GLUT4

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Glucose Transporter Type 4 (GLUT4) is an insulin-regulated membrane protein responsible for decreasing blood glucose concentration found in both adipose tissues as well as striated muscle[1]. Activity of this protein is primarily regulated by the signal transduction pathway and several transcriptional factors found in the tissues where GLUT4 is located[2][3][4]. GLUT4 is responsible for returning blood glucose to a physiological concentration of 5-6mM after the ingestion of carbohydrates, as well as increasing the rate of glycogen synthesis in skeletal muscle following glycogen depleting exercise[5][6].

Image:Glut4_3d_structure.gif

Reaction Mechanism

Image:Glut4mechanism1.jpg

During periods in which insulin is low, GLUT4 is found in intracellular vesicles among adipose and muscle cells. When blood glucose increases and insulin spikes, insulin binds to insulin receptors on the plasma membrane. The insulin receptor’s tyrosine-kinase domain is activated by the binding of insulin. This activation starts a protein activation cascade leading to the translocation of GLUT4, starting with the phosphorylation of Insulin Receptor Substrate, which then binds PI-3 kinase. PI-3 kinase is responsible for the conversion of membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 can then activate protein kinase B, which phosphorylates TBC1 domain family member 4 (TBC1D4). The phosphorylation of TBC1D4 allows for Rab protein to change from its GDP bound state to its GTP bound state. This stimulates translocation of GLUT4 to the plasma membrane.

Once translocation occurs and GLUT4 is inserted into the plasma membrane, glucose absorption in the cell is increased. Facilitated diffusion of glucose down its concentration gradient into the cell occurs. After entering the cell, glucose is phosphorylated in glucose-6-phosphate by hexokinase in most cells, and glucokinase in the liver. Glucose-6-phosphate is incapable of diffusing out of the cell, and it either enters glycolysis or is polymerized into glycogen[7].

Medical Relevance

Disruption of GLUT4 activity can affect insulin resistance as well as glucose tolerance. Decrease of GLUT4 activity leads to a sharp increase in plasma insulin concentration, as well as decreasing the rate of glucose uptake in muscle and fat cells [8]. Targeted GLUT4 disruption has been shown to lead to acute insulin resistance. This causes a much more gradual response to rising blood glucose levels, which in turn can induce hyperglycemia and diabetes [9].


Human glucose Transporter Type 4 (PDB code 1suk)

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References

  1. ↑ Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007 Apr;5(4):237-52. PMID:17403369 doi:http://dx.doi.org/10.1016/j.cmet.2007.03.006
  2. ↑ Im SS, Kwon SK, Kim TH, Kim HI, Ahn YH. Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes. IUBMB Life. 2007 Mar;59(3):134-45. PMID:17487684 doi:http://dx.doi.org/10.1080/15216540701313788
  3. ↑ Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. 2002 Apr;3(4):267-77. PMID:11994746 doi:http://dx.doi.org/10.1038/nrm782
  4. ↑ Klip A. The many ways to regulate glucose transporter 4. Appl Physiol Nutr Metab. 2009 Jun;34(3):481-7. doi: 10.1139/H09-047. PMID:19448718 doi:http://dx.doi.org/10.1139/H09-047
  5. ↑ Jose-Cunilleras E, Hayes KA, Toribio RE, Mathes LE, Hinchcliff KW. Expression of equine glucose transporter type 4 in skeletal muscle after glycogen-depleting exercise. Am J Vet Res. 2005 Mar;66(3):379-85. PMID:15822579
  6. ↑ Henriksen EJ, Bourey RE, Rodnick KJ, Koranyi L, Permutt MA, Holloszy JO. Glucose transporter protein content and glucose transport capacity in rat skeletal muscles. Am J Physiol. 1990 Oct;259(4 Pt 1):E593-8. PMID:1699426
  7. ↑ Watson RT, Kanzaki M, Pessin JE. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev. 2004 Apr;25(2):177-204. PMID:15082519 doi:http://dx.doi.org/10.1210/er.2003-0011
  8. ↑ Rossetti L, Stenbit AE, Chen W, Hu M, Barzilai N, Katz EB, Charron MJ. Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene. J Clin Invest. 1997 Oct 1;100(7):1831-9. PMID:9312184 doi:http://dx.doi.org/10.1172/JCI119711
  9. ↑ Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med. 2000 Aug;6(8):924-8. PMID:10932232 doi:http://dx.doi.org/10.1038/78693

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