INTRAMUSCULAR TRIGLYCERIDE IN IMPAIRED GLUCOSE TOLERANCE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。胰岛素抵抗，定义为胰岛素刺激外周葡萄糖摄取以及抑制肝脏葡萄糖输出和脂解的能力受损，是葡萄糖耐量受损（IGT）和2型糖尿病的主要特征。胰岛素抵抗发生的机制尚不清楚。骨骼肌是负责胰岛素对外周葡萄糖摄取作用的主要组织，因此被认为是胰岛素抵抗发生的主要部位。肌内甘油三酯（IMTG）的含量和营业额，特别是，一直是最近相当感兴趣的话题，因为IMTG的量与胰岛素敏感性密切相关。大量数据表明，健康男性和女性可能会以不同的方式使用IMTG，特别是在运动期间。我们推测，这种性别依赖的IMTG使用机制在IGT的发展中丢失。我们的第一个目标是描述IGT男性和女性在基线和急性运动期间的IMTG含量和营业额。本研究的第二个和第三个目的将试图解释男性和女性一旦发展为IGT就失去翻转IMTG的能力的机制。我们假设，女性依赖于肌肉的氧化能力，而男性依赖于激活的过氧化物酶体增殖物激活受体靶基因，因为这些已经在动物研究中显示。为了区分这些机制，IGT男性和女性将随机接受运动训练计划（以增加氧化能力）或贝特类药物治疗（激活PPAR，持续12周）。我们将结合联合收割机的血液和组织采样，稳定同位素方法，和胰岛素敏感性的措施，在追求这些目标？更好地了解IMTG含量和转换在男性和女性胰岛素抵抗发展中的作用，可能会指导我们预防和治疗糖尿病的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance, defined as an impairment in insulin's ability to stimulate peripheral glucose uptake, as well as suppress hepatic glucose output and lipolysis, are major characteristics of impaired glucose tolerance (IGT) and type 2 diabetes. The mechanisms by which insulin resistance develops are unclear. Skeletal muscle is the major tissue responsible for insulin action on peripheral glucose uptake, and therefore has been implicated as a primary site for the development of insulin resistance. Intramuscular triglyceride (IMTG) content and turnover, specifically, have been the topics of considerable recent interest as the amount of IMTG correlates strongly with insulin sensitivity. Substantial data exists that healthy men and women may use IMTG differently, especially during exercise. We speculate that this gender-dependent mechanism for IMTG use is lost in the development of IGT. Our first aim will describe IMTG content and turnover at baseline and during acute exercise in men and women with IGT. The second and third aims of the study will attempt to explain the mechanisms by which men and women lose the ability to turnover IMTG once they develop IGT. We hypothesize that women rely on oxidative capacity of muscle, whereas men rely on the activation of PPAR target genes, as these have been shown in animal studies. To differentiate these mechanisms, men and women with IGT will be randomized to either an exercise training program (to increase oxidative capacity) or fibrate therapy (to activate PPAR for 12 weeks. Will we combine blood and tissue sampling, stable isotope methodology, and measures of insulin sensitivity in pursuit of these aims? Better understanding the role of IMTG content and turnover in the development of insulin resistance in men and women may guide our therapy in the prevention and treatment of diabetes.