This proposal is for a five year program of study in biological chemistry. The program is designed to strengthen my knowledge of biological chemistry as it applies to energy metabolism and its hormonal regulation and to give me invaluable research experience that will better enable me to investigate the biochemical and molecular basis of hormonal function and dysfunction in the human. Diabetes mellitus is a disorder of energy utilization, with hyperglycemia and tissue starvation caused by consistent overproduction of glucose in the liver coupled with inefficient utilization of glucose in peripheral tissues. Dr. Lane's laboratory has long had a interest in understanding the mechanisms responsible for glucose uptake under normal, as well as under pathologic conditions. They have been studying how insulin and counter-regulatory agents control the expression of genes involved in inulin action and energy storage in the adipocyte. They have clone, determined the structures and studied the regulation of a family of differentially expressed mouse adipocyte genes that encode proteins important for energy storage and insulin action, and are currently investigating the mechanism by which certain of these genes are regulated. Using the 3T3-L1 preadipocyte/adipocyte model system. One of these genes is the insulin-responsive glucose transporter (GLUT4). Initial studies in Dr. Lane's laboratory have found that while GLUT4 activity at the plasma membrane is increased after acute insulin stimulation, GLUT4 expression is inhibited by chronic exposure to insulin. This may be one of the mechanisms by which the elevated insulin levels in obesity and in non-insulin dependent diabetes mellitus leads to a resistance of glucose uptake to insulin stimulation. The focus of its proposal is to determine the biochemical and molecular mechanism for this inhibition. Our hypothesis is that insulin covalently modifies a trans-acting factor that interacts with cis-acting elements in the GLUT4 gene.
The specific aims are to identify the regulatory elements(s) in the GLUT4 gene responsible for this inhibiting and then to characterize and isolate the transacting factor responsible for this inhibition.
| Cooke, D W; Lane, M D (1999) The transcription factor nuclear factor I mediates repression of the GLUT4 promoter by insulin. J Biol Chem 274:12917-24 |
