GLUT4

GLUT4, also known as SLC2A4, is a facilitative glucose transporter predominantly expressed in adipose tissue and skeletal muscle, with some expression in heart. It is one of several GLUT isoforms, but unlike others, GLUT4 is not continuously present on the cell surface.

In adipocytes and muscle cells, GLUT4 resides in intracellular storage vesicles (GLUT4 storage vesicles, GSVs) under basal conditions. After insulin binding to its receptor, a signaling cascade via IRS proteins, phosphoinositide 3-kinase, and AKT2 promotes translocation of GSVs to the plasma membrane, increasing glucose uptake. AS160/TBC1D4 phosphorylation relieves Rab-mediated retention, enabling vesicle fusion with the membrane through SNARE and exocytic machinery. Exercise and other stimuli can also trigger GLUT4 translocation via AMPK and related pathways, partially independent of insulin.

The transporter is then internalized when signaling wanes and recycled back to intracellular vesicles, allowing dynamic control of glucose uptake. This cycle enables rapid adjustment to changing metabolic needs.

Clinically, GLUT4 function is central to postprandial glucose disposal. Reduced GLUT4 expression or impaired translocation is associated with insulin resistance, obesity, and type 2 diabetes. Interventions such as endurance exercise, weight loss, and certain pharmacological agents can enhance GLUT4 translocation and expression, improving glucose homeostasis.

The SLC2A4 gene encodes GLUT4 in humans; its expression is regulated by insulin, energy status, and other hormonal signals. GLUT4 orthologs are conserved in mammals and other vertebrates, reflecting a key role in glucose homeostasis.