MECHANISMS OF HUMAN INSULIN RESISTANCE: ROLE OF LIPID METABOLISM

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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.