**2.8. SGLT5 (***SLC5A10***)**

SGLT5 was recently cloned from human kidney cDNA and characterized as a kidney specific sodium-dependent mannose transporter which is also able to transport glucose and fructose [19]. While specifically expressed in human kidney its precise localization and physiological role remains unknown. Based on amino acid sequence homology SGLT5 represents the closest homologue to SGLT4. In a manner reminiscent of the relationship between SGLT1 and SGLT2, it can be speculated that SGLT4 and SGLT5 may act as complementary mannose transporters that regulate intestinal absorption and renal reabsorption of mannose, respectively.

like neurobehavioral effects. Potentially, the inositol depletion hypothesis as a mode of action for lithium might be supported by the phenotypic characteristics of SMIT1 knockout mice [21].

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 17

SMIT2 was initially cloned by PCR from rabbit kidney cDNA. Sequence analysis indicated 49% and 43% protein sequence identity to SGLT1 and SMIT1, respectively. SMIT2 mRNA is detected in brain, kidney, heart, skeletal muscle, spleen, liver, placenta, lung, leukocytes, and neurons. Three transcript variants named SMIT1a, SMIT1b, and SMIT1c have been identified for the *SLC5A2* gene. It wasn't until 2002, that the cloned product was functionally character‐ ized and identified as a sodium-coupled myoinositol transporter with a Km of 120 µM and 13 mM for myoinositol and sodium, respectively [22]. Transport mediated by SMIT2 is phlorizin

different: SMIT2 shows stereospecific transport of D-glucose and D-xylose without affinity for fucose, while SMIT1 transports L-fucose and L-xylose (but not their D-isomers) and does not distinguish between D-and L-glucose. In contrast to SMIT1, SMIT2 transports d-*chiro*-inositol.

SMIT2 mediated myo-inositol transport has been demonstrated to occur at apical membranes of the rat intestine [23] and at the luminal side of of proximal convoluted tubules in the kidney of rabbits [24], a tissue specificity and principle role that appears similar to the sodium-

Glucose transporters are uniporters that facilitate the diffusion of their respective substrates (e.g. glucose) across cellular membranes along a concentration gradient [2, 4]. The protein family comprises 14 isoforms that share common structural features such as 12 transmembrane domains, N-and C-termini facing the cytoplasm of the cell and an N-glycosylation site within either the first or fifth extracellular loop. Based on their sequence homology (14-63% identity) three classes can be distinguished: Class I includes the 'classic' glucose transporters GLUT1-4 and GLUT14, the Class II members are GLUT5, 7, 9, 11, and the Class III transporters comprise GLUT6, 8, 10, 12 and the proton driven myo-inositol transporter HMIT (or GLUT13). Despite their structural similarities, the different isoforms are characterized by tissue specific expres‐ sion and distinct characteristics such as alternative splicing and (sub) cellular localization. With respect to their substrate specificities, the protein family includes transporters of glucose (GLUT1-4, 8, 14), fructose (GLUT5, 7, 11), polyol (GLUT12), myo-inositol (GLUT13), and urea

dependent uptake and reabsorption of glucose mediated by SGLT-1.

GLUT1-14, Gene Symbols: *SLC2A1-14*, solute carrier family 2A1-14

**3. The family of glucose transport facilitators**

of 76 µm). The substrate specificities of SMIT1 and SMIT2 are remarkably

**2.10. SGLT6 /SMIT2 (***SLC5A11***)**

sensitive (Ki

**3.1. Synonyms**

**3.2. Summary**

(GLUT9) transporters.

#### *Mouse models of SGLT5 deficiency*

Mice deficient for SGLT5 [20] were shown not to display any renal sodium-dependent fructose uptake but increased urinary fructose indicating that SGLT5 is the major transporter respon‐ sible for fructose reabsorption in the kidney. Fructose consumption especially by corn syrup containing beverages has been epidemiologically linked to dyslipidemia, obesity, and diabetes. Despite its role in renal fructose reuptake, knockout of SGLT5 in mice paradoxically exacerbated fructose-induced hepatic steatosis.

The massive urinary fructose excretion was accompanied by reduced levels of plasma triglycerides and epididymal fat but fasting hyperinsulinemia. No difference in food con‐ sumption, water intake, or plasma fructose was described for SGLT5 deficient mice. The phenotype of SGLT5 knockout mice indicated an apparent link between renal fructose reabsorption and hepatic lipid metabolism.

#### **2.9. SMIT1 (***SLC5A3***)**

A Na(+)/myoinositol cotransporter cDNA (SLC5A3) was cloned from canine renal cells and sequenced in 1992 followed by the human SLC5A3 in 1995. The human transporter is mainly expressed in kidney, brain, placenta, pancreas, heart, skeletal muscle, and the lung.

#### *2.9.1. SMIT1 physiology*
