Sodium-glucose transport proteins

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solute carrier family 5 (sodium/glucose cotransporter), member 1
Identifiers
Symbol SLC5A1
Alt. symbolsSGLT1
NCBI gene 6523
HGNC 11036
OMIM 182380
RefSeq NM_000343
UniProt P13866
Other data
Locus Chr. 22 q13.1
Search for
Structures Swiss-model
Domains InterPro
solute carrier family 5 (sodium/glucose cotransporter), member 2
Identifiers
Symbol SLC5A2
Alt. symbolsSGLT2
NCBI gene 6524
HGNC 11037
OMIM 182381
RefSeq NM_003041
UniProt P31639
Other data
Locus Chr. 16 p11.2
Search for
Structures Swiss-model
Domains InterPro
solute carrier family 5 (low affinity glucose cotransporter), member four
Identifiers
Symbol SLC5A4
Alt. symbolsSGLT3, SAAT1, DJ90G24.4
NCBI gene 6527
HGNC 11039
RefSeq NM_014227
UniProt Q9NY91
Other data
Locus Chr. 22 q12.1-12.3
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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. [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]

GeneProteinAcronymTissue distribution
in proximal tubule [7] 		Na+:Glucose
Co-transport ratio		Contribution to glucose
reabsorption (%) [8]
SLC5A1 Sodium/GLucose
coTransporter 1		SGLT1S3 segment2:110
SLC5A2 Sodium/GLucose
coTransporter 2		SGLT2predominantly in the
S1 and S2 segments		1:190

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

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

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

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

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

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 coupled or 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.

<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">Glucose transporter</span> Family of monosaccharide transport proteins

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by the human genome. GLUT is a type of uniporter transporter protein.

Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion and secondary active transport. Active transport is the movement of ions or molecules going against the concentration gradient.

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.

The sodium/phosphate cotransporter is a member of the phosphate:Na+ symporter (PNaS) family within the TOG Superfamily of transport proteins as specified in the Transporter Classification Database (TCDB).

<span class="mw-page-title-main">Symporter</span> Class of membrane transport proteins

A symporter is an integral membrane protein that is involved in the transport of two different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the cell membrane at the same time, and is, therefore, a type of cotransporter. The transporter is called a symporter, because the molecules will travel in the same direction in relation to each other. This is in contrast to the antiport transporter. Typically, the ion(s) will move down the electrochemical gradient, allowing the other molecule(s) to move against the concentration gradient. The movement of the ion(s) across the membrane is facilitated diffusion, and is coupled with the active transport of the molecule(s). In symport, two molecule move in a 'similar direction' at the 'same time'. For example, the movement of glucose along with sodium ions. It exploits the uphill movement of other molecules from low to high concentration, which is against the electrochemical gradient for the transport of solute molecules downhill from higher to lower concentration.

<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">Sodium/glucose cotransporter 2</span> Protein-coding gene in the species Homo sapiens

The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 gene.

In renal physiology, renal sodium reabsorption refers to the process by which the kidneys, having filtered out waste products from the blood to be excreted as urine, re-absorb sodium ions (Na2+) from the waste. It uses Na-H antiport, Na-glucose symport, sodium ion channels (minor). It is stimulated by angiotensin II and aldosterone, and inhibited by atrial natriuretic peptide.

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">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">Robert K. Crane</span> American biochemist

Robert Kellogg Crane was an American biochemist best known for his discovery of sodium–glucose cotransport.

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

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.

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. ↑ 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. 1 2 3 4 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. 1 2 3 4 5 6 7 8 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. 1 2 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. 1 2 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. 1 2 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. 1 2 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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