Sodium-glucose transport proteins

Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST). They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT, via SGLT2). If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

solute carrier family 5 (sodium/glucose cotransporter), member 1
Identifiers
SymbolSLC5A1
Alt. symbolsSGLT1
NCBI gene6523
HGNC11036
OMIM182380
RefSeqNM_000343
UniProtP13866
Other data
LocusChr. 22 q13.1
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StructuresSwiss-model
DomainsInterPro
solute carrier family 5 (sodium/glucose cotransporter), member 2
Identifiers
SymbolSLC5A2
Alt. symbolsSGLT2
NCBI gene6524
HGNC11037
OMIM182381
RefSeqNM_003041
UniProtP31639
Other data
LocusChr. 16 p11.2
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StructuresSwiss-model
DomainsInterPro
solute carrier family 5 (low affinity glucose cotransporter), member four
Identifiers
SymbolSLC5A4
Alt. symbolsSGLT3, SAAT1, DJ90G24.4
NCBI gene6527
HGNC11039
RefSeqNM_014227
UniProtQ9NY91
Other data
LocusChr. 22 q12.1-12.3
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StructuresSwiss-model
DomainsInterPro

Types

The two most well known members of SGLT family are SGLT1 and SGLT2, which are members of the SLC5A gene family. In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A.[1] Of these, SLC5A4/SGLT3 (SAAT1) is a low-affinity transporter for glucose, but seems to have more of an electric function.[2]

GeneProteinAcronymTissue distribution
in proximal tubule[3]		Na+:Glucose
Co-transport ratio		Contribution to glucose
reabsorption (%)[4]
SLC5A1Sodium/GLucose
coTransporter 1		SGLT1S3 segment2:110
SLC5A2Sodium/GLucose
coTransporter 2		SGLT2predominantly in the
S1 and S2 segments		1:190

The other SLC5 proteins transport mannose, myo-inositol, choline, iodide, vitamins, and short-chain fatty acids.[2]

SGLT2 inhibitors for diabetes
Main article: Gliflozin

SGLT2 inhibitors, also called gliflozins,[5] are used in the treatment of type 2 diabetes. SGLT2 is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include dapagliflozin (Farxiga in US, Forxiga in EU), canagliflozin (Invokana) and empagliflozin (Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes.[6] The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.[7]

Function

Firstly, an Na+/K+ ATPase on the basolateral membrane of the proximal tubule cell uses ATP molecules to move 3 sodium ions outward into the blood, while bringing in 2 potassium ions. This action creates a downhill sodium ion gradient from the outside to the inside of the proximal tubule cell (that is, in comparison to both the blood and the tubule itself).

The SGLT proteins use the energy from this downhill sodium ion gradient created by the ATPase pump to transport glucose across the apical membrane, against an uphill glucose gradient. These co-transporters are an example of secondary active transport. Members of the GLUT family of glucose uniporters then transport the glucose across the basolateral membrane, and into the peritubular capillaries. Because sodium and glucose are moved in the same direction across the membrane, SGLT1 and SGLT2 are known as symporters. Of course, sodium can deplete, so Sodium–hydrogen antiporter gets sodium into the cell to begin with. Therefore, glucose actually moved with net protons being pushed out of cell, sodium being the intermediate.

History

In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption.[8]

Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.[9][10]

See also

References
  1. Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509
  2. Gyimesi, Gergely; Pujol-Giménez, Jonai; Kanai, Yoshikatsu; Hediger, Matthias A. (September 2020). "Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application". Pflügers Archiv: European Journal of Physiology. 472 (9): 1177–1206. doi:10.1007/s00424-020-02433-x.
  3. Wright EM, Hirayama BA, Loo DF (January 2007). "Active sugar transport in health and disease". Journal of Internal Medicine. 261 (1): 32–43. doi:10.1111/j.1365-2796.2006.01746.x. PMID 17222166. S2CID 44399123.
  4. Wright EM (January 2001). "Renal Na(+)-glucose cotransporters". American Journal of Physiology. Renal Physiology. 280 (1): F10–8. doi:10.1152/ajprenal.2001.280.1.F10. PMID 11133510.
  5. "SGLT2 Inhibitors (Gliflozins)". Diabetes.co.uk. Retrieved 2015-05-19.
  6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. (November 2015). "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes". The New England Journal of Medicine. 373 (22): 2117–28. doi:10.1056/NEJMoa1504720. hdl:11573/894529. PMID 26378978. S2CID 205098095.
  7. Research, Center for Drug Evaluation and (2018-12-28). "Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors". FDA.
  8. Miller D, Bihler I (1961). "The restrictions on possible mechanisms of intestinal transport of sugars". In Kleinzeller A. Kotyk A (ed.). Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Czech Academy of Sciences & Academic Press. pp. 439–449.
  9. Wright EM, Turk E (February 2004). "The sodium/glucose cotransport family SLC5". Pflügers Archiv. 447 (5): 510–8. doi:10.1007/s00424-003-1063-6. PMID 12748858. S2CID 41985805. Crane in 1961 was the first to formulate the cotransport concept to explain active transport [7]. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across the brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type.
  10. Boyd CA (March 2008). "Facts, fantasies and fun in epithelial physiology". Experimental Physiology. 93 (3): 303–14. doi:10.1113/expphysiol.2007.037523. PMID 18192340. S2CID 41086034. p. 304. "the insight from this time that remains in all current text books is the notion of Robert Crane published originally as an appendix to a symposium paper published in 1960 (Crane et al. 1960). The key point here was 'flux coupling', the cotransport of sodium and glucose in the apical membrane of the small intestinal epithelial cell. Half a century later this idea has turned into one of the most studied of all transporter proteins (SGLT1), the sodium–glucose cotransporter.
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