The stimulation of glucose uptake into selected target cells is the historical standard insulin response. Glucose influx into skeletal muscle, adipose, and cardiac muscle is stimulated by insulin binding to its receptor. When insulin binds to its receptor, it can result in the activation of pathway P4. Thus, the six member signaling pathway starting with CAP and ending with TCIO stimulates translocation of glucose transporter #4 (GLUT4) which is stored in intracellular membranous vesicles in the cell’s cytosol to the cell’s plasma membrane via an exocytosis process. The final outcome on completion of the exocytosis of the GLUT4 is its functioning as a sodium-independent, facilitated-diffusion glucose transporter which stimulates the uptake of extracellular glucose and delivers it into the cytosol of the host cell. The principal participant in this pathway is GLUT4, which is one of 12 sugar transporter proteins. The GLUTs are divided into three classes. CLASS I members are GLUTs 1–4 and each one is a glucose transporter. Class II GLUTs are fructose transporters and Class III GLUTs are structurally atypical members of the GLUT family and their functions are not yet well described.

All GLUTs contain 12 membrane-spanning helices with both the carboxyl and amino terminal ends facing towards the cytosol of the cell (Figure 1). GLUT4 can be considered to be an integral membrane protein; it is present in skeletal, cardiac muscle, and adipose tissue. A major effect of insulin acting through its membrane receptor is to stimulate the translocation of GLUT4-containing vesicles in the intracellular cytosol to migrate to the plasma membrane and by the process of exocytosis. Thus the GLUT4 becomes a functional gated channel in the cell membrane.

Fig1. Schematic presentation of the GLUT4 protein in the cell membrane. GLUT4 is a member of the facilitative glucose transporter family. In each GLUT family member, the peptide chain spans the plasma membrane 12 times; both the amino and carboxyl termini are helices facing towards the cytosol of the cell. The sequence of ~500 amino acids are shown as green or orange spheres that in this example make up the CLASS 1 amino acids; each sphere represents one amino acid residue. A homology plot was made for the entire amino acid sequence for GLUT1 versus GLUT4. The orange spheres indicate residues that are unique to GLUT4 whereas the green spheres indicate amino acid residues that are not conserved for both GLUT1 and GLUT4 proteins. It requires about 20 amino acid residues to span the membrane. Of the 12 sequences that span the membrane, only span #10 which is the third span from the COOH terminus has no conserved residues; i.e., in span #10 all the amino acid residues are colored green. Spans #1 (near the NH2 terminus) , #7, and #12 each only have 1–2 out of 20 residues conserved (both were orange color) and the conserved residues were never in the interior of the membrane. Modified with permission from N.J. Bryan, R. Govers & D.E. James in Nature Reviews; Molecular Cell Biology 3: 267–277 (2002).

Figure 2 illustrates over a 30-minute interval the translocation of GLUT4 from intracellular storage locations to the plasma membrane using a GLUT4 enhanced green fluorescent protein that was transfected into adipocytes. The translocation of GLUT4 is very dynamic. It has been demonstrated to occur within 30 seconds of the arrival of insulin. Then as the stim ulus of glucose absorption dissipates, the decrease in the number of plasma membrane GLUT4 receptors declines. This illustrates the dynamic regulatory properties of the GLUT4 that are required to provide an appropriate number of plasma membrane associated GLUT4 channels to meet the task of the glucose uptake process. The GLUT proteins have only a single substrate binding site (for glucose) which faces alternatively towards the “outside” or “inside” of the cell. Binding of glucose to one site provokes a conformational change associated with transport, so that glucose is released on the other side of the membrane. Thus, GLUT4 is functionally able to both import and export glucose. The glucose-binding sites of GLUT4 are believed to be associated with the transmembrane loops #6, #7, and #8; loop #12 is closest to the GLUT’s COOH group.

Fig2. Insulin binding to its membrane receptor results in the translocation of the GLUT4 transport protein from its intracellular storage sites to the plasma membrane. A GLUT4-enhanced green fluorescent protein construct was transfected into differentiated 3T3L1 adipocytes. They were then incubated in the absence (A) or presence (B) of insulin for 30 minutes. Next the cells were fixed and the location of the GLUT4-labeled green fluorescent protein determined by confocal fluorescent microscopy. This figure was provided by R. T. Watson, M. Kanzaki, & J. E. Pessin, Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocrine Reviews 25(2): 177–204 (2004).

Figure 3 presents a three-dimensional right-handed α-helix barrel model of GLUT4 that has 12 transmembrane α-helix segments surrounding a central pore. The three-dimensional side view (panel A) and top view (panel B) are of the ribbon representations of loop #7 of GLUT4. The key three amino acids, Q (glutamine), L (leucine), and S (serine), are presented as pink CPK space filling spheres in both panels A and B. The QLS site is believed to be structurally involved in creating the pore that is involved in the transport of glucose.

Fig3. Three-dimensional model of the GLUT4 glucose transporter. (A) The GLUT4 model describes a right-handed α-helix barrel that consists of 12-membrane segments that surround a central pore. This side view of the GLUT4 shows the extensive ribbon representation of the entire 3D structure. The QLS (glutamine, leucine, and serine) site, which is believed to be located in the seventh loop of the protein, is colored pink. It is postulated to be structurally involved in creating the pore that is involved in the transport of glucose; it is shown as a CPK space-filling model. The COOH and NH2 terminal regions are presented as a coil. (B) This is a top view of the 3D presentation of the GLUT4 protein ribbon form. The QLS pink sites are presented as a CPK space filling mode; these residues are believed to participate in the process of glucose transport. The transmembrane helices are colored as follows: helix 2 (orange), helix 5 (yellow), helix 7 (red), helix 10 (green), and helix 11 (cyan). P. Strobel et al. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochemical Journal 386: 471–478 (2005); this paper describes a detailed molecular model of the GLUT4 protein.

The uptake of the glucose present in the blood compartment by the process of facilitated diffusion sends glucose down its concentration gradient. Once the glucose enters into the cell cytosol it becomes phosphorylated by hexokinase to yield glucose-6-phosphate which, because of its negative charge, cannot leave the cell by diffusion through GLUT4. When glucose-6 phosphate is metabolized through glycolysis and the Krebs cycle the released energy is stored as ATP. In type 2 diabetes mellitus, there is an impairment of GLUT4 trafficking and translocation in the skeletal muscle, which results in the development of insulin resistance.

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