Glucose transporter 4: cycling, compartments and controversies

Abstract

Insulin promotes glucose uptake into muscle and adipose tissues through glucose transporter 4 (GLUT4). In unstimulated cells, rapid endocytosis, slow exocytosis and dynamic or static retention cause GLUT4 to concentrate in early recycling endosomes, the trans-Golgi network and vesicle-associated protein 2-containing vesicles. The coordinated action of phosphatidylinositol 3-kinase effectors, protein kinase Akt, atypical protein kinase C (aPKC) and Akt substrate of 160-kDa (AS160), regulates the GLUT4 cycle by affecting its translocation, fusion with the plasma membrane, internalization and sorting. We review the evidence that supports such cycling, evaluate current models proposing static or dynamic retention, and highlight how distinct steps of GLUT4 transport are regulated by insulin signals. In particular, fusion seems to be regulated by aPKC (via munc18) and Akt (via syntaxin4-interacting protein (synip)). AS160 participates in GLUT4 intracellular retention, and possibly fusion, through candidate ras-related GTP-binding protein (Rab)2, Rab8, Rab10 and/or Rab14. The localization of the insulin-sensitive GLUT4 compartment and the precise target of insulin-derived signals remain open for future investigation.

Figure 1

Models of insulin-responsive glucose transporter 4 (GLUT4) compartments and cycling. Illustrated is a hypothetical version of GLUT4 cycling summarizing the current literature. GLUT4 cycles between intracellular compartments and the plasma membrane (PM) by the coordinated regulation of exocytic mobilization, fusion with the PM, endocytosis, and inter-endosomal transit and sorting. Each stage of GLUT4 transport is regulated by insulin-derived signals. The contents of the expanded box illustrate aspects of the two debated models of GLUT4 compartments and exit modalities. The models differ in negating or supporting the presence of a static/latent pool of GLUT4, in the contribution of the trans-Golgi network (TGN) as a storage site for GLUT4, and in the number of GLUT4 exit routes towards the PM. The plus symbol (+) indicates stimulation. AS160, Akt-substrate of 160 kDa; ERC, endosomal recycling compartment; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; SE, sorting syndrome; TfR, transferrin receptor.