Template:PBB The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 (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 inhibitors for diabetes
Inhibition of SGLT2 leads to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. Several drug candidates have been developed or are currently undergoing clinical trials, including:[3]
- Dapagliflozin, approval rejected by Food and Drug Administration due to safety concerns,[4] but marketed in Europe
- Canagliflozin, approved in the United States[5]
- Ipragliflozin (ASP-1941), in Phase III clinical trials[6]
- Tofogliflozin, in Phase III clinical trials[6]
- Empagliflozin (BI-10773), in Phase III clinical trials[6]
- Sergliflozin etabonate, discontinued after Phase II trials
- Remogliflozin etabonate, discontinued after Phase II trials
Clinical significance
Mutations in this gene are also associated with renal glucosuria.[7]
Model organisms
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Abnormal[8] |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Salmonella infection | Normal[9] |
| Citrobacter infection | Normal[10] |
| All tests and analysis from[11][12] |
Model organisms have been used in the study of SLC5A2 function. A conditional knockout mouse line, called Slc5a2tm1a(KOMP)Wtsi[13][14] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[15][16][17]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[11][18] Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: males displayed increased drinking behaviour.[11]
See also
- SGLT Family
References
- ^ Wells RG, Mohandas TK, Hediger MA (1993). "Localization of the Na+/glucose cotransporter gene SGLT2 to human chromosome 16 close to the centromere". Genomics. 17 (3): 787–9. doi:10.1006/geno.1993.1411. PMID 8244402.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Entrez Gene: solute carrier family 5 (sodium/glucose cotransporter)".
- ^ InsightPharma (2010). "Diabetes Pipeline: Intense Activity to Meet Unmet Need" (PDF). p. vii.
- ^ Bristol, AstraZeneca Diabetes Drug Fails to Win FDA Backing, Business Week, January 19, 2012
- ^ Invokana, First in New Class of Diabetes Drugs, Approved, MPR, March 29, 2013
- ^ Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, Rueff J (2006). "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting". Kidney Int. 69 (5): 852–5. doi:10.1038/sj.ki.5000194. PMID 16518345.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Indirect calorimetry data for Slc5a2". Wellcome Trust Sanger Institute.
- ^ "Salmonella infection data for Slc5a2". Wellcome Trust Sanger Institute.
- ^ "Citrobacter infection data for Slc5a2". Wellcome Trust Sanger Institute.
- ^ a b c Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ^ "International Knockout Mouse Consortium".
- ^ "Mouse Genome Informatics".
- ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21677750, please use {{cite journal}} with
|pmid=21677750instead. - ^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
Further reading
- van den Heuvel LP, Assink K, Willemsen M, Monnens L (2002). "Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2)". Hum. Genet. 111 (6): 544–7. doi:10.1007/s00439-002-0820-5. PMID 12436245.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Santer R, Kinner M, Lassen CL; et al. (2003). "Molecular analysis of the SGLT2 gene in patients with renal glucosuria". J. Am. Soc. Nephrol. 14 (11): 2873–82. PMID 14569097.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Wells RG, Pajor AM, Kanai Y; et al. (1992). "Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter". Am. J. Physiol. 263 (3 Pt 2): F459-65. PMID 1415574.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Calado J, Sznajer Y, Metzger D; et al. (2008). "Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion". Nephrol. Dial. Transplant. 23 (12): 3874–9. doi:10.1093/ndt/gfn386. PMID 18622023.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Calado J, Soto K, Clemente C; et al. (2004). "Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria". Hum. Genet. 114 (3): 314–6. doi:10.1007/s00439-003-1054-x. PMID 14614622.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Ota T, Suzuki Y, Nishikawa T; et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Strausberg RL, Feingold EA, Grouse LH; et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Magen D, Sprecher E, Zelikovic I, Skorecki K (2005). "A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria". Kidney Int. 67 (1): 34–41. doi:10.1111/j.1523-1755.2005.00053.x. PMID 15610225.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Castaneda F, Burse A, Boland W, Kinne RK (2007). "Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes". Int J Med Sci. 4 (3): 131–9. PMC 1868657. PMID 17505558.
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