Mailing Address Department of Cell Biology
Campus Box 8228
660 S. Euclid Ave.
St. Louis, MO 63110
Office Location 6604 Cancer Research
Phone (314) 362-4160
Lab Phone (314) 362-4161
Fax (314) 362-7463
Metabolic Regulation and Obesity
Signal Transduction/Hormone Action
Category(ies) of Research
Descriptor of Research
Research in my laboratory is concerned with understanding the regulation of glucose metabolism and its derangement in various disease states, most notably non-insulin-dependent diabetes mellitus (NIDDM). Our work is especially focused on glucose transport, insulin signaling, and insulin action. There are currently 2 major ongoing projects: 1) Relatively little is known concerning the structure and mechanism of membrane transport proteins. We are using a combination of biochemical, molecular, and biophysical approaches to study the mechanism of glucose transport via the Glut1 transporter. We have defined the two-dimensional topology of Glut1 in the membrane and, based on a comprehensive series of experiments conducted over the past 20 years, have developed a low-resolution model for the three-dimensional structure of Glut1. This model is currently being tested and refined by further experiments involving site-directed mutagenesis, the substituted cysteine accessibility method, cysteine-scanning mutagenesis, di-cysteine cross-linking studies, and various modes of spectroscopy performed on purified mutant transporters. Methods are also being developed for the large-scale purification and crystallization of recombinant Glut proteins. 2) Peripheral insulin resistance associated with NIDDM is caused by the inability of insulin to appropriately stimulate Glut4 translocation and/or activation in fat and skeletal muscle. Over the past 25 years we have developed unique cellular and molecular biological approaches to study the subcellular trafficking of Glut4 in adipocytes and muscle fibers. These techniques are being used to define the role of various proteins in Glut4 trafficking and to delineate the structural features of Glut4 that dictate its unique insulin-sensitive subcellular trafficking.