Insulin-stimulated GLUT4 translocation in adipocytes can be broken down into multiple steps. The first step involves trafficking of GLUT4-containing vesicles (GSVs) from an intracellular location close to the cell surface. As demonstrated by Kanda et al. in this issue of the JCI (9), this step is regulated by insulin in a PI3K-Akt–independent manner and occurs at low insulin concentrations. The second step involves multiple stages including: (a) tethering – a low-affinity interaction of GSVs with the plasma membrane; (b) activation – modification of the conformation of the Munc18c/syntaxin4 complex; (c) docking – a high-affinity interaction of GSVs with the plasma membrane; and (d) fusion – merging of the lipid bilayers of GSVs and the plasma membrane. The precise role of Munc18c in each of these stages is yet to be determined, but it is likely involved in both activation and docking. Importantly, the Munc18c-dependent stage also likely defines the major PI3K-Akt regulatory event in insulin-stimulated glucose transport under physiological conditions. The absence of Munc18c as described by Kanda et al. overcomes the PI3K-Akt regulation of GLUT4 trafficking, which suggests that Munc18c acts to somehow retain syntaxin4 in the “off” (closed) position and this clamp is removed in the presence of insulin, allowing syntaxin4 to move into the "on" position. This switch may be mediated by the activation of an as-yet-unidentified Rab protein, potentially involving Akt-dependent phosphorylation of the Rab GAP protein AS160 (18).