SLC2A4 Gene: A Promising Target for Pharmacogenomics of Insulin Resistance

Abstract

The SLC2A4 gene The GLUT4 protein, encoded by the solute carrier SLC2A4 gene in humans and Slc2a4 in mice and rats, is preferentially expressed in differentiated myotubes and adipocytes. Described in the early 1990s, GLUT4 is considered the insulin-sensitive glucose transporter based on its particular characteristic of being inserted in membranes of intracellular vesicles, which under insulin stimulus translocate to the plasma membrane, increasing the glucose uptake by these cells; the basis of postprandial glycemic control. Insulin-induced GLUT4 translocation is described as a much more robust phenomenon than it really is in vivo. In vitro translocation compares maximal insulin effect with the socalled basal condition in which insulin is absent. Whenever one tries to compare maximal insulin effect with basal physiological insulin concentrations, GLUT4 translocation is very low [1]. Besides, in skeletal muscle, GLUT4 translocation is also stimulated by muscle contraction, and contractile tonus is enough to induce great levels of translocation. However, a small relative translocation of GLUT4 (e.g., small percentage related to the total content) is able to significantly increase glucose uptake, avoiding impaired postprandial hyperglycemia. Unbelievably, several studies concerning GLUT4 translocation simply analyze the absolute amount of GLUT4 in plasma membrane. We point out that insulin induces vesicle translocation; and reduction in SLC2A4 expression (decreasing GLUT4 density in the vesicles) can explain decreased insulin-stimulated plasma membrane GLUT4 content, despite a preserved translocation system [2]. Finally, although some studies have proposed that molecular changes in the GLUT4 protein might alter its kinetics of transport, no consistent data has confirmed this hypothesis [3,4].