Biology:Sodium-glucose transport proteins
| solute carrier family 5 (sodium/glucose cotransporter), member 1 | |
|---|---|
| Identifiers | |
| Symbol | SLC5A1 |
| Alt. symbols | SGLT1 |
| NCBI gene | 6523 |
| HGNC | 11036 |
| OMIM | 182380 |
| RefSeq | NM_000343 |
| UniProt | P13866 |
| Other data | |
| Locus | Chr. 22 q13.1 |
| solute carrier family 5 (sodium/glucose cotransporter), member 2 | |
|---|---|
| Identifiers | |
| Symbol | SLC5A2 |
| Alt. symbols | SGLT2 |
| NCBI gene | 6524 |
| HGNC | 11037 |
| OMIM | 182381 |
| RefSeq | NM_003041 |
| UniProt | P31639 |
| Other data | |
| Locus | Chr. 16 p11.2 |
| solute carrier family 5 (low affinity glucose cotransporter), member four | |
|---|---|
| Identifiers | |
| Symbol | SLC5A4 |
| Alt. symbols | SGLT3, SAAT1, DJ90G24.4 |
| NCBI gene | 6527 |
| HGNC | 11039 |
| RefSeq | NM_014227 |
| UniProt | Q9NY91 |
| Other data | |
| Locus | Chr. 22 q12.1-12.3 |
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.
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]
| Gene | Protein | Acronym | Tissue distribution in proximal tubule[3] |
Na+:Glucose Co-transport ratio |
Contribution to glucose reabsorption (%)[4] |
|---|---|---|---|---|---|
| SLC5A1 | Sodium/GLucose coTransporter 1 |
SGLT1 | S3 segment | 2:1 | 10 |
| SLC5A2 | Sodium/GLucose coTransporter 2 |
SGLT2 | predominantly in the S1 and S2 segments |
1:1 | 90 |
The other SLC5 proteins transport mannose, myo-inositol, choline, iodide, vitamins, and short-chain fatty acids.[2]
SGLT2 inhibitors for diabetes
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
- Cotransport
- Cotransporter
- Glucose-galactose malabsorption
- Renal sodium reabsorption
- Discovery and development of SGLT-2 inhibitors
References
- ↑ Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509
- ↑ 2.0 2.1 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. PMID 32767111.
- ↑ "Active sugar transport in health and disease". Journal of Internal Medicine 261 (1): 32–43. January 2007. doi:10.1111/j.1365-2796.2006.01746.x. PMID 17222166.
- ↑ "Renal Na(+)-glucose cotransporters". American Journal of Physiology. Renal Physiology 280 (1): F10–8. January 2001. doi:10.1152/ajprenal.2001.280.1.F10. PMID 11133510.
- ↑ "SGLT2 Inhibitors (Gliflozins)". Diabetes.co.uk. http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html.
- ↑ "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes". The New England Journal of Medicine 373 (22): 2117–28. November 2015. doi:10.1056/NEJMoa1504720. PMID 26378978. https://repositorio.unal.edu.co/handle/unal/79412.
- ↑ Research, Center for Drug Evaluation and (2018-12-28). "Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors" (in en). FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors.
- ↑ Kleinzeller A. Kotyk A, ed (1961). "The restrictions on possible mechanisms of intestinal transport of sugars". Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Czech Academy of Sciences & Academic Press. pp. 439–449.
- ↑ "The sodium/glucose cotransport family SLC5". Pflügers Archiv 447 (5): 510–8. February 2004. doi:10.1007/s00424-003-1063-6. PMID 12748858. "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.".
- ↑ "Facts, fantasies and fun in epithelial physiology". Experimental Physiology 93 (3): 303–14. March 2008. doi:10.1113/expphysiol.2007.037523. PMID 18192340. "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.".
External links
- Sodium-Glucose+Transport+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
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