SGLT1

Related Services

Interested in FDA or EMA Compliant Transporter Studies?

SGLT1 transporter (Sodium-glucose cotransporter 1)

SGLT1 is a member of the solute carrier family SLC5 [1]. This transporter is a high affinity Na+/glucose cotransporter which is encoded by the SLC5A1 gene. SGLT1 transporter plays a key role in the translocation of sugar across epithelial cells in the small intestine and in the renal proximal tubule [2].

Localization

SGLT1 is expressed mainly in the intestine, but has also been detected in the kidney (in the late part of renal proximal tubule), the heart, and the parotid and submandibular salivary glands [3-5].

Function, physiology and clinically significant polymorphisms

SGLT1 is a 75-kDa membrane protein which contains 14 transmembrane α-helices, with an extracellular amino-terminus and an intracellular carboxy-terminus [1, 3]. SGLT1 is responsible for the active transport of glucose across the brush border membrane of the small intestine and also plays an important role in water absorption [3]. In the kidney, SGLT1 is responsible for about 10% of the tubular glucose reabsorption [6].
SGLT1 has a high affinity but a low capacity for transporting glucose. The preferred substrates of SGLT1 are D-glucose and D-galactose, whereas mannose (or 2-deoxy-D-glucose) is only slightly transported.  Phlorizin is a high affinity, non-transported competitive inhibitor (Ki ~ 0.2 µM) of SGLT1, naturally present in apple tree bark [3].

Clinical significance

Glucose-galactose malabsorption (GGM, OMIM 182380) is a rare disease with autosomal recessive inheritance. Mutations in the coding sequence of the SGLT1 gene are responsible for this disorder [7]. Symptoms present in neonates with the onset of watery and acidic diarrhea, which occur due to water retention in the intestinal lumen caused by the osmotic loss generated by non-absorbed glucose, galactose and sodium in the intestine [7, 8]. Oral rehydration therapy (ORT) is an effective treatment for GGM, in which sodium and glucose are offered together with water for intestinal absorption. Water is then absorbed by direct cotransport and sodium/glucose-induced osmosis, the latter resulting from sodium and glucose co-transport via SGLT1 in the apical membrane of the enterocytes [9].
Recently, a new selective SGLT1 inhibitor KGA 2727 has been developed as an antidiabetic agent, which efficiently blocks the transporter function in cells overexpressing SGLT1 [10].
 

Regulatory Requirements

To date, there is no FDA or EMA recommendation for SGLT1.

Location
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Intestine,Kidney,Salivary gland, Heart
D-glucose D-galactose
α-methyl-d-glucopyranoside
Phlorizin and derivatives

References

  1. Wright, E.M. and E. Turk, The sodium/glucose cotransport family SLC5. Pflugers Arch., 2004. 447(5): p. 510-8. Epub 2003 May 14.
  2. Castaneda-Sceppa, C. and F. Castaneda, Sodium-dependent glucose transporter protein as a potential therapeutic target for improving glycemic control in diabetes. Nutr Rev., 2011. 69(12): p. 720-9. doi: 10.1111/j.1753-4887.2011.00423.x.
  3. Wright, E.M., et al., Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda). 2004. 19: p. 370-6.
  4. Zhou, L., et al., Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem., 2003. 90(2): p. 339-46.
  5. Sabino-Silva, R., et al., Na+-glucose cotransporter SGLT1 protein in salivary glands: potential involvement in the diabetes-induced decrease in salivary flow. J Membr Biol., 2009. 228(2): p. 63-9. Epub 2009 Feb 24.
  6. Wright, E.M., B.A. Hirayama, and D.F. Loo, Active sugar transport in health and disease. J Intern Med., 2007. 261(1): p. 32-43.
  7. Turk, E., et al., Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature., 1991. 350(6316): p. 354-6.
  8. Melin, K. and G.W. Meeuwisse, Glucose-galactose malabsorption. A genetic study. Acta Paediatr Scand, 1969. 188.
  9. Hirschhorn, N. and W.B. Greenough, 3rd, Progress in oral rehydration therapy. Sci Am., 1991. 264(5): p. 50-6.
  10. Shibazaki, T., et al., KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther., 2012. 342(2): p. 288-96. Epub 2012 Apr 26.

 


Think twice!