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]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors were associated with significant long-term reductions in mortality risk for patients with pulmonary arterial hypertension (PAH), according to an observational cohort study.^[11] The study revealed that after one year, 8.1% of PAH patients prescribed SGLT2 inhibitors had died, compared to 15.5% of those who did not take the medication.

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 . December 2002 . Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2) . Human Genetics . 111 . 6 . 544–547 . 10.1007/s00439-002-0820-5 . 12436245 . 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 . November 2003 . Molecular analysis of the SGLT2 gene in patients with renal glucosuria . Journal of the American Society of Nephrology . 14 . 11 . 2873–2882 . 10.1097/01.asn.0000092790.89332.d2 . 14569097 . free.
• Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA . September 1992 . Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter . The American Journal of Physiology . 263 . 3 Pt 2 . F459–F465 . 10.1152/ajprenal.1992.263.3.F459 . 1415574.
• Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, Scharf M, Tasic V, Greil J, Brinkert F, Kemper MJ, Santer R . December 2008 . 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 . 3874–3879 . 10.1093/ndt/gfn386 . 18622023 . free.
• Calado J, Soto K, Clemente C, Correia P, Rueff J . February 2004 . Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria . Human Genetics . 114 . 3 . 314–316 . 10.1007/s00439-003-1054-x . 14614622 . 23741937.
• Magen D, Sprecher E, Zelikovic I, Skorecki K . January 2005 . A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria . Kidney International . 67 . 1 . 34–41 . 10.1111/j.1523-1755.2005.00053.x . 15610225 . free.
• Castaneda F, Burse A, Boland W, Kinne RK . May 2007 . Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes . International Journal of Medical Sciences . 4 . 3 . 131–139 . 10.7150/ijms.4.131 . 1868657 . 17505558.

Notes and References

1. Wells RG, Mohandas TK, Hediger MA . September 1993 . Localization of the Na+/glucose cotransporter gene SGLT2 to human chromosome 16 close to the centromere . Genomics . 17 . 3 . 787–789 . 10.1006/geno.1993.1411 . 8244402.
2. Web site: Entrez Gene: solute carrier family 5 (sodium/glucose cotransporter) .
3. Bonora BM, Avogaro A, Fadini GP . 2020 . Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence . Diabetes, Metabolic Syndrome and Obesity . 13 . 161–174 . 10.2147/DMSO.S233538 . 6982447 . 32021362 . free.
4. Vallon V, Thomson SC . 2012 . Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney . Annual Review of Physiology . 74 . 351–375 . 10.1146/annurev-physiol-020911-153333 . 3807782 . 22335797.
5. Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MD . November 2014 . Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin . Nutrition & Diabetes . 4 . 11 . e143 . 10.1038/nutd.2014.40 . 4259905 . 25365416.
6. Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J . 2017 . Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma . Endocrinology, Diabetes & Metabolism Case Reports . 2017 . 10.1530/EDM-17-0081 . 5592704 . 28924481.
7. Web site: 2015-05-15 . FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood . Food and Drug Administration, USA.
8. Web site: SGLT2 Inhibitors Associated with Fournier Gangrene . 2019-05-06 . Jwatch.org.
9. Web site: SGLT2 Inhibitors (Gliflozins) . 2015-05-19 . Diabetes.co.uk.
10. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, Rueff J . March 2006 . Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting . Kidney International . 69 . 5 . 852–855 . 10.1038/sj.ki.5000194 . 16518345 . free.
11. Lemonjava . Irakli . Gudushauri . Nino . Tskhakaia . Irakli . Martinez Manzano . Jose Manuel . Azmaiparashvili . Zurab . 2024 . Impact of Sglt2 Inhibitors on Mortality in Pulmonary Arterial Hypertension: Exploring the Association . Chest . en . 166 . 4 . A5793 . 10.1016/j.chest.2024.06.3435.