Sodium-glucose transport proteins

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 a healthy 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]

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 is marketed in Europe and Australia. Dapagliflozin was the first SGLT2 approved anywhere in the world in 2011 by the EU. Dapagliflozin was approved under the brand name "Farxiga" by the FDA on Jan 8, 2014.^[6]
• Canagliflozin, approved in the United States and Canada under the brand name "Invokana"^[7]
• Ipragliflozin (ASP-1941), produced by the Japanese company Astellas Pharma Inc. under the brand name "Suglat"; approved in Japan January 17, 2014.^[8][9]
• Tofogliflozin, approved in Japan under the brand names "Apleway" and "Deberza" by Sanofi and Takeda Pharmaceutical^[10]
• Empagliflozin, approved in the United States under the brand name "Jardiance".^[11]
• Sergliflozin etabonate, discontinued after Phase II trials
• Remogliflozin etabonate(BHV091009), in phase IIb trials by BHV Pharma. BHV (Brighthaven Ventures, LLC) is a private company acquired by Islet Sciences, Inc. in 2014.^[12][13]

Function

Firstly, an Na+/K+ ATPase pump on the basolateral membrane of the proximal tubule cell uses 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.

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. 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 symporters.

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.^[14]

Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.^[15][16]

See also

• Cotransport
• Cotransporter
• Glucose-galactose malabsorption
• Renal sodium reabsorption
• Discovery and development of SGLT-2 inhibitors

References

External links

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