**4.17. GLUT13; HMIT** *(SLC2A13)*

and an irregular vessel wall shape of arteries with increased elastic fibers. Furthermore, the animals displayed endothelial hypertrophy and disarranged elastic fibers that resulted in disruption of internal elastic lamina in the aorta. Neither group analyzed whether the muta‐ tions caused any dysfunction or loss of the target protein, therefore the reported phenotype of

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

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

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

those mice remains inconclusive with respect to GLUT10 function.

indicates the absence of a continuous cycling mechanism for GLUT12.

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

32 Glucose Homeostasis

coupled to an electrochemical gradient.

relevance for GLUT12 remains elusive [37].

Screening of public expressed sequence databases with the GLUT8 protein sequence identified a rat EST clone that allowed cloning of the rat and human HMIT (*SLC2A13*) cDNAs from spleen and frontal cortex cDNA libraries. Despite low level expression in adipose tissue and kidney, HMIT is predominantly expressed in the brain, with high expression found in hippocampus, hypothalamus, cerebellum and brainstem.

The HMIT amino acid sequence contains all motifs known to be important for glucose transport activity. As for other Class III GLUT family members, HMIT is restricted to an intracellular location. Functional characterization of the protein in *Xenopus laevis* oocytes and in mammalian cells has been possible through the introduction of various mutations that yielded significant plasma membrane expression. Surprisingly, no sugar transport activity has been found for HMIT. Instead, HMIT has been identified as a H+ -coupled myoinositol symporter with a *Km* of about 100 µM. More recently, HMIT has been shown to transport inositol-3-phosphate (IP3). HMIT is inhibited by the common GLUT inhibi‐ tors phloretin, phlorizin and cytochalasin B, although at high concentrations. Transloca‐ tion of HMIT to the plasma membrane has been demonstrated to occur in PC12 cells or primary neurons upon depolarization or protein kinase C (PKC) activation resulting in functional HMIT at the plasma membrane evidenced by increased myoinositol uptake in those cells. However, those initial findings were not reproduced by other groups leaving uncertainty about a stimulus that induces plasma membrane translocation of the transport‐ er. In the brain, myo-inositol serves as the precursor for phosphatidylinositol, a key regulator for various signaling pathways. Dysregulation of the phosphatidylinositol signaling has been implicated in psychiatric illness such as bipolar disorder. Standard therapies (lithium, valproic acid and carbamazepine) alter neuronal growth cone morphol‐ ogy, a phenotype that is reversed by extracellular myo-inositol. Because of its predomi‐ nant expression in the brain compared to two other myo-inositol transporters that are sodium-coupled (SMIT1 and SMIT2), interest has been raised as to whether HMIT might play a role in the regulation of myo-inositol/phosphatidylinositol physiology in neurons. Mice deficient for the transporter demonstrated that HMIT is not involved in the neuro‐ nal transport of inositol from the extracellular environment.
