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 ChEMBL: 5874 GeneCards: SLC2A4 Gene
Gene ontology Molecular function • sugar:proton symporter activity • glucose transmembrane transporter activity • protein binding • D-glucose transmembrane transporter activity Cellular component • multivesicular body • cytosol • plasma membrane • integral component of plasma membrane • coated pit • external side of plasma membrane • endomembrane system • vesicle membrane • membrane • clathrin-coated vesicle • trans-Golgi network transport vesicle • T-tubule • insulin-responsive compartment • membrane raft • perinuclear region of cytoplasm • extracellular exosome Biological process • carbohydrate metabolic process • hexose transport • amylopectin biosynthetic process • glucose transport • proton transport • cellular response to insulin stimulus • hexose transmembrane transport • glucose homeostasis • small molecule metabolic process • response to ethanol • glucose import • brown fat cell differentiation • transmembrane transport • membrane organization • cellular response to hypoxia • cellular response to osmotic stress 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	NM_009204
RefSeq (protein)	NP_001033	NP_033230
Location (UCSC)	Chr 17: 7.28 – 7.29 Mb	Chr 11: 69.94 – 69.95 Mb
PubMed search	[1]	[2]

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. The gene that encodes GLUT4 was cloned and mapped in 1989.

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.

Tissue distribution

GLUT4 is primarily found in:

• Skeletal muscle
• Cardiac muscle
• Adipose tissue

Regulation

Insulin

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. 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.

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 heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.

Muscle contraction

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.

Interactions

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

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]

File:WP534.png

Glycolysis and Gluconeogenesis edit

External links

• GLUT4 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• USCD—Nature molecule pages: The signaling pathway", "GLUT4"; contains a high-resolution network map. Accessed 25 December 2009.