GLUT4 AND CARDIAC METABOLISM AND PHYSIOLOGY

DESCRIPTION (adapted from the applicant's abstract): The applicant states that the expression of GLUT4, the insulin responsive glucose transporter, found specifically in the heart, skeletal muscle, and adipose tissue, has been shown to be down regulated in metabolically altered states such as diabetes and obesity. According to the applicant, GLUT4 null mice (genetically altered mice which do not make GLUT4) exhibit modified glucose and fat metabolism, and exhibit significant cardiac hypertrophy independent of increased arterial blood pressure. The precise mechanisms controlling the development of this hypertrophy are not well understood. The GLUT4 null mice and GLUT4 null mice complemented with a transgene specifically engineered to express GLUT4 in the heart only (HO mice) will be used in in vivo and in vitro experiments to study the consequences of altered substrate availability on cardiac structure and function. Experiments employing these mouse models will answer the following questions: 1. What changes occur in structure and function in the heart of GLUT4 null mice as hypertrophy develops, and does putting GLUT4 back into the heart of the HO mouse to make glucose uptake more normal affect the development of this hypertrophy? In vitro 31P nuclear magnetic resonance (NMR) spectroscopy and in vivo 1H magnetic resonance imaging (MRI) will be used at various time points to evaluate bioenergetic status, myocardial morphology (mass, dimensions) and function (ejection fraction). 2. What is the substrate utilization profile in the GLUT4 null and HO hearts as compared to control mice, and do alterations in these profiles affect function? Isolated perfused hearts of GLUT4 null and HO mice will be used to determine changes in substrate utilization and function at different time points in the development of hypertrophy. 3. How does the hypertrophic heart of the GLUT4 null mouse and the complemented heart of the HO mouse respond to metabolic and hemodynamic stress? Several methods will be used to assess what effect the lack of GLUT4 and its consequent effect on cardiac glucose uptake has on the ability of the GLUT4 null and HO heart to withstand stress conditions.