GLUT4

Glucose transporter type 4, also known as GLUT4, is a is_associated_with::protein encoded, in humans, by the GLUT4 is_associated_with::gene. GLUT4 is the is_associated_with::insulin-regulated is_associated_with::glucose transporter found primarily in is_associated_with::adipose tissues and is_associated_with::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:
 * is_associated_with::Skeletal muscle
 * is_associated_with::Cardiac muscle
 * is_associated_with::Adipose tissue

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 is_associated_with::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 is_associated_with::PIP2 to is_associated_with::PIP3. PIP3 is specifically recognized by the PH domains of PKB (is_associated_with::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 is_associated_with::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 is_associated_with::phosphorylated by is_associated_with::glucokinase in the liver and is_associated_with::hexokinase in other tissues to form is_associated_with::glucose-6-phosphate, which then enters is_associated_with::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 is_associated_with::insulin resistance in their muscles as well as is_associated_with::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.