|, GLUT4, solute carrier family 2 member 4|
|RNA expression pattern|
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.
GLUT4 is primarily found in:
In striated muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction.
During exercise, the body needs to convert glucose to ATP to be used as energy. As G-6-P concentrations decrease, hexokinase becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This also means that muscle cells are able to take in more glucose as its intracellular concentrations decrease. GLUT4 is the primary transporter for facilitated diffusion of glucose into the cell. 
Although muscle contractions function in a similar way and also induce the translocation of GLUT4 into the plasma membrane, the two processes obtain different elements of intracellular GLUT4, either positive or negative. GLUT4-positive elements are utilized during insulin stimulation, while the negative elements are active during contractions.
Cardiac muscles are slightly different from skeletal muscles. As rest, they prefer to utilize fatty acids as their main energy source. As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.
An analysis of mRNA levels of GLUT1 and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles. GLUT4, however, is still believed to be the primary transporter for glucose.
Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell. 
Adipose tissue, commonly known as fat, is a depository for energy in order to conserve metabolic homeostasis. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen primarily in adipose tissue and liver or muscle cells.
As we eat and glucose levels increase, insulin is released from the pancreas and into the blood stream. Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors.
An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell hypertrophy and hyperplasia, which lead to obesity. In addition, mutations in GLUT4 genes in adipocytes can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. If GLUT4 is over-expressed, it can actually alter nutrient distribution and send excess glucose into adipose tissue, leading to increased adipose tissue mass.
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. RAC1 is a GTPase which is also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton  which allows for the GLUT4 vesicles to be inserted into the plasma membrane. RAC1 Knockout mouse have reduced glucose uptake in muscle.
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.
Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 are what allow it to transport glucose across the plasma membrane. In addition to the phenylalanine on the N-terminus, two Leucine residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of endocytosis and exocytosis. 
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. In skeletal muscle, muscle contraction increase GLUT4 translocation several fold  and this is likely regulated by RAC1  and AMP-activated protein kinase.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
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