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

it can be speculated that SGLT4 and SGLT5 may act as complementary mannose transporters

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

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

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

Myoinositol is a precursor of the main inositol-containing phospholipids phosphatidylinositol and phosphatidylinositol-4,5-bisphosphate, a key molecule in cellular signal transduction. In addition, myoinositol has an important role in osmoregulation. The highest myoinositol levels are found in certain regions of the brain with cerebrospinal fluid levels ranging from 2-25 mM,

One hypothesis as to why lithium is effective in the treatment of bipolar disorders is based on its effect on reducing cellular concentrations of myoinositol (the inositol depletion model). Ablation of the murine *SLC5A3* gene demonstrated the significant role of this transporter in maintaining central myoinositol concentrations. SMIT1 knockout mice have significantly reduced central inositol levels with no changes in phosphatidylinositol concentrations. Besides the severe myoinositol deficiency in the brain, those animals display congenital central apnea due to abnormal respiratory rhythmogenesis leading to death shortly after birth. The neonatal lethality of SMIT1 knockout animals appears to be caused by failures in development of peripheral nerves, specifically in nerves controlling breathing. The peripheral nerve abnor‐ malities can be corrected by prenatal myoinositol supplementation suggesting that myoino‐ sitol is required for peripheral nerve development. Phenotypic analysis of homozygous SMIT1 knockout mice indicated, that a reduction of central inositol levels is associated with lithium-

expressed in kidney, brain, placenta, pancreas, heart, skeletal muscle, and the lung.

that regulate intestinal absorption and renal reabsorption of mannose, respectively.

*Mouse models of SGLT5 deficiency*

16 Glucose Homeostasis

exacerbated fructose-induced hepatic steatosis.

reabsorption and hepatic lipid metabolism.

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

*2.9.1. SMIT1 physiology*

*Phenotype of mice deficient for SMIT1*

which are higher than levels in the blood.

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 sensitive (Ki of 76 µm). The substrate specificities of SMIT1 and SMIT2 are remarkably 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 sodiumdependent uptake and reabsorption of glucose mediated by SGLT-1.
