Regulated Membrane Trafficking of the Insulin-Responsive Glucose Transporter 4 in Adipocytes
Since the discovery of insulin roughly 80 yr ago, much has been learned about how target cells receive, interpret, and respond to this peptide hormone. For example, we now know that insulin activates the tyrosine kinase activity of its cell surface receptor, thereby triggering intracellular signaling cascades that regulate many cellular processes. With respect to glucose homeostasis, these include the function of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and adipose tissues, the latter resulting from the translocation of the glucose transporter 4 (GLUT4) to the cell surface membrane. Although simple in broad outline, elucidating the molecular intricacies of these receptor-signaling pathways and membrane-trafficking processes continues to challenge the creative ingenuity of scientists, and many questions remain unresolved, or even perhaps unasked. The identification and functional characterization of specific molecules required for both insulin signaling and GLUT4 vesicle trafficking remain key issues in our pursuit of developing specific therapeutic agents to treat and/or prevent this debilitating disease process. To this end, the combined efforts of numerous research groups employing a range of experimental approaches has led to a clearer molecular picture of how insulin regulates the membrane trafficking of GLUT4. (Endocrine Reviews 25: 177-204, 2004) I. Introduction II. The Hexose Transporter Family A. Family members, structure, and function B. GLUT4 III. Intracellular GLUT4 Storage Compartments A. The specialized GLUT4 storage compartment B. Insulin-regulated amino peptidase (IRAP) C. GLUT4 targeting motifs IV. Regulated GLUT4 Exocytosis A. The IR: structure and function B. The IR: knockout mouse models C. The IR: complex signaling networks D. The PI3K and GLUT4 translocation E. Protein kinase B (PKB) and atypical protein kinase C (aPKC) F. A second insulin-signaling pathway regulating GLUT4 translocation? V. Role of the Cytoskeleton in Insulin-Stimulated GLUT4 Translocation A. Actin B. Microtubules VI. The IR: Attenuation of Receptor Signaling VII. GLUT4 Vesicle Docking and Fusion with the Plasma Membrane A. SNARE proteins B. SNARE-associated proteins in GLUT4 translocation C. Exocyst in GLUT4 translocation