(taken from the application) Glucose enters the heart via glucose transporters GLUT1 and GLUT4. GLUT1 mediates basal glucose uptake and GLUT4 translocation is responsible for the acute increase in cardiac glucose uptake in response to: insulin and catecholamine stimulation, hypoxia, ischemia and increased workload. GLUT4 expression in the heart is reduced in diabetes and in cardiac hypertrophy. The reduction in GLUT4 may increase the susceptibility of the heart to ischemic injury. Recent studies in mice with heart selective ablation of GLUT4 confirm the important role of GLUT4 in protecting the heart against ischemic injury. The current proposal seeks to address the question as to whether or not upregulation of cardiac GLUT4 expression will protect the heart from ischemic injury. Two models with upregulation of GLUT4 in the heart have been developed, namely: Mice with cardiac specific deletion of the insulin receptor, and mice treated with low dose isoproterenol. Studies proposed will determine: (1) If these hearts exhibit increased insulin or catecholamine induced glucose uptake in vivo, (2) If these hearts exhibit altered in vivo cardiac physiology (3) If these hearts exhibit diminished susceptibility to ischemic injury (4) The signal transduction pathways which are responsible for the upregulation of cardiac GLUT4 expression. If a positive benefit of increased cardiac GLUT4 expression can be demonstrated and the signal transduction pathways which mediate GLUT4 upregulation are elucidated, these findings will lead to the development of novel therapeutic strategies to treat various cardiac disorders such as hypertrophy, heart failure, ischemic heart disease and diabetic cardiomyopathy.
