗。我们进一步假设(2)阻力运动训练主要通过蛋白激酶哺乳动物雷帕霉素靶标(MTOR)增加白色纤维尺寸来增强全身胰岛素的作用，并通过增加主要在训练肌肉的白色纤维中GLUT4的表达来改善胰岛素刺激的葡萄糖摄取。在这项申请中，我们将对10名患有代谢综合征的高危2型糖尿病患者和10名久坐不动的对照组受试者进行为期8周的递增力量训练。这个项目建立在我们对集中阻力训练的研究经验的基础上，其结果在本申请中公布。在这项初步研究中，受试者在固定自行车上锻炼六周，导致肌肉GLUT4和Phopo-mTOR显著增加，但最大摄氧量(VO2max)、磷酸化AMP激活的蛋白激酶(AMPK)、过氧化物酶体增殖物激活的受体-3共激活物(PGC-11)和线粒体标志物没有变化。我们的假设将通过两个具体目标进行检验。(1)糖尿病高危人群将接受递增强度的阻力运动训练，力量的增加和胰岛素反应性的改善都将被量化，以证明显著的益处；(2)阻力运动训练对肌肉解剖和功能适应的影响将被量化。我们将描述纤维类型、纤维大小、线粒体DNA和酶的纤维特异性变化、肌肉中主要葡萄糖转运蛋白(GLUT4、GLUT5和GLUT12)的纤维特异性变化，并使用肌肉亚细胞片段的免疫印迹和免疫组织化学技术评估两种不同的肌肉内途径(AMPK、mTOR)和调节因子(PGC-11、PPAR3、PPAR4)的变化。这些分子机制的评估还将包括评估完整的人类Affymetrix基因阵列数据的变化，这些数据可能会将我们转移到新的潜在抗药性训练调节的基因靶点。这个研究团队的长期目标是了解生活方式变化和药物在糖尿病预防和治疗中的相互作用。我们的结果将有助于开发更有效的临床选择，以扭转肥胖和糖尿病在美国的流行。公共卫生相关性：糖尿病的预防和治疗策略以运动为基石。尽管耐力训练和力量训练都能改善胰岛素抵抗，但力量训练可能更适合2型糖尿病高危人群。我们将扩大我们对阻力运动训练诱导的肌肉适应的试点研究，以确定使代谢综合征患者从高强度力量训练中获得主要好处的生化机制。

DESCRIPTION (provided by applicant): Life style alterations can be powerful deterrents to developing type 2 diabetes and are cornerstones of the treatment of this condition. Both aerobic and resistance exercise improve diabetes blood glucose control and insulin resistance. These two types of exercise appear to exert their effects on different muscle fiber types - red for endurance and white for strength. Similar to the effects of endurance exercise training, strength training increases muscle glucose transporter isoform 4 (GLUT4), but in contrast, mitochondria numbers do not increase. We hypothesize (1) that strength training in persons with pre-diabetes may be effective in reversing insulin resistance by novel mechanisms that are distinct from the endurance training-induced mitochondrial biogenesis. We further hypothesize (2) that resistance exercise training enhances whole body insulin action primarily by increasing the white fiber size via the protein kinase mammalian target of rapamycin (mTOR) and improves insulin-stimulated glucose uptake by increased GLUT4 expression primarily in white fibers of the trained muscles. In this application, we will perform eight weeks of progressive strength training on ten subjects with the Metabolic Syndrome who are at high risk for developing type 2 diabetes and on ten sedentary control subjects. This project builds on our experience with a study of focused resistance training whose results are presented in this application. In this pilot study, subjects exercised on stationary bicycles for six weeks causing muscle GLUT4 and phopho-mTOR to increase substantially, but maximal oxygen uptake (VO2max), phospho-AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-3 co-activator (PGC-11), and mitochondrial markers did not change. Our hypotheses will be tested by two Specific Aims. (1) Subjects at high risk for diabetes will undergo progressively increasing intensity resistance exercise training and increased strength and improved insulin responsiveness will both be quantified to demonstrate significant benefit, and (2) quantify the effect of resistance exercise training on anatomic and functional adaptation in muscle. We will characterize fiber type, fiber size, fiber-specific changes in mitochondrial DNA and enzymes, fiber-specific changes in the principle glucose transporters in muscle (GLUT4, GLUT5, and GLUT12), and evaluate changes in two distinct intramuscular pathways (AMPK, mTOR) and regulatory factors (PGC-11, PPAR3, PPAR4) using immunoblots of muscle subcellular fractions and immunohistochemical techniques. These evaluations of molecular mechanisms will also include assessing changes in full human Affymetrix gene array data that may move us to new potential resistance training-regulated gene targets. It is the long-term goal of this team of investigators to understand the interplay between life style changes and pharmacological agents in the prevention and treatment of diabetes. Our results will facilitate the development of more effective clinical options to turn back the epidemic of obesity and diabetes in the United States. PUBLIC HEALTH RELEVANCE: Prevention and treatment strategies for diabetes use exercise as the cornerstone. Even though endurance training and strength training both improve insulin resistance, strength training may be better suited for persons at risk for type 2 diabetes. We will expand our pilot studies of muscle adaptation induced by resistance exercise training to determine the biochemical mechanisms that will cause people with the Metabolic Syndrome to secure major benefit from intense strength training.