GLUT4

Solute carrier family 2 (facilitated glucose transporter), member 4
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
Identifiers
Symbols	SLC2A4; GLUT4
External IDs	OMIM: 138190 MGI: 95758 HomoloGene: 74381 GeneCards: SLC2A4 Gene
Gene Ontology Molecular function • glucose transmembrane transporter activity • protein binding • substrate-specific transmembrane transporter activity • D-glucose transmembrane transporter activity Cellular component • integral to membrane of membrane fraction • membrane fraction • soluble fraction • cytoplasm • endosome • multivesicular body • microsome • plasma membrane • integral to plasma membrane • coated pit • external side of plasma membrane • vesicle membrane • clathrin-coated vesicle • trans-Golgi network transport vesicle • cytoplasmic vesicle membrane • vesicle • insulin-responsive compartment • sarcolemma • perinuclear region of cytoplasm • extracellular vesicular exosome Biological process • carbohydrate metabolic process • carbohydrate transport • hexose transport • glucose transport • glucose homeostasis • response to ethanol • glucose import • brown fat cell differentiation • transmembrane transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6517	20528
Ensembl	ENSG00000181856	ENSMUSG00000018566
UniProt	P14672	P14142
RefSeq (mRNA)	NM_001042.2	NM_009204.2
RefSeq (protein)	NP_001033.1	NP_033230.2
Location (UCSC)	Chr 17: 7.19 – 7.19 Mb	Chr 11: 69.76 – 69.76 Mb
PubMed search	[1]	[2]

Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose translocation into the cell. This protein is expressed primarily in muscle and fat cells, the major tissues in the body that respond to insulin. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

Tissue distribution

GLUT4 is primarily found in:

• Skeletal muscle
• Cardiac muscle
• Adipose tissue

Regulation

Insulin

Under conditions of low insulin, 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.

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.

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.

Knockout mice that are heterogenous for GLUT4 develop insulin resistance in their muscles as well as diabetes.

Contraction

Contraction also stimulates the cell to translocate GLUT4 receptors to the surface. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle.

Interactions

GLUT4 has been shown to interact with Death-associated protein 6.

Further reading

• Slot JW, Geuze HJ, Gigengack S, Lienhard GE, James DE (April 1991). "Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat". J. Cell Biol. 113 (1): 123–35. doi:10.1083/jcb.113.1.123. PMC 2288909. PMID 2007617. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2288909. 
• Govers R, Coster AC, James DE (July 2004). "Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway". Mol. Cell. Biol. 24 (14): 6456–66. doi:10.1128/MCB.24.14.6456-6466.2004. PMC 434240. PMID 15226445. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=434240. 
• Ng Y, Ramm G, Lopez JA, James DE (April 2008). "Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes". Cell Metab. 7 (4): 348–56. doi:10.1016/j.cmet.2008.02.008. PMID 18396141. 
• Foster LJ, Klip A (2000). "Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells". Am. J. Physiol., Cell Physiol. 279 (4): C877–90. PMID 11003568. 
• Bryant NJ, Govers R, James DE (2002). "Regulated transport of the glucose transporter GLUT4". Nat. Rev. Mol. Cell Biol. 3 (4): 267–77. doi:10.1038/nrm782. PMID 11994746. 
• Baumann MU, Deborde S, Illsley NP (2003). "Placental glucose transfer and fetal growth". Endocrine 19 (1): 13–22. doi:10.1385/ENDO:19:1:13. PMID 12583599. 
• Olson AL, Knight JB (2004). "Regulation of GLUT4 expression in vivo and in vitro". Front. Biosci. 8 (1-3): s401–09. doi:10.2741/1072. PMID 12700047. 
• McCarthy AM, Elmendorf JS (2007). "GLUT4's itinerary in health & disease". Indian J. Med. Res. 125 (3): 373–88. PMID 17496362. 
• Buse JB, Yasuda K, Lay TP, et al. (1992). "Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation". Diabetes 41 (11): 1436–45. doi:10.2337/diabetes.41.11.1436. PMID 1397719. 
• O'Rahilly S, Krook A, Morgan R, et al. (1992). "Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population". Diabetologia 35 (5): 486–89. doi:10.1007/BF02342449. PMID 1521731. 
• Liu ML, Olson AL, Moye-Rowley WS, et al. (1992). "Expression and regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice". J. Biol. Chem. 267 (17): 11673–36. PMID 1601840. 
• Choi WH, O'Rahilly S, Buse JB, et al. (1992). "Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects". Diabetes 40 (12): 1712–18. doi:10.2337/diabetes.40.12.1712. PMID 1756912. 
• Kusari J, Verma US, Buse JB, et al. (1991). "Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus". J. Clin. Invest. 88 (4): 1323–30. doi:10.1172/JCI115437. PMC 295602. PMID 1918382. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=295602. 
• Fukumoto H, Kayano T, Buse JB, et al. (1989). "Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues". J. Biol. Chem. 264 (14): 7776–79. PMID 2656669. 
• Chiaramonte R, Martini R, Taramelli R, Comi P (1993). "Identification of the 5' end of the gene encoding a human insulin-responsive glucose transporter". Gene 130 (2): 307–08. doi:10.1016/0378-1119(93)90438-9. PMID 7916714. 
• Verhey KJ, Birnbaum MJ (1994). "A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts". J. Biol. Chem. 269 (4): 2353–56. PMID 8300557. 
• Lee W, Samuel J, Zhang W, et al. (1997). "A myosin-derived peptide C109 binds to GLUT4-vesicles and inhibits the insulin-induced glucose transport stimulation and GLUT4 recruitment in rat adipocytes". Biochem. Biophys. Res. Commun. 240 (2): 409–14. doi:10.1006/bbrc.1997.7671. PMID 9388492. 
• Shi Y, Samuel SJ, Lee W, et al. (1999). "Cloning of an L-3-hydroxyacyl-CoA dehydrogenase that interacts with the GLUT4 C-terminus". Arch. Biochem. Biophys. 363 (2): 323–32. doi:10.1006/abbi.1998.1088. PMID 10068455. 
• Abel ED, Kaulbach HC, Tian R, et al. (2000). "Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart". J. Clin. Invest. 104 (12): 1703–14. doi:10.1172/JCI7605. PMC 409881. PMID 10606624. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=409881. 
• Abel ED, Peroni O, Kim JK, et al. (2001). "Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver". Nature 409 (6821): 729–33. doi:10.1038/35055575. PMID 11217863. 

External links

• MeSH GLUT4+Protein
• USCD—Nature molecule pages: The signaling pathway", "GLUT4"; contains a high-resolution network map. Accessed 25 December 2009.