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SGLT1 (sodium/glucose cotransporter 1)

Aliases: D22S675, NAGT
Gene name:  Solute carrier family 5 member 1 (SLC5A1)


SGLT1, a member of the solute carrier family SLC5 [1], is a high-affinity Na+/glucose cotransporter [2]. SGLT1 transports glucose and galactose across the luminal (gut) side of enterocytes, and is the first step in the absorption of sugars from nutrients. In the kidney, SGLT1 is located on the apical (urine) side of the proximal tubule, and facilitates the reabsorption of urinary glucose from the glomerular filtrate [3].


SGLT1 is mainly expressed on the apical membrane (i.e. the gut side) of enterocytes.  It is also present in the kidney (in the latter part of renal proximal tubule), the heart, and the parotid and submandibular salivary glands [4-6].

Function, physiology, and clinically significant polymorphisms

SGLT1 is a 75-kDa membrane protein with 14 transmembrane α-helices, an extracellular amino terminus and an intracellular carboxyl terminus [1, 4]. SGLT1 is responsible for the sodium-dependent, active uptake of glucose across the apical membrane of the small intestine.  In the kidney, SGLT1 is responsible for about 10% of the tubular glucose reabsorption [7].  Another member of the SLC5 family, SGLT2 (SLC5A2) is the primary renal glucose transporter. The final steps of glucose oral absorption and renal reabsorption are primarily facilitated by another transporter family – the SLC2A or GLUTs.  SGLTs and GLUTs perform other important physiological roles, too, particularly in water absorption [4].
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 and SGLT2, naturally present in the bark of the apple and other fruit trees [4].

Clinical significance

Glucose transporter inhibitors are under evaluation as therapeutic agents to treat type 2 diabetes [8].  The selective SGLT1 inhibitor KGA 2727 has been developed as an antidiabetic agent, and it efficiently blocks the transporter function in cells overexpressing SGLT1 [9]. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Although diarrhea is a common consequence of intestinal glucose retention, LX4211 was well tolerated without evidence of increased gastrointestinal side effects [10]. The selective SGLT1 inhibitor GSK-1614235 blocked glucose absorption but also impaired glucose-dependent insulinotropic peptide release in a Phase I clinical trial [11].
Glucose-galactose malabsorption (GGM, OMIM 182380) is a rare inherited autosomal recessive disease caused by mutations in the coding sequence of the SGLT1 [12]. 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 [12, 13]. 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 co-transport and sodium/glucose-induced osmosis, the latter resulting from sodium and glucose co-transport via SGLT1 in the apical membrane of the enterocytes [14].

Regulatory requirements

Glucose transporters are not significantly involved in DDI or drug ADME, and therefore do not feature in FDA or EMA guidances.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors
intestine, kidney, salivary gland, heart D-glucose, D-galactose α-methyl-d-glucopyranoside   phlorizin and derivatives, KGA 2727, LX4211, GSK-1614235



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.    Lehmann, A. and P.J. Hornby, Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol, 2016. 310(11): p. G887-98.
3.    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.
4.    Wright, E.M., et al., Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda). 2004. 19: p. 370-6.
5.    Zhou, L., et al., Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem., 2003. 90(2): p. 339-46.
6.    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.
7.    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.
8.    Song, P., et al., Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets, 2016. 20(9): p. 1109-25.
9.    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.
10.    Zambrowicz, B., et al., LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther, 2012. 92(2): p. 158-69.
11.    Dobbins, R.L., et al., Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol, 2015. 308(11): p. G946-54.
12.    Turk, E., et al., Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature., 1991. 350(6316): p. 354-6.
13.    Melin, K. and G.W. Meeuwisse, Glucose-galactose malabsorption. A genetic study. Acta Paediatr Scand, 1969. 188.
14.    Hirschhorn, N. and W.B. Greenough, 3rd, Progress in oral rehydration therapy. Sci Am., 1991. 264(5): p. 50-6.


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