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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). 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 the nephron.

Types

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.^[1]

Gene	Protein	Acronym	Tissue distribution in proximal tubule^[2]	Na⁺:Glucose Co-transport ratio	Contribution to glucose reabsorption (%)^[3]
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

SGLT2 inhibitors for diabetes

Inhibition of SGLT2 leads to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. Several drug candidates have been developed or are currently undergoing clinical trials, including:^[4]

Dapagliflozin, approval rejected in 2012 by Food and Drug Administration due to safety concerns however after resubmitting additional clinical data is under review with Dec 12, 2013 as PDUFA Date,^[5] but marketed in Europe and Australia. Dapagliflozin was the first SGLT2 approved anywhere in the world in 2011 by the EU.
Canagliflozin, approved in the United States and Canada^[6]
Ipragliflozin (ASP-1941), in Phase III clinical trials^[7]
Tofogliflozin, in Phase III clinical trials^[7]
Empagliflozin, approved in the United States^[8]
Sergliflozin etabonate, discontinued after Phase II trials
Remogliflozin etabonate, in phase IIb trials

Function

Firstly, the Na+/K+ ATPase pump on the basolateral membrane of the proximal tubule cell uses ATP to move 3 sodium ions outward into the blood, while bringing in 2 potassium ions. This creates a downhill sodium ion gradient inside the proximal tubule cell in comparison to both the blood and the tubule. 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. Therefore, these co-transporters are an example of secondary active transport. (The GLUT uniporters then transport the glucose across the basolateral membrane, into the peritubular capillaries.) Both SGLT1 and SGLT2 are known as symporters, since both sodium ions and glucose are transported in the same direction across the membrane.

Discovery of sodium-glucose cotransport

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.^[9]

Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.^[10]^[11]

References

^ Ensembl release 48: Homo sapiens Ensembl protein family ENSF00000000509
^ Wright EM, Hirayama BA, Loo DF (January 2007). "Active sugar transport in health and disease". J. Intern. Med. 261 (1): 32–43. doi:10.1111/j.1365-2796.2006.01746.x. PMID 17222166.
^ Wright EM (January 2001). "Renal Na(+)-glucose cotransporters". Am. J. Physiol. Renal Physiol. 280 (1): F10–8. PMID 11133510.
^ InsightPharma (2010). "Diabetes Pipeline: Intense Activity to Meet Unmet Need". p. vii.
^ Bristol, AstraZeneca Diabetes Drug Fails to Win FDA Backing, Business Week, January 19, 2012
^ Invokana, First in New Class of Diabetes Drugs, Approved, MPR, March 29, 2013
^ ^a ^b SGLT2 inhibitor approval race
^ "FDA approves Jardiance® (empagliflozin) tablets for adults with type 2 diabetes". Boehringer Ingelheim / Eli Lilly and Company. 1 August 2014. Retrieved 5 November 2014.
^ Miller D, Bihler I (1961). "The restrictions on possible mechanisms of intestinal transport of sugars". In Kleinzeller A. Kotyk A. Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Czech Academy of Sciences & Academic Press. pp. 439–449.
^ Wright EM, Turk E (February 2004). "The sodium/glucose cotransport family SLC5". Pflugers Arch. 447 (5): 510–8. doi:10.1007/s00424-003-1063-6. PMID 12748858. 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.
^ Boyd CA (March 2008). "Facts, fantasies and fun in epithelial physiology". Exp. Physiol. 93 (3): 303–14. doi:10.1113/expphysiol.2007.037523. PMID 18192340. 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.

External links

Sodium-Glucose Transport Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)

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UpToDate Contents

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1. 糖尿病患者における高血圧治療 treatment of hypertension in patients with diabetes mellitus
2. 成人における肥満：病因および自然経過 obesity in adults etiology and natural history
3. 消化管の発達に関する概要 overview of the development of the gastrointestinal tract
4. 成人の2型糖尿病治療におけるメトホルミン metformin in the treatment of adults with type 2 diabetes mellitus
5. 乳糖不耐症 lactose intolerance

English Journal

A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trials.

Musso G, Gambino R, Cassader M, Pagano G.SourceGradenigo Hospital , Turin , Italy.
Annals of medicine.Ann Med.2012 Jun;44(4):375-93. Epub 2011 Apr 15.
Abstract Background. Current treatment of hyperglycemia in type 2 diabetes (T2DM) is often ineffective and has unwanted effects. Therefore, novel antidiabetic drugs are under development. Objective. To assess efficacy and safety of the new antidiabetic drugs sodium glucose co-transport-2 (SGLT2)
PMID 21495788

EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells.

Huber SM, Misovic M, Mayer C, Rodemann HP, Dittmann K.SourceDepartment of Radiation Oncology, University of Tübingen, Germany.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.Radiother Oncol.2012 Apr 17. [Epub ahead of print]
BACKGROUND AND PURPOSE: Solid tumor cells may adapt to an ischemic microenvironment by upregulation of sodium/glucose cotransport (SGLT) in the plasma membrane which supplies the tumor cell with glucose even at very low extracellular glucose concentration. Since SGLT activity has been shown to depen
PMID 22516777

Japanese Journal

口腔扁平上皮癌におけるEGFRとSGLT1の発現解析

花畑泰子
口腔病学会雑誌 78(1), 12-18, 2011-03-31
NAID 10028159154

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice.

Ogawa Eiichi,Hosokawa Masaya,Harada Norio,Yamane Shunsuke,Hamasaki Akihiro,Toyoda Kentaro,Fujimoto Shimpei,Fujita Yoshihito,Fukuda Kazuhito,Tsukiyama Katsushi,Yamada Yuichiro,Seino Yutaka,Inagaki Nobuya
Biochemical and biophysical research communications 404(1), 115-120, 2011-01-07
… Incorporation of [(14)C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). … In vitro examination of [(14)C]-glucose uptake revealed that 100nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. …
NAID 120002737766

Related Pictures

★リンクテーブル★

リンク元	「グルコース」
拡張検索	「SGLT1」「SGLT2」「SGLT1 gene」
関連記事	「SG」

「グルコース」

solute carrier family 5 (low affinity glucose cotransporter), member 4
Identifiers
Symbol	SLC5A4
Alt. symbols	SGLT3, SAAT1, DJ90G24.4
Entrez	6527
HUGO	11039
RefSeq	NM_014227
UniProt	Q9NY91
Other data
Locus	Chr. 22 q12.1-12.3

solute carrier family 5 (sodium/glucose cotransporter), member 2
Identifiers
Symbol	SLC5A2
Alt. symbols	SGLT2
Entrez	6524
HUGO	11037
OMIM	182381
RefSeq	NM_003041
UniProt	P31639
Other data
Locus	Chr. 16 p11.2

solute carrier family 5 (sodium/glucose cotransporter), member 1
Identifiers
Symbol	SLC5A1
Alt. symbols	SGLT1
Entrez	6523
HUGO	11036
OMIM	182380
RefSeq	NM_000343
UniProt	P13866
Other data
Locus	Chr. 22 q13.1

　　[★]

英: glucose, grape sugar, dextrose
商: ブドウ糖注、グルノン
関: GLUT、血中グルコース濃度、血糖値、GLUT; グルコース1-リン酸、グルコース6-リン酸

分子量

分子量：180 g/mol

血糖 100 mg/dl -> 1000 mg/l ; 1000 mg/l / 180 g/mol ≒5.6 mmol/l = 5.6 mM

尿細管におけるグルコースの再吸収 SP.801

近位尿細管における刷子縁で行われる。
管腔側に糖/Na+共輸送体 SGLT(SGLT1とSGLT2)が存在し、Naとグルコースを共輸送する
SGLT2がグルコースの取り込みに貢献している(低親和性、高用量の輸送担体)

	SGLT1	SGLT2
局在	近位尿細管	近位尿細管
	中間部(S2)	起始部(S1)
	終末部(S3)	起始部(S1)
グルコースの親和性	高親和性	低親和性