In unstimulated cells, GLUT4 is localized predominantly in the perinuclear region in small, insulin-responsive vesicles (IRVs). In addition to GLUT4, these vesicles contain IRAP, LRP1, and VAMP2, as well as sortilin, a cargo adaptor protein. The IRVs exist in a dynamic equilibrium with donor membranes that are likely a sub-domain of the trans-Golgi network (TGN) and/or recycling endosomes. Formation of the IRVs requires GGA and ACAP1 adaptor proteins, clathrin, and probably phosphatidylinositol 4-phosphate (PI4P). Once formed, IRVs are retained intracellularly by TUG, Ubc9, and other proteins, which may constrain an intracellular cycle of budding and fusion. Upon insulin addition, IRVs are mobilized and fuse with the plasma membrane. The IRV component proteins are internalized into sorting endosomes and returned to donor membranes by cellugyrin-containing transport vesicles. As diagrammed, the IRVs are labeled in magenta, proteins and lipids are denoted in blue, donor membranes in red, and retention and mobilization steps are in green.