SGLT2

SLC5A2
Identifiers
Aliases	SLC5A2 , SGLT2, solute carrier family 5 member 2
External IDs	OMIM: 182381 MGI: 2181411 HomoloGene: 2289 GeneCards: SLC5A2
Gene location (Human)
Chr.	Chromosome 16 (human) [1]
End	31,490,860 bp [1]
Gene location (Mouse)
Chr.	Chromosome 7 (mouse) [2]
End	128,272,430 bp [2]
Gene ontology
Molecular function	• low-affinity glucose:sodium symporter activity ; • symporter activity ; • transporter activity ; • glucose:sodium symporter activity ; • transmembrane transporter activity ;
Cellular component	• integral component of membrane ; • plasma membrane ; • extracellular exosome ; • membrane ; • integral component of plasma membrane ;
Biological process	• carbohydrate transport ; • ion transport ; • glucose transmembrane transport ; • sodium ion transport ; • transmembrane transport ; • hexose transport ; • transport ; • carbohydrate metabolic process ;
	Sources:Amigo / QuickGO
Orthologs
	6524
	246787
	ENSG00000140675
	ENSMUSG00000030781
	P31639
	Q923I7
	NM_003041
	NM_133254
	NP_003032
	NP_573517
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated February 19, 2019

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]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

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]

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 is excreted in urine (glucosuria) because SGLT are saturated with the filtered glucose. Glucose is never secreted by a healthy nephron.

Glucose (also called dextrose) is a simple sugar with the molecular formula C₆H₁₂O₆_{_{_{_{_{_{_{_{_{_{_{_{_{_{_{_{_{. Glucose is the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using energy from sunlight. There it is used to make cellulose in cell walls, which is the most abundant carbohydrate. In energy metabolism, glucose is the most important source of energy in all organisms. Glucose for metabolism is partially stored as a polymer, in plants mainly as starch and amylopectin and in animals as glycogen. Glucose circulates in the blood of animals as blood sugar. The naturally occurring form of glucose is D-glucose, while L-glucose is produced synthetically in comparably small amounts and is of lesser importance.}}}}}}}}}}}}}}}}}

SGLT2 inhibitors for diabetes

SGLT2 inhibitors are called gliflozins. They lead to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. Gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure.^[7] The gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to euglycemic ketoacidosis.^[8] Other side effects of gliflozins include increased risk of (generally mild) genital infections, such as candidal vulvovaginitis.^[9]

Blood pressure pressure exerted by circulating blood upon the walls of blood vessels

Blood pressure (BP) is the pressure of circulating blood on the walls of blood vessels. Most of this pressure is due to the work done by the heart in pumping blood round the circulation. Used without further specification, "blood pressure" usually refers to the pressure in large arteries of the systemic circulation. Blood pressure is usually expressed in terms of the systolic pressure over diastolic pressure and is measured in millimeters of mercury (mmHg), above the surrounding atmospheric pressure.

Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate.

Clinical significance

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

Model organisms

*Slc5a2* knockout mouse phenotype
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^[11]
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^[12]
Citrobacter infection	Normal^[13]
All tests and analysis from^[14]^[15]

Model organisms have been used in the study of SLC5A2 function. A conditional knockout mouse line, called Slc5a2^{tm1a(KOMP)Wtsi}^[16]^[17] 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.^[18]^[19]^[20]

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to research human disease when human experimentation would be unfeasible or unethical. This strategy is made possible by the common descent of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution.

A knockout mouse or knock-out mouse is a genetically modified mouse in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to create knockout mice to study. Many of the targeted alleles are designed so that they can generate both complete and conditional gene knockout mice. The IKMC was initiated on March 15, 2007 at a meeting in Brussels. By 2011, Nature reported that approximately 17,000 different genes have already been disabled by the consortium, "leaving only around 3,000 more to go".

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[14]^[21] Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: males displayed increased drinking behaviour.^[14]

Mutant organism or a new genetic character arising or resulting from an instance of mutation, which is an alteration of the DNA sequence of a gene or chromosome of an organism

In biology and especially genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. The term mutant is also applied to a virus with an alteration in its nucleotide sequence whose genome is RNA, rather than DNA. In multicellular eukaryotes, a DNA sequence may be altered in an individual somatic cell that then gives rise to a mutant somatic cell lineage as happens in cancer progression. Also in eukaryotes, alteration of a mitochondrial or plastid DNA sequence may give rise to a mutant lineage that is inherited separately from mutant genotypes in the nuclear genome. The natural occurrence of genetic mutations is integral to the process of evolution. The study of mutants is an integral part of biology; by understanding the effect that a mutation in a gene has, it is possible to establish the normal function of that gene.

Related Research Articles

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

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 elevated blood glucose levels, most commonly due to untreated diabetes mellitus. 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.

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 gene SLC12A3 (solute carrier family 12 member 3) located in 16q13.

Glucose-galactose malabsorption is a rare condition in which the cells lining the intestine cannot take in the sugars glucose and galactose, which prevents proper digestion of these molecules and larger molecules made from them.

Sodium/glucose cotransporter 1 also known as solute carrier family 5 member 1 is a protein that in humans is encoded by the SLC5A1 gene.

Electrogenic sodium bicarbonate cotransporter 1 is a membrane transport protein that in humans is encoded by the SLC4A4 gene.

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.

Sodium-dependent phosphate transport protein 1 is a protein that in humans is encoded by the SLC17A1 gene.

Solute carrier family 13 member 2 is a protein that is encoded in humans by the SLC13A2 gene.

Electrogenic sodium bicarbonate cotransporter 4 is a protein that in humans is encoded by the SLC4A5 gene.

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

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

Canagliflozin is a medication used for the treatment of type 2 diabetes. It is of the gliflozin class or subtype 2 sodium-glucose transport (SGLT-2) inhibitors class.

The low affinity sodium-glucose cotransporter also known as the sodium/glucose cotransporter 3 (SGLT3) or solute carrier family 5 member 4 (SLC5A4) is a protein that in humans is encoded by the SLC5A4 gene.

Sodium-coupled neutral amino acid transporter 10 also known as solute carrier family 38, member 10 is a protein that in humans is encoded by the SLC38A10 gene.

Empagliflozin, sold under the trade name Jardiance among others, is a medication used together with diet and exercise for the treatment of type 2 diabetes. It may be used together with metformin or insulin. It is not useful for type 1 diabetes. It is taken by mouth.

Tofogliflozin is an experimental drug for the treatment of diabetes mellitus and is being developed by Chugai Pharma in collaboration with Kowa and Sanofi. It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.

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.

Gliflozin drugs are a class of medications that inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2), and are therefore also called SGLT2 inhibitors. Gliflozins are used in the treatment of type II diabetes mellitus (T2DM). Apart from glycemic control, gliflozins have been shown to provide significant cardiovascular benefit in T2DM patients. Several drugs of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the drug was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000140675 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030781 - Ensembl, May 2017
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ Wells RG, Mohandas TK, Hediger MA (Sep 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.
↑ "Entrez Gene: solute carrier family 5 (sodium/glucose cotransporter)".
↑ Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MD (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.
↑ "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.
↑ "SGLT2 Inhibitors (Gliflozins)". Diabetes.co.uk . Retrieved 2015-05-19.
↑ Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, Rueff J (Mar 2006). "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting". Kidney International. 69 (5): 852–5. doi:10.1038/sj.ki.5000194. PMID 16518345.
↑ "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.
1 2 3 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".
↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410  . PMID 21677750.
↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837  . PMID 21722353.