Aliases: KST1, SMIT2
Gene name: Solute carrier family 5 member 11 (SLC5A11)
SGLT6, also known as the sodium/myo-inositol transporter 2 (SMIT2), is a member of the Na-glucose cotransporter (SGLT, SLC5) family that consists of 12 members involved in the Na-coupled transport of sugars, iodide, monocarboxylates, and vitamins. The 66-kDa protein expressed from the SLC5A11 gene cotransports myo-inositol (MI) with a Km of 120 μM. SGLT6 also exhibits stereospecific cotransport of both D-glucose and D-xylose but does not transport L-fucose. D-chiro-inositol (DCI) – a stereoisomer of MI – is a preferred substrate of SGLT6 with a Km of 111 μM but not of the sodium/MI cotransporter-1 (SMIT1, SLC5A3). SGLT6 shares functional similarities with SMIT1 such as high affinity for MI, overall substrate and inhibitor specificities, and 2:1 Na+-MI stoichiometry, but they have some differences in tissue distribution. With potential roles in nutrient sensing and brain osmoregulation proposed in animal models but not confirmed in humans, the physiological functions of SGLT6 remain largely unknown. The current guidelines from FDA and EMA do not contain recommendations on in vitro testing of NCEs for SGLT6 inhibition.
SGLT6 is chiefly expressed in the small intestine, kidney, brain and spinal cord, with weaker expression detected in the heart, skeletal muscle, liver, and placenta [1-5]. Unlike SMIT1, which is highly expressed in the kidney medulla, SGLT6 is predominantly located in the kidney cortex where it is expressed at the apical domain of proximal tubule cells [6, 7]. Based on MI uptake studies performed on purified rabbit kidney brush border membrane vesicles (BBMv)  and on a stably SGLT6-transfected cell line (MDCK-SMIT2) , SGLT6 transporter is believed to be responsible for the reabsorption of MI from the glomerular filtrate in rabbits. In rats, SGLT6 is expressed at the apical membrane of enterocytes and is responsible for all MI absorption, while the rabbit intestine appears to lack apical transport of MI .
Function, physiology, and clinically significant polymorphisms
The chromosomal location of the SLC5A11 gene is 16p12.1 . The SGLT6-coding gene is divided into 16 exons, extending over more than 75 kb of genomic sequence. The SGLT6 protein is believed to share the five-transmembrane segment inverted repeat with the LeuT structural family . The presence of the inverted repeat architecture is a strong support for the alternate access mechanism where the displacement of two broken helices is thought to provide access of the binding sites to one side of the membrane at a time . Human SGLT6 displays 23% sequence identity and 43% similarity with the crystallized bacterial homolog vSGLT [10, 11], and among SGLTs it has the lowest (50%) amino acid identity with the prototype family member SGLT1 .
Functional analysis of rat SGLT6 revealed high affinities for myo-inositol (0.150 ± 0.040 mM), D-chiro-inositol (0.31 ± 0.06 mM), and phlorizin (0.016 ± 0.007 mM); low affinity for glucose (36 ± 7 mM); and no affinity for L-fucose [8, 12]. D-chiro-inositol (DCI) – a stereoisomer of MI – is a preferred substrate of SGLT6 with a Km of 111 μM but not of sodium/MI cotransporter-1 (SMIT1) [3, 13]. Beside potent generic SGLT inhibitors such as canagliflozin , dapagliflozin and phlorizin , a potent and central nervous system-penetrable inhibitor termed “Cpd B” was developed to selectively block SGLT6 .
The relevance of SGLT6 to human physiology is largely unexplored. Myo-inositol, synthetized from glucose 6-phosphate through the intermediate inositol 1-phosphate, is an important organic osmolyte that helps maintain cellular osmotic pressure and is thought to protect tissues, especially the brain, against osmotic disturbances. MI can maintain an ideal osmotic state even when a cell is placed in a hypertonic environment. When osmolarity increases, intracellular MI concentration may rise to 500-fold above its plasma concentration of ~30 µM [15-17]. To reach such high intracellular MI concentrations, secondary active transport systems like SGLT6, as well as the sodium/myo-inositol transporter 1 (SMIT1), and HMIT, a H+/MI cotransporter from a completely different protein family [8, 18], are required.
A role for SLGT6 in guiding the sugar preference of fruit flies was proposed based on the observation that whereas wild-type Drosophila flues choose D-glucose when hungry and shift their preference for the sweeter but non-caloric L-glucose when fed, dSLC5A11-deficient flies prefer L-glucose over D-glucose independently of their state of satiety . In mice, however, potent inhibition of SGLT6 by Cpd B did not result in a significant change on sugar preference, indicating that in mammals SGLT6 does not play a major role in post-ingestive nutrient sensing .
Although several non-pathogenic mutations were found within the coding sequence of the SLC5A11 gene , no gene variants with disease associations have been described.
Conditions in the brain such as trauma , edema and hypernatremia [21-23] have been shown to increase MI level. SGLT6 is the major contributor to myo-inositol transport into the brain parenchyma, and along with other myo-inositol transporters it responds to ischemic stroke by increased myo-inositol uptake into astrocytes, thus protecting them against ischemia-reperfusion injury .
D-chiro-inositol transport is upregulated by insulin and competitively inhibited by millimolar levels of glucose (Ki of 6.1 mM ). Therefore, the expression and/or function of SGLT6 may be reduced in diabetes mellitus, insulin resistance and polycystic ovary syndrome, causing the abnormal DCI metabolism observed in these conditions .
The SLC5A11 gene was identified as an autoimmune modifier gene that interacts with immune-related genes in systemic lupus erythematosus. SLC5A11 may induce apoptosis via the tumor necrosis factor-alpha (TNF-α) pathway .
The current guidelines from FDA and EMA do not contain recommendations on in vitro testing of NCEs for SGLT6 inhibition.
In vitro substrates used experimentally
small intestine, kidney cortex, brain and spinal cord, heart, skeletal muscle, liver, placenta
myo-inositol, D-chiro-inositol, D-glucose
myo-inositol, D-chiro-inositol, D-glucose, D-xylose, L-glucose
glucose, canagliflozin, dapagliflozin, phlorizin, Cpd B
1. Roll, P., et al., New human sodium/glucose cotransporter gene (KST1): identification, characterization, and mutation analysis in ICCA (infantile convulsions and choreoathetosis) and BFIC (benign familial infantile convulsions) families. Gene, 2002. 285(1-2): p. 141-8.
2. Whaley, J.M., et al., Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus. Diabetes Metab Syndr Obes, 2012. 5: p. 135-48.
3. Wright, E.M., D.D. Loo, and B.A. Hirayama, Biology of human sodium glucose transporters. Physiol Rev, 2011. 91(2): p. 733-94.
4. Chen, J., et al., Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther, 2010. 1(2): p. 57-92.
5. Baader-Pagler, T., et al., SGLT6 - A pharmacological target for the treatment of obesity? Adipocyte, 2018. 7(4): p. 277-284.
6. Bissonnette, P., M.J. Coady, and J.Y. Lapointe, Expression of the sodium-myo-inositol cotransporter SMIT2 at the apical membrane of Madin-Darby canine kidney cells. J Physiol, 2004. 558(Pt 3): p. 759-68.
7. Lahjouji, K., et al., Expression and functionality of the Na+/myo-inositol cotransporter SMIT2 in rabbit kidney. Biochim Biophys Acta, 2007. 1768(5): p. 1154-9.
8. Aouameur, R., et al., SMIT2 mediates all myo-inositol uptake in apical membranes of rat small intestine. Am J Physiol Gastrointest Liver Physiol, 2007. 293(6): p. G1300-7.
9. Sasseville, L.J., et al., The transport mechanism of the human sodium/myo-inositol transporter 2 (SMIT2/SGLT6), a member of the LeuT structural family. Am J Physiol Cell Physiol, 2014. 307(5): p. C431-41.
10. Krishnamurthy, H., C.L. Piscitelli, and E. Gouaux, Unlocking the molecular secrets of sodium-coupled transporters. Nature, 2009. 459(7245): p. 347-55.
11. Faham, S., et al., The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science, 2008. 321(5890): p. 810-4.
12. Coady, M.J., et al., Identification of a novel Na+/myo-inositol cotransporter. J Biol Chem, 2002. 277(38): p. 35219-24.
13. Lin, X., et al., Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells. Arch Biochem Biophys, 2009. 481(2): p. 197-201.
14. Demin, O., Jr., et al., Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model. Front Pharmacol, 2014. 5: p. 218.
15. Clements, R.S., Jr. and A.G. Diethelm, The metabolism of myo-inositol by the human kidney. J Lab Clin Med, 1979. 93(2): p. 210-9.
16. Dawson, R.M. and N. Freinkel, The distribution of free mesoinositol in mammalian tissues, including some observations on the lactating rat. Biochem J, 1961. 78: p. 606-10.
17. Dolhofer, R. and O.H. Wieland, Enzymatic assay of myo-inositol in serum. J Clin Chem Clin Biochem, 1987. 25(10): p. 733-6.
18. Uldry, M., et al., Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J, 2001. 20(16): p. 4467-77.
19. Dus, M., M. Ai, and G.S. Suh, Taste-independent nutrient selection is mediated by a brain-specific Na+ /solute co-transporter in Drosophila. Nat Neurosci, 2013. 16(5): p. 526-8.
20. Pascual, J.M., et al., Time course of early metabolic changes following diffuse traumatic brain injury in rats as detected by (1)H NMR spectroscopy. J Neurotrauma, 2007. 24(6): p. 944-59.
21. Lien, Y.H., J.I. Shapiro, and L. Chan, Effects of hypernatremia on organic brain osmoles. J Clin Invest, 1990. 85(5): p. 1427-35.
22. Lien, Y.H., J.I. Shapiro, and L. Chan, Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis. J Clin Invest, 1991. 88(1): p. 303-9.
23. Yamashita, T., et al., Induction of Na+/myo-inositol co-transporter mRNA after rat cryogenic injury. Brain Res Mol Brain Res, 1997. 46(1-2): p. 236-42.
24. Villalba, H., et al., Potential role of myo-inositol to improve ischemic stroke outcome in diabetic mouse. Brain Res, 2018. 1699: p. 166-176.
25. Tsai, L.J., et al., The sodium-dependent glucose cotransporter SLC5A11 as an autoimmune modifier gene in SLE. Tissue Antigens, 2008. 71(2): p. 114-26.