**4.16. GLUT12** *(SLC2A12)*

GLUT12 was identified by 5' and 3' RACE-PCR from the human breast cancer cell line MCF-7. Strong GLUT12 expression is found in ductal cell carcinoma *in situ* when compared to benign ducts of breast cancer tissues. GLUT12 is mainly expressed in skeletal muscle, heart, small intestine, adipose tissue, and prostate. GLUT12 shows glucose transport when functionally characterized in *Xenopus laevis* oocytes that can be competed with fructose, galactose, 2-DG, and cytochalasin B. The transport activity of GLUT12 has been demonstrated to be affected by pH and in other reports by sodium, indicating its activity might be directly or indirectly coupled to an electrochemical gradient.

As a Class III isoform GLUT12 also contains a dileucine motif – both at the N-and C-terminal ends of the protein. Furthermore, the transporter does not contain GLUT12 contains a hydrophobic residue in position 314 which has been implicated in case of the isoleucine for GLUT2, 5, and 7 with the capability of fructose transport. This structural feature goes along with the substrate specificity of GLUT1. Endogenous as well as overexpressed GLUT12 protein localizes to intracellular compartments as well as to the plasma membrane in various cell lines. The N-terminal dileucine signal of GLUT12 is similar to that of GLUT8 which is the [DE]XXXL[LI] consensus sequence that represents a late endosomal/lysosomal sorting signal. However, GLUT12 does not colocalize with GLUT8, but rather resides in the Golgi network and at the plasma membrane. Plasma membrane associated GLUT12 is not endocytosed, which indicates the absence of a continuous cycling mechanism for GLUT12.

The phenotypic characterization of mice deficient in GLUT4 indicates the presence of a second transporter that facilitates insulin-stimulated glucose transport. Due to its tissue expression and its biological characteristics, GLUT12 was studied for its ability to respond to insulininduced plasma membrane translocation of the protein. Indeed, in human skeletal muscle insulin induces an increase in plasma membrane GLUT12 which is comparable to the insulinstimulated GLUT4 translocation. Although GLUT12 expression in skeletal muscle is unaltered under pathophysiological conditions such as of obesity and type 2 diabetes these data imply that an additional transporter is expressed in human muscle that is insulin-responsive in a PI3 kinase dependent manner. Mice with transgenic overexpression of GLUT12 display increased insulin sensitivity in insulin-sensitive tissues, while basal (non-stimulated) glucose uptake into adipose tissue and skeletal muscle was unaffected [36] indicating that GLUT12 might contrib‐ ute to insulin-stimulated glucose uptake in those tissues, an effect not observed in heart muscle. Besides its potential importance for substrate transport in insulin-sensitive tissues, GLUT12 also appears relevant in prostate and breast cancer. However, the physiological role and relevance for GLUT12 remains elusive [37].
