GLUT4

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SLC2A4
Insulin glucose metabolism ZP.svg
Identifiers
Aliases SLC2A4, GLUT4, solute carrier family 2 member 4
External IDs OMIM: 138190 MGI: 95758 HomoloGene: 74381 GeneCards: 6517
RNA expression pattern
PBB GE SLC2A4 206603 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001042

NM_009204

RefSeq (protein)

NP_001033.1

NP_033230.2

Location (UCSC) Chr 17: 7.28 – 7.29 Mb Chr 11: 69.94 – 69.95 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Glucose transporter type 4, also known as GLUT4, is a protein encoded, in humans, by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988.[1] The gene that encodes GLUT4 was cloned[2][3] and mapped in 1989.[4]

Recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the hippocampus. Moreover, impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behaviour and cognitive dysfunction.[5][6][7]

Tissue distribution[edit]

GLUT4 is primarily found in:

Regulation[edit]

Insulin[edit]

Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. Insulin induces a rapid increase in the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.[8] Insulin’s actions are effectively abolished in the genetically engineered muscle insulin receptor knock‐out (MIRKO) mouse because they have a complete lack of the insulin‐sensitive glucose transport protein, GLUT4, in muscle, so insulin has no effect on glucose uptake. Fascinatingly, this is of little or no consequence to the animal that does not have fasting hyperglycaemia or diabetes.[9]

The insulin signal transduction pathway begins when insulin binds to the insulin receptor proteins. Once the transduction pathway is completed, the GLUT-4 storage vesicles becomes one with the cellular membrane. As a result the GLUT-4 protein channels become embedded into the membrane, allowing allowing glucose to be transported into the cell.

Insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then phosphorylates and subsequently recruits Insulin Receptor Substrate or IRS-1, which in turn binds the enzyme PI-3 kinase through the binding of the enzyme's SH2 domain to the pTyr of IRS. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by the PH domains of PKB (protein kinase B) or AKT, and also for PDK1 which, being localized together with PKB, can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GAP domain or the GTPase-activating domain associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form and stimulates GLUT4 to be expressed on the plasma membrane. RAC1 is a GTPase which is also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton [10] which allows for the GLUT4 vesicles to be inserted into the plasma membrane.[11][12] RAC1 Knockout mouse have reduced glucose uptake in muscle.[12]

At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.[13]

Knockout mice that are heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.[14]

Muscle contraction[edit]

Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle.[15] In skeletal muscle, muscle contraction increase GLUT4 translocation several fold [16] and this is likely regulated by RAC1 [17][18] and AMP-activated protein kinase.[19]

Muscle stretching[edit]

Muscle stretching also stimulate GLUT4 translocation and glucose uptake in rodent muscle via RAC1[20]

Interactions[edit]

GLUT4 has been shown to interact with death-associated protein 6.[21]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

References[edit]

  1. ^ James DE, Brown R, Navarro J, Pilch PF (May 1988). "Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein". Nature 333 (6169): 183–5. doi:10.1038/333183a0. PMID 3285221. 
  2. ^ James DE, Strube M, Mueckler M (Mar 1989). "Molecular cloning and characterization of an insulin-regulatable glucose transporter". Nature 338 (6210): 83–7. doi:10.1038/338083a0. PMID 2645527. 
  3. ^ Birnbaum MJ (Apr 1989). "Identification of a novel gene encoding an insulin-responsive glucose transporter protein". Cell 57 (2): 305–15. doi:10.1016/0092-8674(89)90968-9. PMID 2649253. 
  4. ^ Bell GI, Murray JC, Nakamura Y, Kayano T, Eddy RL, Fan YS, Byers MG, Shows TB (Aug 1989). "Polymorphic human insulin-responsive glucose-transporter gene on chromosome 17p13". Diabetes 38 (8): 1072–5. doi:10.2337/diabetes.38.8.1072. PMID 2568955. 
  5. ^ Patel SS, Udayabanu M (Mar 2014). "Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice". Metabolic Brain Disease 29 (1): 121–30. doi:10.1007/s11011-014-9480-0. PMID 24435938. 
  6. ^ Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP (2007). "Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus". Neuroendocrinology 85 (2): 71–80. doi:10.1159/000101694. PMID 17426391. 
  7. ^ Huang CC, Lee CC, Hsu KS (2010). "The role of insulin receptor signaling in synaptic plasticity and cognitive function". Chang Gung Medical Journal 33 (2): 115–25. PMID 20438663. 
  8. ^ Cushman SW, Wardzala LJ (May 1980). "Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane" (PDF). The Journal of Biological Chemistry 255 (10): 4758–62. PMID 6989818. 
  9. ^ Sonksen P, Sonksen J (Jul 2000). "Insulin: understanding its action in health and disease". British Journal of Anaesthesia 85 (1): 69–79. doi:10.1093/bja/85.1.69. PMID 10927996. 
  10. ^ JeBailey L, Wanono O, Niu W, Roessler J, Rudich A, Klip A (Feb 2007). "Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells". Diabetes 56 (2): 394–403. doi:10.2337/db06-0823. PMID 17259384. 
  11. ^ Sylow L, Kleinert M, Pehmøller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (Feb 2014). "Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance". Cellular Signalling 26 (2): 323–31. doi:10.1016/j.cellsig.2013.11.007. PMID 24216610. 
  12. ^ a b Sylow L, Jensen TE, Kleinert M, Højlund K, Kiens B, Wojtaszewski J, Prats C, Schjerling P, Richter EA (Jun 2013). "Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle". Diabetes 62 (6): 1865–75. doi:10.2337/db12-1148. PMC 3661612. PMID 23423567. 
  13. ^ Watson RT, Kanzaki M, Pessin JE (Apr 2004). "Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes". Endocrine Reviews 25 (2): 177–204. doi:10.1210/er.2003-0011. PMID 15082519. 
  14. ^ Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ (Oct 1997). "GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes". Nature Medicine 3 (10): 1096–101. doi:10.1038/nm1097-1096. PMID 9334720. 
  15. ^ Lund S, Holman GD, Schmitz O, Pedersen O (Jun 1995). "Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin". Proceedings of the National Academy of Sciences of the United States of America 92 (13): 5817–21. doi:10.1073/pnas.92.13.5817. PMC 41592. PMID 7597034. 
  16. ^ Jensen TE, Sylow L, Rose AJ, Madsen AB, Angin Y, Maarbjerg SJ, Richter EA (Oct 2014). "Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca(2+) release". Molecular Metabolism 3 (7): 742–53. doi:10.1016/j.molmet.2014.07.005. PMC 4209358. PMID 25353002. 
  17. ^ Sylow L, Møller LL, Kleinert M, Richter EA, Jensen TE (Dec 2014). "Rac1--a novel regulator of contraction-stimulated glucose uptake in skeletal muscle". Experimental Physiology 99 (12): 1574–80. doi:10.1113/expphysiol.2014.079194. PMID 25239922. 
  18. ^ Sylow L, Jensen TE, Kleinert M, Mouatt JR, Maarbjerg SJ, Jeppesen J, Prats C, Chiu TT, Boguslavsky S, Klip A, Schjerling P, Richter EA (Apr 2013). "Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle". Diabetes 62 (4): 1139–51. doi:10.2337/db12-0491. PMC 3609592. PMID 23274900. 
  19. ^ Mu J, Brozinick JT, Valladares O, Bucan M, Birnbaum MJ (May 2001). "A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle". Molecular Cell 7 (5): 1085–94. PMID 11389854. 
  20. ^ Sylow L, Møller LL, Kleinert M, Richter EA, Jensen TE (Feb 2015). "Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1". The Journal of Physiology 593 (3): 645–56. doi:10.1113/jphysiol.2014.284281. PMC 4324711. PMID 25416624. 
  21. ^ Lalioti VS, Vergarajauregui S, Pulido D, Sandoval IV (May 2002). "The insulin-sensitive glucose transporter, GLUT4, interacts physically with Daxx. Two proteins with capacity to bind Ubc9 and conjugated to SUMO1". The Journal of Biological Chemistry 277 (22): 19783–91. doi:10.1074/jbc.M110294200. PMID 11842083. 

Further reading[edit]

External links[edit]