Insulin resistance, which precedes the development of non-insulin dependent diabetes mellitus in Pima Indians, appears to result from a postreceptor defect in signal transduction that affects the ability of insulin to regulate glycogen synthase activity in skeletal muscle. There is evidence in the literature that the influences of insulin on gene transcription may be mediated by a mechanism different from that by which the hormone influences metabolic processes as much as glycogen synthesis. Accordingly, we are undertaking this project to determine if insulin resistance in Pima Indians affects the ability of insulin to regulate transcription of the insulin-sensitive glucose transporter gene (GLUT 4) and of the proto-oncogene, c-fos. The project will also involve identification of insulin-sensitive cis-acting elements in the promoter regions of these genes and characterization of putative transacting factors. that may bind to these elements and mediate effects of insulin on transcription.
