Reactome | SLC5A2 binds gliflozins

SLC5A2 binds gliflozins

Stable Identifier

R-HSA-9728150

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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The human gene SLC5A2 encodes sodium/glucose cotransporter 2 (SGLT2). At the plasma membrane, it co-transports extracellular sodium ions and glucose into the cytosol. SLC5A2 is located in the early proximal tubule, and absorbs 80-90% of the glucose filtered by the kidney glomerulus. The majority of the remaining glucose is absorbed by sodium/glucose cotransporter 1 (SLC5A1, SGLT1) in more distal sections of the proximal tubule.

SLC5A2 inhibitors, collectively called 'gliflozins', inhibit SLC5A2 in proximal tubules of renal glomeruli, causing inhibition of glucose reabsorption, resulting in glycosuria in diabetics which in turn lowers plasma glucose levels (Katsuno et al. 2007, Pajor et al. 2008, Hummel et al. 2012, review - Chao 2014). Therefore, gliflozins can be used in the treatment of type II diabetes mellitus (T2DM); dapagliflozin (Zhang et al. 2010), ertugliflozin (Mascitti et al. 2011), canagliflozin (Liang et al. 2012), sotagliflozin (Zambrowicz et al. 2012), tofogliflozin (Grempler et al. 2012), tofogliflozin (Ohtake et al. 2012), and ipragliflozin (Imamura et al. 2012). Dapagliflozin was the first gliflozin approved for the treatment of T2DM. They are most often used as second- or third-line treatment of T2DM because other anti-diabetics have better safety records and are less expensive than gliflozins. They are good options for diabetics who fail with metformin monotherapy or in combination therapy, for example metformin plus gliflozin. The most common adverse effect of gliflozin treatment is genital infections.

Gliflozins have shown protective effects in heart failure. This is primarily due to haemodynamic effects, where gliflozins potently reduce intravascular volume through osmotic diuresis and natriuresis. Consequently, this may lead to a reduction in cardiac workload and improving left ventricular function (Lan et al. 2019, Chan et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
21940664	Structural selectivity of human SGLT inhibitors Kepe, V, Lu, C, Ghezzi, C, Loo, DD, Hirayama, BA, Liu, J, Wright, EM, Barrio, JR, Hummel, CS	Am J Physiol Cell Physiol	2012
18063724	Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters Kerner, SA, Smith, CD, Pajor, AM, Randolph, KM	J Pharmacol Exp Ther	2008
17050778	Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level Fujimori, Y, Komatsu, Y, Takemura, Y, Katsuno, K, Isaji, M, Fujikura, H, Itoh, F, Hiratochi, M	J Pharmacol Exp Ther	2007