GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac).

GLUT4 is distinctive because it is predominantly stored within intracellular vesicles, highlighting the importance of its trafficking and regulation as a central area of research.

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.

[10] Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 is what allows 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.

As G-6-P concentrations decrease, hexokinase becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed.

[20] 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.

As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen (primarily in the liver, muscle cells), or as triglyceride in adipose tissue.

[29] The mechanism for GLUT4 is an example of a cascade effect, where binding of a ligand to a membrane receptor amplifies the signal and causes a cellular response.

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 stimulates reorganization of the cortical Actin cytoskeleton[31] which allows for the GLUT4 vesicles to be inserted into the plasma membrane.

[40][41] This mechanism remains functional in insulin-resistant states, establishing the muscle-contraction pathway's independence from insulin stimulation.

Phosphorylation of TBC1D1/4 inactivates it, allowing Rab proteins to load GTP and directly participate in the trafficking of GLUT4 to the membrane.

[46] In addition, 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.