Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [8] for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. D-glucose), but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na⁺ that causes membrane depolarization [2].

Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De-oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see [8] for a detailed quantification). Although SGLT1 and SGLT2 have been described as high- and low-affinity sodium glucose co-transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions [3]. Selective blockers of SGLT2, and thus blocking ~50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [1]).

1. Chao EC, Henry RR. (2010) SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov, 9 (7): 551-9. [PMID:20508640]

2. Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C, Wright EM, Koepsell H. (2003) A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci USA, 100 (20): 11753-8. [PMID:13130073]

3. Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM. (2011) Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol, Cell Physiol, 300 (1): C14-21. [PMID:20980548]

4. Inoue T, Takemura M, Fushimi N, Fujimori Y, Onozato T, Kurooka T, Asari T, Takeda H, Kobayashi M, Nishibe H et al.. (2017) Mizagliflozin, a novel selective SGLT1 inhibitor, exhibits potential in the amelioration of chronic constipation. Eur J Pharmacol, 806: 25-31. [PMID:28410751]

5. Kanai Y, Lee WS, You G, Brown D, Hediger MA. (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest, 93 (1): 397-404. [PMID:8282810]

6. Kang SY, Song KS, Lee J, Lee SH, Lee J. (2010) Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors. Bioorg Med Chem, 18 (16): 6069-79. [PMID:20637636]

7. Voss AA, Díez-Sampedro A, Hirayama BA, Loo DD, Wright EM. (2007) Imino sugars are potent agonists of the human glucose sensor SGLT3. Mol Pharmacol, 71 (2): 628-34. [PMID:17110502]

8. Wright EM, Loo DD, Hirayama BA. (2011) Biology of human sodium glucose transporters. Physiol Rev, 91 (2): 733-94. [PMID:21527736]