Skeletal muscle and adipose tissue are the major sites of postprandial glucose disposal. The insulin-regulated transport of glucose into these tissues is a multi-step process that begins with the binding of insulin to its cell surface receptor. Once activated, the insulin receptor generates multiple intracellular signaling cascades, some of which induce the rapid redistribution of the GLUT4 facilitative glucose transporter from intracellular compartments to the plasma membrane. Although probably best known for its role in glucose homeostasis, insulin regulates a variety of metabolic, mitogenic, and anti-apoptotic processes in specific tissues. Moreover, in addition to insulin several other hormones and growth factors can also activate signaling targets that function downstream of the insulin receptor. For example, phosphatidylinositol-3′-kinase (PI3K), a key enzyme in the signaling pathway leading to insulin-stimulated glucose uptake, can be activated by many extracellular signals. However, only insulin and highly related hormones such as IGF-I efficiently stimulate acute glucose transport. These observations suggest that cellular mechanisms have evolved for maintaining specificity among signaling pathways mediated by various hormones and growth factors. Elucidating the underlying mechanisms for this specificity is a current challenge engaging the attention of many researchers, and will require a thorough understanding of the signaling pathway responsible for each cellular response. To this end, recent work suggests that the coordination of multiple pathways occurs in part through the intracellular compartmentalization of key signaling molecules. Indeed, subcellular compartmentalization plays a critical role in maintaining the specificity of insulin signaling and the fidelity of GLUT4 vesicle trafficking.
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