Sodium/glucose cotransporter 2 explained

The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the (solute carrier family 5 (sodium/glucose cotransporter)) gene.^[1]

Function

SGLT2 is a member of the sodium glucose cotransporter family, which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney.^[2] SGLT2 is located in the early proximal tubule, and is responsible for reabsorption of 80-90% of the glucose filtered by the kidney glomerulus.^[3] Most of the remaining glucose absorption is by sodium/glucose cotransporter 1 (SGLT1) in more distal sections of the proximal tubule.^[4]

SGLT2 inhibitors for diabetes

See main article: SGLT2 inhibitor. SGLT2 inhibitors are also called gliflozins or flozins. They lead to a reduction in blood glucose levels, and therefore have potential use in the treatment of type 2 diabetes. Gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure.^[5] The gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to euglycemic ketoacidosis.^{[6] [7]} Other side effects of gliflozins include increased risk of Fournier gangrene^[8] and of (generally mild) genital infections such as candidal vulvovaginitis.^[9]

Clinical significance

Mutations in this gene are also associated with renal glycosuria.^[10]

See also

• SGLT Family
• Discovery and development of gliflozins
• Phlorizin — a competitive inhibitor of SGLT1 and SGLT2

Further reading

• van den Heuvel LP, Assink K, Willemsen M, Monnens L . Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2) . Human Genetics . 111 . 6 . 544–7 . Dec 2002 . 12436245 . 10.1007/s00439-002-0820-5 . 28089635 .
• Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D . Molecular analysis of the SGLT2 gene in patients with renal glucosuria . Journal of the American Society of Nephrology . 14 . 11 . 2873–82 . Nov 2003 . 14569097 . 10.1097/01.asn.0000092790.89332.d2 . free .
• Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA . Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter . The American Journal of Physiology . 263 . 3 Pt 2 . F459-65 . Sep 1992 . 1415574 . 10.1152/ajprenal.1992.263.3.F459.
• Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, Scharf M, Tasic V, Greil J, Brinkert F, Kemper MJ, Santer R . Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion . Nephrology, Dialysis, Transplantation . 23 . 12 . 3874–9 . Dec 2008 . 18622023 . 10.1093/ndt/gfn386 . free .
• Calado J, Soto K, Clemente C, Correia P, Rueff J . Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria . Human Genetics . 114 . 3 . 314–6 . Feb 2004 . 14614622 . 10.1007/s00439-003-1054-x . 23741937 .
• Magen D, Sprecher E, Zelikovic I, Skorecki K . A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria . Kidney International . 67 . 1 . 34–41 . Jan 2005 . 15610225 . 10.1111/j.1523-1755.2005.00053.x . free .
• Castaneda F, Burse A, Boland W, Kinne RK . Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes . International Journal of Medical Sciences . 4 . 3 . 131–9 . 2007 . 17505558 . 1868657 . 10.7150/ijms.4.131 .

Notes and References

1. Wells RG, Mohandas TK, Hediger MA . Localization of the Na+/glucose cotransporter gene SGLT2 to human chromosome 16 close to the centromere . Genomics . 17 . 3 . 787–9 . Sep 1993 . 8244402 . 10.1006/geno.1993.1411 .
2. Web site: Entrez Gene: solute carrier family 5 (sodium/glucose cotransporter).
3. Bonora BM, Avogaro A, Fadini GP . Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence . . 13 . 161–174 . 2020 . 10.2147/DMSO.S233538 . 6982447 . 32021362 . free .
4. Vallon V, Thomson SC . Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney . . 74 . 351–375 . 2012 . 10.1146/annurev-physiol-020911-153333 . 3807782 . 22335797.
5. Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MD . Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin . Nutrition & Diabetes . 4 . 11 . e143 . 2014 . 25365416 . 10.1038/nutd.2014.40 . 4259905.
6. Rawla . P . Vellipuram . AR . Bandaru . SS . Pradeep Raj . J . Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. . Endocrinology, Diabetes & Metabolism Case Reports . 2017 . 2017 . 10.1530/EDM-17-0081 . 28924481. 5592704 .
7. Web site: FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015-05-15. Food and Drug Administration, USA.
8. Web site: SGLT2 Inhibitors Associated with Fournier Gangrene. Jwatch.org. 2019-05-06.
9. Web site: SGLT2 Inhibitors (Gliflozins). Diabetes.co.uk. 2015-05-19.
10. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, Rueff J . Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting . Kidney International . 69 . 5 . 852–5 . Mar 2006 . 16518345 . 10.1038/sj.ki.5000194 . free .