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{{Short description|Group of transport proteins}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{infobox protein
{{infobox protein
| Name = solute carrier family 5 (sodium/glucose cotransporter), member 1
| Name = solute carrier family 5 (sodium/glucose cotransporter), member 1
| caption =
| caption =
| image =
| image =
| width =
| width =
| HGNCid = 11036
| HGNCid = 11036
| Symbol = [[SLC5A1]]
| Symbol = [[SLC5A1]]
Line 11: Line 13:
| RefSeq = NM_000343
| RefSeq = NM_000343
| UniProt = P13866
| UniProt = P13866
| PDB =
| PDB =
| ECnumber =
| ECnumber =
| Chromosome = 22
| Chromosome = 22
| Arm = q
| Arm = q
| Band = 13.1
| Band = 13.1
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
{{infobox protein
{{infobox protein
| Name = solute carrier family 5 (sodium/glucose cotransporter), member 2
| Name = solute carrier family 5 (sodium/glucose cotransporter), member 2
| caption =
| caption =
| image =
| image =
| width =
| width =
| HGNCid = 11037
| HGNCid = 11037
| Symbol = [[SLC5A2]]
| Symbol = [[SLC5A2]]
Line 30: Line 32:
| RefSeq = NM_003041
| RefSeq = NM_003041
| UniProt = P31639
| UniProt = P31639
| PDB =
| PDB =
| ECnumber =
| ECnumber =
| Chromosome = 16
| Chromosome = 16
| Arm = p
| Arm = p
| Band = 11.2
| Band = 11.2
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
{{infobox protein
{{infobox protein
| Name = solute carrier family 5 (low affinity glucose cotransporter), member 4
| Name = solute carrier family 5 (low affinity glucose cotransporter), member four
| caption =
| caption =
| image =
| image =
| width =
| width =
| HGNCid = 11039
| HGNCid = 11039
| Symbol = [[SLC5A4]]
| Symbol = [[SLC5A4]]
| AltSymbols = SGLT3, SAAT1, DJ90G24.4
| AltSymbols = SGLT3, SAAT1, DJ90G24.4
| EntrezGene = 6527
| EntrezGene = 6527
| OMIM =
| OMIM =
| RefSeq = NM_014227
| RefSeq = NM_014227
| UniProt = Q9NY91
| UniProt = Q9NY91
| PDB =
| PDB =
| ECnumber =
| ECnumber =
| Chromosome = 22
| Chromosome = 22
| Arm = q
| Arm = q
| Band = 12.1-12.3
| Band = 12.1-12.3
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
'''Sodium-dependent glucose cotransporters''' (or '''sodium-glucose linked transporter''', '''SGLT''') are a family of [[glucose transporter]] found in the intestinal [[mucosa]] ([[enterocytes]]) of the [[small intestine]] (SGLT1) and the [[proximal tubule]] of the [[nephron]] (SGLT2 in [[Proximal convoluted tubule|PCT]] and SGLT1 in [[Proximal straight tubule|PST]]). They contribute to [[renal glucose reabsorption]]. In the kidneys, 100% of the filtered glucose in the [[glomerulus]] has to be reabsorbed along the nephron (98% in [[Proximal convoluted tubule|PCT]], via SGLT2). In case of too high plasma glucose concentration ([[hyperglycemia]]), glucose is excreted in urine ([[glucosuria]]) because SGLT are saturated with the filtered [[monosaccharide]]. Glucose is never secreted by a healthy [[Proximal convoluted tubule|nephron]].
'''Sodium-dependent glucose cotransporters''' (or '''sodium-glucose linked transporter''', '''SGLT''') are a family of [[glucose transporter]] found in the intestinal [[mucosa]] ([[enterocytes]]) of the [[small intestine]] (SGLT1) and the [[proximal tubule]] of the [[nephron]] ([[SGLT2]] in [[Proximal convoluted tubule|PCT]] and SGLT1 in [[Proximal straight tubule|PST]]). They contribute to [[renal glucose reabsorption]]. In the kidneys, 100% of the filtered glucose in the [[Glomerulus (kidney)|glomerulus]] has to be reabsorbed along the nephron (98% in [[Proximal convoluted tubule|PCT]], via SGLT2). If the plasma glucose concentration is too high ([[hyperglycemia]]), glucose passes into the urine ([[glucosuria]]) because SGLT are saturated with the filtered glucose.


== Types ==
== Types ==


The sodium-glucose linked transporters (SGLTs) are responsible for the active transport of glucose across cell membranes. SGLT1 and SGLT2 are the most well-studied members of this family.<ref name="Thorens_2010">{{cite journal | vauthors = Thorens B, Mueckler M | title = Glucose transporters in the 21st Century | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 298 | issue = 2 | pages = E141–5 | date = February 2010 | pmid = 20009031 | pmc = 2822486 | doi = 10.1152/ajpendo.00712.2009 | department = review }}</ref><ref name="Dominguez_Rieg_2020">{{cite journal | vauthors = Dominguez Rieg JA, Xue J, Rieg T | title = Tubular effects of sodium-glucose cotransporter 2 inhibitors: intended and unintended consequences | journal = Current Opinion in Nephrology and Hypertension | volume = 29 | issue = 5 | pages = 523–530 | date = September 2020 | pmid = 32701600| pmc = 8772383 | doi = 10.1097/MNH.0000000000000632 | department = review }}</ref> Both SGLT1 and SGLT2 function as [[symporter]]s, utilizing the energy from the sodium gradient created by the Na+/K+ ATPase to transport glucose against its concentration gradient.<ref name="Dominguez_Rieg_2020" /><ref name="Hotait_2022" />
⚫
The two most well known members of SGLT family are SGLT1 and SGLT2, which are members of the SLC5A gene family. In addition to SGLT1 and SGLT2, there are five other members in the human protein family SLC5A, several of which may also be sodium-glucose transporters.<ref>[http://www.ensembl.org/Homo_sapiens/familyview?family=ENSF00000000509 Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509<!-- Bot generated title -->]</ref>

SGLT2, encoded by the SLC5A2 gene, is predominantly expressed in the S1 and S2 segments of the [[proximal renal tubule]] and is responsible for approximately 97% of glucose reabsorption in the kidneys under normal conditions.<ref name="Dominguez_Rieg_2020" /><ref name="Hotait_2022" /> SGLT1, encoded by the SLC5A1 gene, is primarily expressed in the late proximal tubule (S3 segment) and accounts for the remaining 3% of glucose reabsorption.<ref name="Dominguez_Rieg_2020" /><ref name="Hotait_2022" />

⚫
In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A.<ref>[http://www.ensembl.org/Homo_sapiens/familyview?family=ENSF00000000509 Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509<!-- Bot generated title -->]</ref>

SLC5A4, also known as SGLT3, is a member of the sodium-glucose cotransporter family. Unlike SGLT1 and SGLT2, which are efficient glucose transporters, SGLT3 functions primarily as a glucose sensor rather than a transporter. It has a low affinity for glucose and does not significantly contribute to glucose transport across cell membranes. Instead, SGLT3 acts as a glucose-gated ion channel, generating small depolarizing currents in response to extracellular glucose. This electrical signaling function suggests a role in glucose sensing and signaling pathways rather than in glucose transport.<ref name="Diez-Sampedro_2003">{{cite journal | vauthors = Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C, Wright EM, Koepsell H | title = A glucose sensor hiding in a family of transporters | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 20 | pages = 11753–8 | date = September 2003 | pmid = 13130073 | pmc = 208830 | doi = 10.1073/pnas.1733027100 | doi-access = free | bibcode = 2003PNAS..10011753D | department = primary }}</ref><ref name= Gyimesi>{{cite journal | vauthors = Gyimesi G, Pujol-Giménez J, Kanai Y, Hediger MA | title = Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application | journal = Pflügers Archiv | volume = 472 | issue = 9 | pages = 1177–1206 | date = September 2020 | pmid = 32767111 | pmc = 7462921 | doi = 10.1007/s00424-020-02433-x | doi-access = free }}</ref>


{| class="wikitable" style="text-align:center"
{| class="wikitable" style="text-align:center"
! Gene !! Protein !! Acronym !! Tissue distribution<br/>in proximal tubule<ref name="pmid17222166">{{cite journal | author = Wright EM, Hirayama BA, Loo DF | title = Active sugar transport in health and disease | journal = J. Intern. Med. | volume = 261 | issue = 1 | pages = 32–43 |date=January 2007 | pmid = 17222166 | doi = 10.1111/j.1365-2796.2006.01746.x | url = | issn = }}</ref>!! Na<sup>+</sup>:Glucose<br/>Co-transport ratio !! Contribution to glucose<br/>reabsorption (%)<ref name="pmid11133510">{{cite journal | author = Wright EM | title = Renal Na(+)-glucose cotransporters | journal = Am. J. Physiol. Renal Physiol. | volume = 280 | issue = 1 | pages = F10–8 |date=January 2001 | pmid = 11133510 | doi = | url = | issn = }}</ref>
! Gene !! Protein !! Acronym !! Tissue distribution<br />in proximal tubule<ref name="pmid17222166">{{cite journal | vauthors = Wright EM, Hirayama BA, Loo DF | title = Active sugar transport in health and disease | journal = Journal of Internal Medicine | volume = 261 | issue = 1 | pages = 32–43 | date = January 2007 | pmid = 17222166 | doi = 10.1111/j.1365-2796.2006.01746.x | s2cid = 44399123 | doi-access = }}</ref>!! Na<sup>+</sup>:Glucose<br />Co-transport ratio !! Contribution to glucose<br />reabsorption (%)<ref name="pmid11133510">{{cite journal | vauthors = Wright EM | title = Renal Na(+)-glucose cotransporters | journal = American Journal of Physiology. Renal Physiology | volume = 280 | issue = 1 | pages = F10–8 | date = January 2001 | pmid = 11133510 | doi = 10.1152/ajprenal.2001.280.1.F10 }}</ref>
|-
|-
| ''[[SLC5A1]]'' || '''S'''odium/'''GL'''ucose<br/>co'''T'''ransporter '''1''' || SGLT1 || S3 segment || 2:1 || 10
| ''[[SLC5A1]]'' || '''S'''odium/'''GL'''ucose<br />co'''T'''ransporter '''1''' || SGLT1 || S3 segment || 2:1 || 10
|-
|-
| ''[[SLC5A2]]'' || '''S'''odium/'''GL'''ucose<br/>co'''T'''ransporter '''2''' || SGLT2 || predominantly in the<br/>S1 and S2 segments || 1:1 || 90
| ''[[SLC5A2]]'' || '''S'''odium/'''GL'''ucose<br />co'''T'''ransporter '''2''' || SGLT2 || predominantly in the<br />S1 and S2 segments || 1:1 || 90
|}
|}


The SLC5 family includes transporters for a diverse range of substrates beyond glucose. Specific members of this family are specialized for the transport of:
⚫
== SGLT2 inhibitors for diabetes ==
⚫
{{Main|Gliflozin}}
SGLT2 inhibitors, also called ''gliflozins'',<ref>{{cite web|url=http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html|title=SGLT2 Inhibitors (Gliflozins)|publisher=[[Diabetes.co.uk]]|accessdate=2015-05-19}}</ref> are used in the treatment of [[type II diabetes]]. Examples include [[dapagliflozin|dapagliflozin (Farziga,]][[dapagliflozin|Forziga)]], [[canagliflozin]] ('''Invokana)''' and [[empagliflozin]] ('''Jardiance''').


* [[Mannose]] ([[SLC5A9]], also known as SGLT4)
⚫
== Function ==
* [[Myo-inositol]] ([[SLC5A3]], also known as SMIT1)
Firstly, an [[Na+/K+ ATPase]] pump on the [[Cell membrane#Membrane polarity|basolateral]] membrane of the proximal tubule cell uses [[Adenosine triphosphate|ATP]] molecules to move 3 sodium ions outward into the blood, while bringing in 2 potassium ions. This action creates a downhill sodium ion gradient from the inside of the [[proximal tubule]] cell towards the outside (that is, in comparison to both the blood and the tubule itself).
* [[Choline]] ([[SLC5A7]], also known as CHT1)
* [[Iodide]] ([[SLC5A5]], also known as NIS)
* Vitamins, specifically [[biotin]] and [[pantothenate]] ([[SLC5A6]], also known as SMVT)
* [[Short-chain fatty acid]]s ([[SLC5A8]] and [[SLC5A12]], also known as SMCT1 and SMCT2 respectively)


Each of these transporters plays a specific role in cellular metabolism and homeostasis, often utilizing sodium gradients for substrate transport similar to the glucose transporters in this family.<ref name="Wright_2011">{{cite journal | vauthors = Wright EM, Loo DD, Hirayama BA | title = Biology of human sodium glucose transporters | journal = Physiological Reviews | volume = 91 | issue = 2 | pages = 733–94 | date = April 2011 | pmid = 21527736 | doi = 10.1152/physrev.00055.2009 | department = review }}</ref><ref name=Gyimesi/>
The SGLT proteins use the energy from this downhill sodium ion gradient created by the ATPase pump to transport [[glucose]] across the [[apical membrane]], against an uphill glucose gradient. These co-transporters are an example of [[secondary active transport]]. Members of the GLUT family of glucose [[uniporters]] then transport the glucose across the basolateral membrane, and into the [[peritubular capillaries]]. Because sodium and glucose are in the same direction across the membrane, SGLT1 and SGLT2 are known as [[symporter]]s.

== Mechanism ==

The transport of glucose across the proximal tubule cell membrane involves a complex process of [[Active transport#Secondary active transport|secondary active transport]] (also known as co-transport).<ref name="Hotait_2022" /> This process begins with the [[Na+/K+ ATPase|Na<sup>+</sup>/K<sup>+</sup> ATPase]] on the [[Cell membrane#Membrane polarity|basolateral]] membrane. This enzyme uses [[Adenosine triphosphate|ATP]] to pump 3 sodium ions out of the cell into the blood while bringing 2 potassium ions into the cell.<ref name="Vallon_2002">{{cite journal | vauthors = Vallon V | title = Glucose transporters in the kidney in health and disease | journal = Pflügers Archiv: European Journal of Physiology | volume = 472 | issue = 9 | pages = 1345–1370 | date = September 2020 | pmid = 32144488 | pmc = 7483786 | doi = 10.1007/s00424-020-02361-w | department = review }}</ref> This action creates a sodium concentration gradient across the cell membrane, with a lower concentration inside the cell compared to both the blood and the tubular lumen.<ref name="Hotait_2022" />

SGLT proteins utilize this sodium gradient to transport [[glucose]] across the [[apical membrane]] into the cell, even against the glucose concentration gradient.<ref name="Mudaliar_2015">{{cite journal | vauthors = Mudaliar S, Polidori D, Zambrowicz B, Henry RR | title = Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside | journal = Diabetes Care | volume = 38 | issue = 12 | pages = 2344–53 | date = December 2015 | pmid = 26604280 | doi = 10.2337/dc15-0642 | department = review }}</ref><ref name="Hotait_2022">{{cite journal | vauthors = Hotait ZS, Lo Cascio JN, Choos EN, Shepard BD | title = The sugar daddy: the role of the renal proximal tubule in glucose homeostasis | journal = American Journal of Physiology. Cell Physiology | volume = 323 | issue = 3 | pages = C791–C803 | date = September 2022 | pmid = 35912988 | pmc = 9448277 | doi = 10.1152/ajpcell.00225.2022 | department = review }}</ref> This mechanism is an example of secondary active transport. Once inside the cell, glucose is then moved across the basolateral membrane into the [[peritubular capillaries]] by members of the GLUT family of glucose [[uniporters]].<ref name="Hotait_2022" />

SGLT1 and SGLT2 are classified as [[symporter]]s because they move sodium and glucose in the same direction across the membrane.<ref name="Mudaliar_2015" /><ref name="Hotait_2022" /> To maintain this process, the [[Sodium–hydrogen antiporter]] plays a crucial role in replenishing intracellular sodium levels.<ref name="Nwia_2022">{{cite journal | vauthors = Nwia SM, Li XC, Leite AP, Hassan R, Zhuo JL | title = The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension | journal = Frontiers in Physiology | volume = 13 | issue = | pages = 861659 | date = 2022 | pmid = 35514347 | pmc = 9062697 | doi = 10.3389/fphys.2022.861659 | doi-access = free | department = review }}</ref><ref name="Liu_2021">{{cite journal | vauthors = Liu J, Tian J, Sodhi K, Shapiro JI | title = The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road? | journal = The Journal of Membrane Biology | volume = 254 | issue = 5–6 | pages = 513–529 | date = December 2021 | pmid = 34297135 | doi = 10.1007/s00232-021-00192-z | pmc = 8595165 | department = review }}</ref> Consequently, the net effect of glucose transport is coupled with the extrusion of protons from the cell, with sodium serving as an intermediate in this process.<ref name="Nwia_2022" /><ref name="Liu_2021" />

⚫
== SGLT2 inhibitors for diabetes ==
⚫
{{Main|Gliflozin}}
SGLT2 inhibitors, also called ''gliflozins'',<ref>{{cite web|url=http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html|title=SGLT2 Inhibitors (Gliflozins)|publisher=[[Diabetes.co.uk]]|access-date=2015-05-19}}</ref> are used in the treatment of [[type 2 diabetes]]. SGLT2 is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include [[dapagliflozin]] (Farxiga in US, Forxiga in EU), [[canagliflozin]] (Invokana) and [[empagliflozin]] (Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes.<ref>{{cite journal | vauthors = Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE | title = Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes | journal = The New England Journal of Medicine | volume = 373 | issue = 22 | pages = 2117–28 | date = November 2015 | pmid = 26378978 | doi = 10.1056/NEJMoa1504720 | hdl = 11573/894529 | s2cid = 205098095 | url = https://repositorio.unal.edu.co/handle/unal/79412 | hdl-access = free }}</ref> The safety and efficacy of SGLT2 inhibitors have not been established in patients with [[type 1 diabetes]], and FDA has not approved them for use in these patients.<ref>{{Cite web | work = Center for Drug Evaluation and Research (CDER) |date=2018-12-28|title=Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors|url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors| publisher = U.S. Food and Drug Administration (FDA) |language=en}}</ref>


⚫
== History ==
== Discovery of sodium-glucose cotransport ==


In August 1960, in Prague, [[Robert K. Crane]] presented for the first time his discovery of the sodium-glucose [[Co-transport|cotransport]] as the mechanism for intestinal glucose absorption.<ref>{{cite book|title=Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960|editor=Kleinzeller A. Kotyk A|publisher=[[Academy of Sciences of the Czech Republic|Czech Academy of Sciences]] & Academic Press|chapter = The restrictions on possible mechanisms of intestinal transport of sugars| author = Miller D, Bihler I | pages = 439–449 | year = 1961 }}</ref>
In August 1960, in Prague, [[Robert K. Crane]] presented for the first time his discovery of the sodium-glucose [[Co-transport|cotransport]] as the mechanism for intestinal glucose absorption.<ref>{{cite book | vauthors = Crane RK, Miller D, Bihler I |chapter = The restrictions on possible mechanisms of intestinal transport of sugars | title=Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960| veditors = Kleinzeller A, Kotyk A |publisher=[[Academy of Sciences of the Czech Republic|Czech Academy of Sciences]] & Academic Press | pages = 439–449 | year = 1961 }}</ref>


[[Robert K. Crane|Crane]]'s discovery of cotransport was the first-ever proposal of flux coupling in biology.<ref name="pmid12748858">{{cite journal | author = Wright EM, Turk E | title = The sodium/glucose cotransport family SLC5 | journal = Pflugers Arch. | volume = 447 | issue = 5 | pages = 510–8 |date=February 2004 | pmid = 12748858 | doi = 10.1007/s00424-003-1063-6 | url = | issn = | quote = [[Robert K. Crane|Crane]] in 1961 was the first to formulate the cotransport concept to explain active transport [7]. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across the brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type.}}</ref><ref name="pmid18192340">{{cite journal | author = Boyd CA | title = Facts, fantasies and fun in epithelial physiology | journal = Exp. Physiol. | volume = 93 | issue = 3 | pages = 303–14 |date=March 2008 | pmid = 18192340 | doi = 10.1113/expphysiol.2007.037523 | url = | issn = | quote = p. 304. “the insight from this time that remains in all current text books is the notion of [[Robert K. Crane|Robert Crane]] published originally as an appendix to a symposium paper published in 1960 ([[Robert K. Crane|Crane]] et al. 1960). The key point here was 'flux coupling', the [[Co-transport|cotransport]] of sodium and glucose in the apical membrane of the small intestinal epithelial cell. Half a century later this idea has turned into one of the most studied of all transporter proteins (SGLT1), the sodium–glucose cotransporter. }}</ref>
[[Robert K. Crane|Crane]]'s discovery of cotransport was the first-ever proposal of flux coupling in biology.<ref name="pmid12748858">{{cite journal | vauthors = Wright EM, Turk E | title = The sodium/glucose cotransport family SLC5 | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 510–8 | date = February 2004 | pmid = 12748858 | doi = 10.1007/s00424-003-1063-6 | s2cid = 41985805 | quote = [[Robert K. Crane|Crane]] in 1961 was the first to formulate the cotransport concept to explain active transport [7]. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across the brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type. }}</ref><ref name="pmid18192340">{{cite journal | vauthors = Boyd CA | title = Facts, fantasies and fun in epithelial physiology | journal = Experimental Physiology | volume = 93 | issue = 3 | pages = 303–14 | date = March 2008 | pmid = 18192340 | doi = 10.1113/expphysiol.2007.037523 | s2cid = 41086034 | quote = p. 304. "the insight from this time that remains in all current text books is the notion of [[Robert K. Crane|Robert Crane]] published originally as an appendix to a symposium paper published in 1960 ([[Robert K. Crane|Crane]] et al. 1960). The key point here was 'flux coupling', the [[Co-transport|cotransport]] of sodium and glucose in the apical membrane of the small intestinal epithelial cell. Half a century later this idea has turned into one of the most studied of all transporter proteins (SGLT1), the sodium–glucose cotransporter. | doi-access = free }}</ref>


== See also ==
== See also ==
Line 93: Line 115:


== References ==
== References ==
{{Reflist}}
{{Reflist|30em}}


== External links ==
== External links ==
Line 100: Line 122:
{{Ion pumps}}
{{Ion pumps}}
{{Membrane transport proteins|bg|bg0}}
{{Membrane transport proteins|bg|bg0}}
{{Sodium-glucose transporter modulators}}


[[Category:Solute carrier family]]
[[Category:Solute carrier family]]

Latest revision as of 18:49, 17 November 2024

solute carrier family 5 (sodium/glucose cotransporter), member 1
Identifiers
SymbolSLC5A1
Alt. symbolsSGLT1
NCBI gene6523
HGNC11036
OMIM182380
RefSeqNM_000343
UniProtP13866
Other data
LocusChr. 22 q13.1
Search for
StructuresSwiss-model
DomainsInterPro
solute carrier family 5 (sodium/glucose cotransporter), member 2
Identifiers
SymbolSLC5A2
Alt. symbolsSGLT2
NCBI gene6524
HGNC11037
OMIM182381
RefSeqNM_003041
UniProtP31639
Other data
LocusChr. 16 p11.2
Search for
StructuresSwiss-model
DomainsInterPro
solute carrier family 5 (low affinity glucose cotransporter), member four
Identifiers
SymbolSLC5A4
Alt. symbolsSGLT3, SAAT1, DJ90G24.4
NCBI gene6527
HGNC11039
RefSeqNM_014227
UniProtQ9NY91
Other data
LocusChr. 22 q12.1-12.3
Search for
StructuresSwiss-model
DomainsInterPro

Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST). They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT, via SGLT2). If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

Types

[edit]

The sodium-glucose linked transporters (SGLTs) are responsible for the active transport of glucose across cell membranes. SGLT1 and SGLT2 are the most well-studied members of this family.[1][2] Both SGLT1 and SGLT2 function as symporters, utilizing the energy from the sodium gradient created by the Na+/K+ ATPase to transport glucose against its concentration gradient.[2][3]

SGLT2, encoded by the SLC5A2 gene, is predominantly expressed in the S1 and S2 segments of the proximal renal tubule and is responsible for approximately 97% of glucose reabsorption in the kidneys under normal conditions.[2][3] SGLT1, encoded by the SLC5A1 gene, is primarily expressed in the late proximal tubule (S3 segment) and accounts for the remaining 3% of glucose reabsorption.[2][3]

In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A.[4]

SLC5A4, also known as SGLT3, is a member of the sodium-glucose cotransporter family. Unlike SGLT1 and SGLT2, which are efficient glucose transporters, SGLT3 functions primarily as a glucose sensor rather than a transporter. It has a low affinity for glucose and does not significantly contribute to glucose transport across cell membranes. Instead, SGLT3 acts as a glucose-gated ion channel, generating small depolarizing currents in response to extracellular glucose. This electrical signaling function suggests a role in glucose sensing and signaling pathways rather than in glucose transport.[5][6]

Gene Protein Acronym Tissue distribution
in proximal tubule[7]		 Na+:Glucose
Co-transport ratio		 Contribution to glucose
reabsorption (%)[8]
SLC5A1 Sodium/GLucose
coTransporter 1		 SGLT1 S3 segment 2:1 10
SLC5A2 Sodium/GLucose
coTransporter 2		 SGLT2 predominantly in the
S1 and S2 segments		 1:1 90

The SLC5 family includes transporters for a diverse range of substrates beyond glucose. Specific members of this family are specialized for the transport of:

Each of these transporters plays a specific role in cellular metabolism and homeostasis, often utilizing sodium gradients for substrate transport similar to the glucose transporters in this family.[9][6]

Mechanism

[edit]

The transport of glucose across the proximal tubule cell membrane involves a complex process of secondary active transport (also known as co-transport).[3] This process begins with the Na+/K+ ATPase on the basolateral membrane. This enzyme uses ATP to pump 3 sodium ions out of the cell into the blood while bringing 2 potassium ions into the cell.[10] This action creates a sodium concentration gradient across the cell membrane, with a lower concentration inside the cell compared to both the blood and the tubular lumen.[3]

SGLT proteins utilize this sodium gradient to transport glucose across the apical membrane into the cell, even against the glucose concentration gradient.[11][3] This mechanism is an example of secondary active transport. Once inside the cell, glucose is then moved across the basolateral membrane into the peritubular capillaries by members of the GLUT family of glucose uniporters.[3]

SGLT1 and SGLT2 are classified as symporters because they move sodium and glucose in the same direction across the membrane.[11][3] To maintain this process, the Sodium–hydrogen antiporter plays a crucial role in replenishing intracellular sodium levels.[12][13] Consequently, the net effect of glucose transport is coupled with the extrusion of protons from the cell, with sodium serving as an intermediate in this process.[12][13]

SGLT2 inhibitors for diabetes

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Main article: Gliflozin

SGLT2 inhibitors, also called gliflozins,[14] are used in the treatment of type 2 diabetes. SGLT2 is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include dapagliflozin (Farxiga in US, Forxiga in EU), canagliflozin (Invokana) and empagliflozin (Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes.[15] The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.[16]

History

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In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption.[17]

Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.[18][19]

See also

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References

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  1. ^ Thorens B, Mueckler M (February 2010). "Glucose transporters in the 21st Century". review. American Journal of Physiology. Endocrinology and Metabolism. 298 (2): E141–5. doi:10.1152/ajpendo.00712.2009. PMC 2822486. PMID 20009031.
  2. ^ a b c d Dominguez Rieg JA, Xue J, Rieg T (September 2020). "Tubular effects of sodium-glucose cotransporter 2 inhibitors: intended and unintended consequences". review. Current Opinion in Nephrology and Hypertension. 29 (5): 523–530. doi:10.1097/MNH.0000000000000632. PMC 8772383. PMID 32701600.
  3. ^ a b c d e f g h Hotait ZS, Lo Cascio JN, Choos EN, Shepard BD (September 2022). "The sugar daddy: the role of the renal proximal tubule in glucose homeostasis". review. American Journal of Physiology. Cell Physiology. 323 (3): C791 – C803. doi:10.1152/ajpcell.00225.2022. PMC 9448277. PMID 35912988.
  4. ^ Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509
  5. ^ Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C, et al. (September 2003). "A glucose sensor hiding in a family of transporters". primary. Proceedings of the National Academy of Sciences of the United States of America. 100 (20): 11753–8. Bibcode:2003PNAS..10011753D. doi:10.1073/pnas.1733027100. PMC 208830. PMID 13130073.
  6. ^ a b Gyimesi G, Pujol-Giménez J, Kanai Y, Hediger MA (September 2020). "Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application". Pflügers Archiv. 472 (9): 1177–1206. doi:10.1007/s00424-020-02433-x. PMC 7462921. PMID 32767111.
  7. ^ Wright EM, Hirayama BA, Loo DF (January 2007). "Active sugar transport in health and disease". Journal of Internal Medicine. 261 (1): 32–43. doi:10.1111/j.1365-2796.2006.01746.x. PMID 17222166. S2CID 44399123.
  8. ^ Wright EM (January 2001). "Renal Na(+)-glucose cotransporters". American Journal of Physiology. Renal Physiology. 280 (1): F10–8. doi:10.1152/ajprenal.2001.280.1.F10. PMID 11133510.
  9. ^ Wright EM, Loo DD, Hirayama BA (April 2011). "Biology of human sodium glucose transporters". review. Physiological Reviews. 91 (2): 733–94. doi:10.1152/physrev.00055.2009. PMID 21527736.
  10. ^ Vallon V (September 2020). "Glucose transporters in the kidney in health and disease". review. Pflügers Archiv: European Journal of Physiology. 472 (9): 1345–1370. doi:10.1007/s00424-020-02361-w. PMC 7483786. PMID 32144488.
  11. ^ a b Mudaliar S, Polidori D, Zambrowicz B, Henry RR (December 2015). "Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside". review. Diabetes Care. 38 (12): 2344–53. doi:10.2337/dc15-0642. PMID 26604280.
  12. ^ a b Nwia SM, Li XC, Leite AP, Hassan R, Zhuo JL (2022). "The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension". review. Frontiers in Physiology. 13: 861659. doi:10.3389/fphys.2022.861659. PMC 9062697. PMID 35514347.
  13. ^ a b Liu J, Tian J, Sodhi K, Shapiro JI (December 2021). "The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?". review. The Journal of Membrane Biology. 254 (5–6): 513–529. doi:10.1007/s00232-021-00192-z. PMC 8595165. PMID 34297135.
  14. ^ "SGLT2 Inhibitors (Gliflozins)". Diabetes.co.uk. Retrieved 2015-05-19.
  15. ^ Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. (November 2015). "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes". The New England Journal of Medicine. 373 (22): 2117–28. doi:10.1056/NEJMoa1504720. hdl:11573/894529. PMID 26378978. S2CID 205098095.
  16. ^ "Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors". Center for Drug Evaluation and Research (CDER). U.S. Food and Drug Administration (FDA). 2018-12-28.
  17. ^ Crane RK, Miller D, Bihler I (1961). "The restrictions on possible mechanisms of intestinal transport of sugars". In Kleinzeller A, Kotyk A (eds.). Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Czech Academy of Sciences & Academic Press. pp. 439–449.
  18. ^ Wright EM, Turk E (February 2004). "The sodium/glucose cotransport family SLC5". Pflügers Archiv. 447 (5): 510–8. doi:10.1007/s00424-003-1063-6. PMID 12748858. S2CID 41985805. Crane in 1961 was the first to formulate the cotransport concept to explain active transport [7]. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across the brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type.
  19. ^ Boyd CA (March 2008). "Facts, fantasies and fun in epithelial physiology". Experimental Physiology. 93 (3): 303–14. doi:10.1113/expphysiol.2007.037523. PMID 18192340. S2CID 41086034. p. 304. "the insight from this time that remains in all current text books is the notion of Robert Crane published originally as an appendix to a symposium paper published in 1960 (Crane et al. 1960). The key point here was 'flux coupling', the cotransport of sodium and glucose in the apical membrane of the small intestinal epithelial cell. Half a century later this idea has turned into one of the most studied of all transporter proteins (SGLT1), the sodium–glucose cotransporter.
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