**4.5. GLUT4 signalling and cell biology**

GLUT4 contains unique sorting motifs at its N-terminus (FQQI) and C-terminus (dileucine) are critical for its capability to traffic between specific intracellular compartments and translocate to theplasma membrane in response todifferent stimuli.Insulin andexercise are able to rapidly and acutely stimulate GLUT4 translocation to the plasma membrane and thereby influence glucose uptake in muscle and adipose tissue via distinct signalling mechanisms. Activation of the insulin receptor (IR) leads to its autophosphorylation and subsequent signalling through the insulin receptor substrate proteins (IRS) and recruitment of PI 3-kinase catalyzes the formation of phosphatidylinositol (3,4,5)-3-phosphate (PIP3). PIP3 itself activates the protein kinase Akt via two intermediate protein kinases, PDK1 andRictor/ mTOR. Akt2 ratherthan the Akt1 or Akt3 isoforms appears to control GLUT4 trafficking. With the identification of the Akt substrates TBC1D4 (AS160), and more recently TBC1D1, two GTPase activating proteins have been identified that appearto bridge the gap between insulin-signalling and trafficking events. For TBC1D4 the substrate is the rab GTPase rab10 which has been shown to be required for insulin-stimulated translocation of GLUT4 vesicles to the plasma membrane.

Exercise has also been shown to induce TBC1D4 phosphorylation but apparently via a distinct PI3-kinase independent mechanism that requires activation of AMPK. However, simultaneous disruption of AMPK and Akt failed to completely inhibit contraction-induced AS160 phos‐ phorylation hinting towards alternative signalling events leading to GLUT4 translocation. A PI 3-kinase-independent pathway has been proposed that involves the adaptor molecules APS and CAP that bind to the insulin receptor and recruit c-Cbl. C-Cbl signals to the guanine nucleotide exchange factor C3G which activates the small GTP binding protein TC10. How‐ ever, recent data indicated a rather minor contribution for this pathway in insulin mediated GLUT4 translocation.

## *4.5.1. GLUT4 physiology*
