Sodium/glucose cotransporter 2

Last updated

SLC5A2
SGLT2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SLC5A2 , SGLT2, solute carrier family 5 member 2
External IDs OMIM: 182381; MGI: 2181411; HomoloGene: 2289; GeneCards: SLC5A2; OMA:SLC5A2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_003041

NM_133254

RefSeq (protein)

NP_003032

NP_573517

Location (UCSC) Chr 16: 31.48 – 31.49 Mb Chr 7: 127.86 – 127.87 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5]

Contents

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. [6] SGLT2 is located in the early proximal tubule, and is responsible for reabsorption of 80-90% of the glucose filtered by the kidney glomerulus. [7] Most of the remaining glucose absorption is by sodium/glucose cotransporter 1 (SGLT1) in more distal sections of the proximal tubule. [8]

SGLT2 inhibitors for diabetes

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. [9] The gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to euglycemic ketoacidosis. [10] [11] Other side effects of gliflozins include increased risk of Fournier gangrene [12] and of (generally mild) genital infections such as candidal vulvovaginitis. [13]

Clinical significance

Mutations in this gene are also associated with renal glycosuria. [14]

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. [15] 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

Related Research Articles

<span class="mw-page-title-main">Glycosuria</span> Medical condition

Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused by an elevated blood sugar level, most commonly due to untreated diabetes. Rarely, glycosuria is due to an intrinsic problem with glucose reabsorption within the kidneys, producing a condition termed renal glycosuria. Glycosuria leads to excessive water loss into the urine with resultant dehydration, a process called osmotic diuresis.

<span class="mw-page-title-main">Gitelman syndrome</span> Genetic kidney disorder

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

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

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

<span class="mw-page-title-main">Renal glycosuria</span> Medical condition

Renal glycosuria is a rare condition in which the simple sugar glucose is excreted in the urine despite normal or low blood glucose levels. With normal kidney (renal) function, glucose is excreted in the urine only when there are abnormally elevated levels of glucose in the blood. However, in those with renal glycosuria, glucose is abnormally elevated in the urine due to improper functioning of the renal tubules, which are primary components of nephrons, the filtering units of the kidneys.

<span class="mw-page-title-main">Sodium/glucose cotransporter 1</span>

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

<span class="mw-page-title-main">Dapagliflozin</span> Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.

Renal glucose reabsorption is the part of kidney (renal) physiology that deals with the retrieval of filtered glucose, preventing it from disappearing from the body through the urine.

<span class="mw-page-title-main">Sodium-dependent phosphate transport protein 2C</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent phosphate transport protein 2C is a protein that in humans is encoded by the SLC34A3 gene.

<span class="mw-page-title-main">Sergliflozin etabonate</span> Chemical compound

Sergliflozin etabonate is an investigational anti-diabetic drug being developed by GlaxoSmithKline. It did not undergo further development after phase II.

<span class="mw-page-title-main">Remogliflozin etabonate</span> Chemical compound

Remogliflozin etabonate (INN/USAN) is a drug of the gliflozin class for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes. Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being developed by BHV Pharma, a wholly owned subsidiary of North Carolina, US-based Avolynt, and Glenmark Pharmaceuticals through a collaboration with BHV. In 2002, GlaxoSmithKline (GSK) received a license to use it. From 2002 to 2009, GSK carried out a significant clinical development program for the treatment of type-2 diabetes mellitus in various nations across the world and obesity in the UK. Remogliflozin etabonate's pharmacokinetics, pharmacodynamics, and clinical dose regimens were characterized in 18 Phase I and 2 Phase II investigations. Due to financial concerns, GSK stopped working on remogliflozin and sergliflozin, two further SGLT2 inhibitors that were licensed to the company, in 2009. Remogliflozin was commercially launched first in India by Glenmark in May 2019.

<span class="mw-page-title-main">Iminoglycinuria</span> Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

<span class="mw-page-title-main">Phlorizin</span> Chemical compound

Phlorizin is a glucoside of phloretin, a dihydrochalcone. A white solid, samples often appear yellowing to impurities. It is of sweet taste and contains four molecules of water in the crystal. It is poorly soluble in ether and cold water, but soluble in ethanol and hot water. Upon prolonged exposure to aqueous solutions phlorizin hydrolyzes to phloretin and glucose.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes. It is taken by mouth.

Dicarboxylic aminoaciduria is a rare form of aminoaciduria which is an autosomal recessive disorder of urinary glutamate and aspartate due to genetic errors related to transport of these amino acids. Mutations resulting in a lack of expression of the SLC1A1 gene, a member of the solute carrier family, are found to cause development of dicarboxylic aminoaciduria in humans. SLC1A1 encodes for EAAT3 which is found in the neurons, intestine, kidney, lung, and heart. EAAT3 is part of a family of high affinity glutamate transporters which transport both glutamate and aspartate across the plasma membrane.

Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.

SGLT2 inhibitors are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium/glucose cotransporter 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Sotagliflozin, sold under the brand name Inpefa among others, is a medication used to reduce the risk of death due to heart failure. It is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. It is taken by mouth.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140675 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030781 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. doi:10.1006/geno.1993.1411. PMID   8244402.
  6. "Entrez Gene: solute carrier family 5 (sodium/glucose cotransporter)".
  7. 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. doi: 10.2147/DMSO.S233538 . PMC   6982447 . PMID   32021362.
  8. 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. doi:10.1146/annurev-physiol-020911-153333. PMC   3807782 . PMID   22335797.
  9. 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. doi:10.1038/nutd.2014.40. PMC   4259905 . PMID   25365416.
  10. Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J (2017). "Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma". Endocrinology, Diabetes & Metabolism Case Reports. 2017. doi:10.1530/EDM-17-0081. PMC   5592704 . PMID   28924481.
  11. "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. 2015-05-15.
  12. "SGLT2 Inhibitors Associated with Fournier Gangrene". Jwatch.org . Retrieved 2019-05-06.
  13. "SGLT2 Inhibitors (Gliflozins)". Diabetes.co.uk . Retrieved 2015-05-19.
  14. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, et al. (March 2006). "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting". Kidney International. 69 (5): 852–855. doi: 10.1038/sj.ki.5000194 . PMID   16518345.
  15. Lemonjava I, Gudushauri N, Tskhakaia I, Martinez Manzano JM, Azmaiparashvili Z (2024). "IMPACT OF SGLT2 INHIBITORS ON MORTALITY IN PULMONARY ARTERIAL HYPERTENSION: EXPLORING THE ASSOCIATION". CHEST. 166 (4): A5793. doi:10.1016/j.chest.2024.06.3435.

Further reading