ABSTRACT
Skeletal muscle is the main site of glucose disposal in response to insulin. The GLUT4 glucose transporter mediates glucose uptake across the plasma membrane and transverse tubules. Insulin increases the content of GLUT4 in both surface locations, drawing from intracellular compartments that are heterogeneous and poorly characterized. Here we gather information suggesting that GLUT4 may be housed in the myoplasm in the following separate compartments: endocytic vesicles, sorting endosomes, insulin-sensitive vesicles, exercise-sensitive vesicles. These compartments are not separated by immunopurification with anti-GLUT4 antibodies, but this approach has identified a select number of proteins that segregate with GLUT4. Among these are the aminopeptidase IRAP, the SNAREs VAMP2 and syntaxin4, and minor levels of transferrin receptors, sortilin and SCAMPs. In fat and muscle cells in culture, VAMP2 mediates a fusion step that leads to GLUT4 externalization. Recent additional techniques such as velocity gradients in sucrose, glycerol and other materials have separated subsets of insulin-sensitive and insensitive compartments. In streptozocin-diabetes, in addition to reduced GLUT4 levels, there is incomplete recruitment of GLUT4 to the plasma membrane and transverse tubules, and this is accompanied by changes in the levels of SNARE proteins. In particular, VAMP2 is reduced intracellularly and elevated in the surface membranes, whereas syntaxin4 is elevated in both locations. Some of these changes might be adaptive reactions attempting to improve GLUT4 incorporation into surface membranes. Conversely, in muscles from mice overexpressing GLUT4, there is a selective rise in syntaxin4 in the GLUT4-containing compartments and an improved incorporation of GLUT4 into the plasma membrane. The challenge for the future will be to capitalize on the knowledge of the function of SNAREs and other proteins in order to improve GLUT4 traffic in insulin resistant states.
