SGLT6

SGLT6 (sodium/glucose cotransporter 6)

Aliases: KST1, SMIT2

Gene name: Solute carrier family 5 member 11 (SLC5A11)

Summary

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 K_m 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.

Localization

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) [7] and on a stably SGLT6-transfected cell line (MDCK-SMIT2) [6], 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 [8].

Function, physiology, and clinically significant polymorphisms

The chromosomal location of the SLC5A11 gene is 16p12.1 [4]. 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 [9]. 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 [10]. 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 [3].
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 [14], dapagliflozin and phlorizin [9], a potent and central nervous system-penetrable inhibitor termed “Cpd B” was developed to selectively block SGLT6 [5].
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 [19]. 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 [5].
Although several non-pathogenic mutations were found within the coding sequence of the SLC5A11 gene [1], no gene variants with disease associations have been described.

Clinical significance

Conditions in the brain such as trauma [20], 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 [24].
D-chiro-inositol transport is upregulated by insulin and competitively inhibited by millimolar levels of glucose (K_i of 6.1 mM [3]). 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 [13].
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 [25].
 

Regulatory requirements

The current guidelines from FDA and EMA do not contain recommendations on in vitro testing of NCEs for SGLT6 inhibition.