MECHANISMS OF HUMAN INSULIN RESISTANCE: ROLE OF LIPID METABOLISM

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。胰岛素抵抗综合征为2型糖尿病和心血管疾病的发展提供了“共同土壤”，并导致了我们社会中广泛的发病率和死亡率。本研究的总体目标是更好地定义这些脂肪代谢异常及其与IR发展的关系。这些体内研究将定义FFA周转率，脂质氧化，IR之间的关系，并为解释分子数据提供功能基础。将招募具有IR特征的受试者（如肥胖、葡萄糖耐量受损、高脂血症和/或糖尿病）用于研究。进入GCRC后，受试者将接受初步病史、体格检查、EKG、血压和血液/尿液实验室检查，然后进行一系列代谢研究，以测量身体组成、能量消耗、葡萄糖耐量、体内胰岛素敏感性和葡萄糖代谢、胰岛素分泌和脂质代谢。然后，他们将被置于非常低热量的饮食1周，并重复一系列的代谢研究。一旦完成，受试者将进入3期，接受1200-1800卡路里/天的减肥饮食，并在门诊GCRC中进行监测，直至初始体重减轻15%。受试者将返回GCRC住院部重复进行代谢研究，如第1和第2阶段所述。脂肪和肌肉组织中的分子测量将通过酶测定、蛋白质印迹、mRNA定量、亚分级、cDNA微阵列和蛋白质组学进行分析。

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. The insulin resistance syndrome provides the "common soil" for the development of Type 2 Diabetes and Cardiovascular Disease and is responsible for extensive morbidity and mortality in our society. The overall aims of this study are to better define these abnormalities in fat metabolism and their relationship to the development of IR. These in-vivo studies will define the relationship between FFA turnover, lipid oxidation, IR, and provide a functional basis for interpreting the molecular data. Subjects characterized with IR such as obesity, impaired glucose tolerance, hyperlipidemia, and/or diabetes will be recruited for study. Admitted to the GCRC, subjects will undergo preliminary medical history, physical exam, EKG, blood pressure and blood/urine labs, followed by a series of metabolic studies to measure body composition, energy expenditure, glucose tolerance, in vivo insulin sensitivity and glucose metabolism, insulin secretion, and lipid metabolism. They will then be placed on a very low calorie diet for 1 week and repeat the series of metabolic study. Once completed, the subjects will enter phase 3 being placed on a weight loss diet of 1200-1800 calories/day and monitored in the outpatient GCRC until 15% of initial body weight is lost. Subjects will return to GCRC inpatient for a repeat of the metabolic studies, as described in phases 1 and 2. Molecular measurements in fat and muscle tissue will be analyzed with enzyme assay, western blot, mRNA quantification, subfractionation, cDNA microarray, and proteomics.