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Sodium-glucose transport proteins

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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.

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
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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
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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

Types

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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]

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] 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]

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

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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". Pflugers 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. Pflugers 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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