At present most of our research is focused on GLUT4, the insulin-responsive glucose transporter. Glucose homeostasis depends mainly on controlled changes in glucose transport in insulin-responsive tissues such as muscle and adipose cells. GLUT4 is expressed in cells in which glucose transport is regulated by insulin and is thought to be the major glucose transporter in these tissues. By using techniques such as recombinant DNA methods, immunofluorescence microscopy, chimeric gene transfections and transgenic mouse designs we hope to study: the regulation of GLUT4 throughout development and into disease states (i.e. diabetes mellitus and cancer); the role of GLUT4 in normal glucose homeostasis; targeting of GLUT4 in heterologous organs (i.e. brain and kidney). By integrating the findings from this type of multidisciplinary study we ultimately hope to be able to make practical applications in the field of gene therapy and treatment of diabetes mellitus, a disease which afflicts more than 16 million Americans.
We have shown that the expression of GLUT4 mRNA and protein is altered in skeletal muscle and adipose tissue in diabetic animals. We wish to understand the physiological role of GLUT4 in normal glucose homeostasis. Transgenic mouse experiments are underway to examine: 1) the overexpression of GLUT4 in several tissues and 2) the physiological consequence(s) of "knocking out" one or both alleles of GLUT4 from the genome using homologous recombination techniques. These studies will enable us to examine the influence of the above alterations in the physiological context of a developing animal.
In contrast to our studies on the insulin action and glucose uptake we are also studying the glucagon receptor. Glucagon is a peptide hormone that functions to elevate serum glucose levels (in opposition to insulin). We have cloned the glucagon receptor gene and studied its regulation by hormones and nutrients. We are interested in studying the structural-functional features of the receptor, the interaction of the receptor with glucagon and other ligands and the mechanism of signal transduction. We are currently studying the role of the glucagon receptor in the pathophysiology of diabetes mellitus through tissue specific gene knockout and transgenic mouse studies.
References
Katz, E.B., A.E. Stenbit, K. Hatton, R. DePinho and M.J. Charron. (1995). Genetic ablation of GLUT4 results in decreased longevity, heart and adipose tissue abnormalities but not diabetes. Nature 377: 151-155.
Burcelin, R., J. Li and M.J. Charron. (1995). Molecular cloning and sequence analysis of the murine glucagon receptor gene. Gene 164: 305-310.
Tsao, T.-S., R. Burcelin, E.B. Katz, L. Huang and M.J. Charron. (1995). Enhanced insulin action due to targeted GLUT4 overexpression only in skeletal muscle. Diabetes 45: 28-36.
Tsao, T.S., R. Burcelin and M.J. Charron. (1996). Regulation of hexokinase II gene expression by glucose flux in skeletal muscle. J. Biol. Chem., in press.
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