Human Transporters


SGLT2 (sodium/glucose cotransporter 2)

Aliases: None
Gene name:  Solute carrier family 5 member 2 (SLC5A2)


SGLT2 is a member of the SGLT (SLC5) family that contains six SGLT proteins, including SGLT3 which is a glucose sensor expressed in neurons [1]. SGLT2 transports D-glucose with low affinity and high capacity (a KM of 5 mM was detected in HEK293 cells overexpressing SGLT2) [2]. It also transports - methyl-D-glucopyranoside (AMG) with similar affinity, while its affinity for galactose is significantly lower [2]. SGLT2-mediated glucose transport is electrogenic, and coupled with Na+ transport in a stoichiometric ratio of 1:1 [2]. Phlorizin as an inhibitor is an order of magnitude more potent towards SGLT2 than towards SGLT1 (Ki = 10-39 nM vs. 200-300 nM), which makes phlorizin somewhat specific to SGLT2 over SGLT1 [1-4].
SGLT2 is exclusively expressed in the early proximal convoluted tubule and plays a crucial role in glucose reabsorption from the filtrate. As a prominent contributor to glucose homeostasis, SGLT2 is an important drug target in type 2 diabetes (T2D). Over the past decades, numerous SGLT2-specific inhibitors were developed along the strategy of modifying phlorizin structure to enhance selectivity towards SGLT2. The first SGLT2-specific inhibitor, T-1095, was reported in 1999 [5]. It was followed by canagliflozin, dapagliflozin, and empagliflozin, all of which have two orders of magnitude higher selectivity towards SGLT2 compared to SGLT1. These three drugs are now approved by the FDA for the treatment of T2D as single-ingredient products or in combination with other diabetes medicines such as metformin. Additional SGLT2 inhibitors are in the pipeline, or even in clinical trials. 


The sodium/glucose cotransport hypothesis was introduced as early as 1960 by Crane B [6], but the first transporter of the sodium/glucose cotransporter family, SGLT1, was only cloned in the late 1980s [7, 8]. Using low-stringency screening with human SGLT1 as a probe, a 672-residue protein with 59% identity at the amino acid level to SGLT1 was cloned from the human kidney in 1992 [9]. The clone encoding the SGLT2 protein was exclusively found in the kidney [10], more specifically in the early proximal tubule. This expression pattern was further confirmed with Western blot analysis of tissue samples from Sglt2-knockout and wild-type mice [11], where a specific 70-kDa protein was found. Immunostaining with a specific antibody confirmed Slgt2 localization in the apical brush border membrane of early proximal convoluted tubules [12]. SGLT2 was also found in pancreatic -cells [13], where SGLT2 inhibition stimulates glucagon secretion though the upregulation of SGLT1 expression [14]. Low mRNA expression was also detected in the cerebellum, and even lower levels may be present in the liver, thyroid muscle, and heart, based on unpublished data by Wright [1].
Relatively little information is available on the regulation of SGLT2 gene expression. The promoter contains a binding site for hepatocyte nuclear factor-1 (HNF-1), and HNF-1 was shown to enhance the promoter activity [15]. 

Function, physiology, and clinically significant polymorphisms

A two-tier sodium-dependent transport mechanism is responsible for glucose reabsorption in the kidney. Glucose is freely filtered across the glomerulus, and more than 97% of the filtered amount is reabsorbed in healthy individuals. This reabsorption is saturated when glucose concentration in the filtrate exceeds 20 mM. Studies on rat, rabbit, and frog nephrons support a hypothesis that active glucose reabsorption occurs in the early convoluted proximal tubule via a low affinity, high capacity system, whereas in the late proximal tubule a high affinity (Km 0.5), low capacity (10 pmol/min/mm) system is at work [1]. Based on their localization, as well as the characteristics and physiological parameters of transporter-knockout mice, the low affinity / high capacity SGLT2 mediates the bulk reabsorption (80-90%) of glucose across the apical membrane of early proximal tubule cells, whereas SGLT1 with high affinity and low capacity is responsible for further reducing luminal glucose concentration to a very low level in the distal part of the proximal tubule [1, 16, 17]. 
In addition to glucose, SGTL2 also transports -methyl-D-glucopyranoside (AMG) with similar affinity to glucose (Km 6 mM); galactose transport by SGLT2, however, showed a KM higher than 100mM in transiently expressing HEK293 cells [2]. SGLT2-mediated transport is specifically inhibited by phlorizin, which has an order of magnitude higher affinity (Ki = 10-39 nM) towards SGLT2 compared to SGLT1 (200-300 nM) [1-4]. Galactose is also transported by SGLT2, albeit with a 10-fold lower apparent affinity than glucose (Km = 6 vs 0.5 mM) [2]. SGLT2-mediated glucose transport is electrogenic, and coupled with Na+ transport at a stoichiometric ratio of 1:1 [2]. 
Mutations in SGLT2 are associated with familial renal glucosuria (FRG), a rare autosomal recessive disorder where glucose is excreted into the urine despite of normal blood glucose levels and glucose tolerance tests [18]. All other renal functions are normal, and most patients do not seem to develop significant clinical problems over time. Since this hereditary condition results in benign glucosuria and no long-term renal abnormalities, this natural analogy encouraged the pharmaceutical industry to develop SGLT2 inhibitors for the treatment of T2D [18, 19]. 

Clinical significance

Because intravenous phlorizin normalized blood glucose levels and reversed insulin resistance in diabetic animals [20], and given that FRG is a benign disorder with no long-term renal abnormalities, SGLT2 inhibitors have been extensively investigated as potential therapeutics for type 2 diabetes (T2D). In the last decade, numerous SGLT2-specific inhibitors have been developed and studied for use in combination with diet and exercise to lower blood sugar in adults with T2D [21]. 
Since phlorizin has a fourfold higher affinity for SGLT2 compared to SGLT1 [4, 22, 23], the strategy chosen by pharmaceutical companies was to modify phlorizin structure to enhance selectivity. The first SGLT2-specific inhibitor, T-1095, was a phlorizin derivative developed in 1999 [5]. It could be administered orally in the form of a prodrug that did not interact with SGLT1, and the active drug had a fourfold increase in SGLT2/SGLT1 selectivity. The drug elicited renal glucose excretion and lowered glucose levels in diabetic animals. In addition, it also suppressed postprandial hyperglycemia, and reduced hyperinsulinemia and hypertriglyceridemia [5]. 
There are currently four SGLT2 inhibitors approved by the FDA: canagliflozin, dapagliflozin, empagliflozin and ertugliflozin [24, 25], all of which are available as single-ingredient products or in combination with other diabetes medicines such as metformin [26, 27]. SGLT2 selectivity over SGLT1 is increasing from 1:414 of canagliflozin to 1:1200 of dapagliflozin, 1:2000 of ertugliflozin, and 1:2500 of empagliflozin [28]. In addition to these three drugs, ipragliflozin, luseogliflozin, and tofogliflozin are marketed in Japan [17], and some other SGLT2 inhibitors are currently in the pipeline: remogliflozin has already been commercialized in India and is awaiting approval from the FDA, while the dual SGLT1/SGLT2 inhibitor sotagliflozin has completed phase III [17, 28]. All marketed drugs have been shown to have additional beneficial effects to glucose control, such as reduction of HbA1c [29-31], fasting plasma glucose (FPG), body weight (BW), and blood pressure (BP), as well as slightly increased HDL-cholesterol [32]. Importantly, long-term studies have found that SGLT2 inhibitors cause more durable reduction in HbA1c level than sulfonylureas and dipeptidyl peptidase (DPP)-4 inhibitors [33-35]. Since cardiovascular mortality is the primary cause of death in patients with T2D [17], the beneficial effects of SGLT2 inhibitors on the cardiovascular system are of high importance and subject to intensive study. Protection against cardiovascular events has already been reported for dapagliflozin [36] and empagliflozin [37-41] [ref]. A study with empagliflozin showed long-term beneficial effects on cardiovascular outcome, and significant reduction in the risk of worsening or incident nephropathy among patients with T2D at high cardiovascular risk [38]. In another study empagliflozin displayed an anti-inflammatory activity, suggesting a novel cardioprotective mechanism of this SGLT2 inhibitor via the AMPK activation-mediated energy repletion [42]. Other mechanisms by which SGLT2 inhibitors protect cardiovascular and renal function still need to be elucidated [17, 39]. 
Available safety data indicate that SGLT2 inhibitors are generally well tolerated, with several exceptions [43-45]. A recent study has shown that co-administration of the antidiabetic drugs dapagliflozin, metformin and sitagliptin to a type 2 diabetes mellitus patient was linked to the development of a life-threatening condition known as Fournier’s gangrene [46]. Surgical intervention and permanent discontinuation of dapagliflozin treatment was required. FDA warning of a serious infection associated with SGLT2 inhibitors has been added to the medication guide announcement [47]. The FDA also confirmed an increased risk of foot and leg amputations associated with the administration of the type 2 diabetes drug canagliflozin announcement [48, 49].

Regulatory requirements

Glucose transporters are not significantly involved in DDI or drug ADME, and therefore do not feature in FDA or EMA guidances.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors
kidney proximal tubule cells, pancreatic a-cells, cerebellum glucose α- methyl-D-glucopyranoside (AMG)   phlorizin, dapaglifozin, canagliflozin, empagliflozin, ipragliflozin luseogliflozin tofogliflozin, ertugliflozin, remogliflozin, sotagliflozin, DJT1116PG [50], DWP16001 [51],
quinidine, cloperastine,
(+)‐pteryxin, bepridil, trihexyphenidyl, bupivacaine, 
(+)‐ε‐viniferin [52]



1.    Wright, E.M., D.D. Loo, and B.A. Hirayama, Biology of human sodium glucose transporters. Physiol Rev, 2011. 91(2): p. 733-94.
2.    Hummel, C.S., et al., Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol, 2011. 300(1): p. C14-21.
3.    Hirayama, B.A., et al., Kinetic and specificity differences between rat, human, and rabbit Na+-glucose cotransporters (SGLT-1). Am J Physiol, 1996. 270(6 Pt 1): p. G919-26.
4.    Pajor, A.M., et al., Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters. J Pharmacol Exp Ther, 2008. 324(3): p. 985-91.
5.    Oku, A., et al., T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes, 1999. 48(9): p. 1794-800.
6.    AKA, K., Membrane Transport and Metabolism Praha Publishing House of the Chechoslovak Academy of Sciences, 1961: p. 608.
7.    Hediger, M.A., et al., Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature, 1987. 330(6146): p. 379-81.
8.    Hediger, M.A., et al., Expression of size-selected mRNA encoding the intestinal Na/glucose cotransporter in Xenopus laevis oocytes. Proc Natl Acad Sci U S A, 1987. 84(9): p. 2634-7.
9.    Wells, R.G., et al., Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol, 1992. 263(3 Pt 2): p. F459-65.
10.    Nishimura, M. and S. Naito, Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet, 2005. 20(6): p. 452-77.
11.    Vallon, V., et al., Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol, 2013. 304(2): p. F156-67.
12.    Vallon, V. and T. Rieg, Regulation of renal NaCl and water transport by the ATP/UTP/P2Y2 receptor system. Am J Physiol Renal Physiol, 2011. 301(3): p. F463-75.
13.    Bonner, C., et al., Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med, 2015. 21(5): p. 512-7.
14.    Solini, A., et al., Dapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells. Diabetes Metab, 2017.
15.    Pontoglio, M., et al., HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep, 2000. 1(4): p. 359-65.
16.    Wright, E.M., Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol, 2001. 280(1): p. F10-8.
17.    DeFronzo, R.A., L. Norton, and M. Abdul-Ghani, Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol, 2017. 13(1): p. 11-26.
18.    Santer, R. and J. Calado, Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol, 2010. 5(1): p. 133-41.
19.    Calado, J., et al., Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant, 2008. 23(12): p. 3874-9.
20.    Rossetti, L., et al., Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest, 1987. 80(4): p. 1037-44.
21.    Weir, M.R., The kidney and type 2 diabetes mellitus: therapeutic implications of SGLT2 inhibitors. Postgrad Med, 2016. 128(3): p. 290-8.
22.    Hummel, C.S., et al., Structural selectivity of human SGLT inhibitors. Am J Physiol Cell Physiol, 2012. 302(2): p. C373-82.
23.    Katsuno, K., et al., 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. J Pharmacol Exp Ther, 2007. 320(1): p. 323-30.
24.    Jia, Y.M., et al., Multidrug Resistance-Associated Protein 3 Is Responsible for the Efflux Transport of Curcumin Glucuronide from Hepatocytes to the Blood. Drug Metab Dispos, 2020. 48(10): p. 966-971.
25.    Kovacich, N. and B. Chavez, Ertugliflozin (Steglatro): A New Option for SGLT2 Inhibition. P T, 2018. 43(12): p. 736-742.
26.    Zhou, S.F., et al., Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem., 2008. 15(20): p. 1981-2039.
27.    Simes, B.C. and G.G. MacGregor, Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician's Guide. Diabetes Metab Syndr Obes, 2019. 12: p. 2125-2136.
28.    Inzucchi, S.E., et al., SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res, 2015. 12(2): p. 90-100.
29.    Vasilakou, D., et al., Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med, 2013. 159(4): p. 262-74.
30.    Bailey, C.J., et al., Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet, 2010. 375(9733): p. 2223-33.
31.    Haring, H.U., et al., Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care, 2014. 37(6): p. 1650-9.
32.    Zaccardi, F., et al., Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: Systematic review and network meta-analysis. Diabetes Obes Metab, 2016.
33.    Lavalle-Gonzalez, F.J., et al., Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia, 2013. 56(12): p. 2582-92.
34.    Schernthaner, G., et al., Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care, 2013. 36(9): p. 2508-15.
35.    Scheen, A.J., Reduction in HbA1c with SGLT2 inhibitors vs. DPP-4 inhibitors as add-ons to metformin monotherapy according to baseline HbA1c: A systematic review of randomized controlled trials. Diabetes Metab, 2020. 46(3): p. 186-196.
36.    Hardy E, P.A., de Bruin TWA, Johnsson E, Parikh SJ, List J, et al., Changes in lipid profiles of patients with type 2 diabetes mellitus on dapagliflozin therapy. . Diabetologie und Stoffwechsel, 2014. 9(S 01): p. 947.
37.    Zinman, B., et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015. 373(22): p. 2117-28.
38.    Abdul-Ghani, M., et al., SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study. Diabetes Care, 2016. 39(5): p. 717-25.
39.    Imran, H., et al., Role of sodium glucose co-transporter 2 inhibitors in patients with heart failure: an elusive mechanism. Ann Med, 2020. 52(5): p. 178-190.
40.    Fitchett, D., et al., Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation, 2019. 139(11): p. 1384-1395.
41.    Wiviott, S.D., et al., Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 2019. 380(4): p. 347-357.
42.    Koyani, C.N., et al., Empagliflozin protects heart from inflammation and energy depletion via AMPK activation. Pharmacol Res, 2020. 158: p. 104870.
43.    Boyle, L.D. and J.P. Wilding, A safety evaluation of canagliflozin : a first-in-class treatment for type 2 diabetes. Expert Opin Drug Saf, 2014. 13(11): p. 1535-44.
44.    Monami, M., C. Nardini, and E. Mannucci, Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab, 2014. 16(5): p. 457-66.
45.    Wu, J.H., et al., Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol, 2016.
46.    Rodler, S., et al., Fournier s Gangrene Under Sodium-Glucose Cotransporter 2 Inhibitor Therapy as a Life-Threatening Adverse Event: A Case Report and Review of the Literature. Cureus, 2019. 11(9): p. e5778.
47.    FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Available from:
48.    Matthews, D.R., et al., Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia, 2019. 62(6): p. 926-938.
49.    FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Available from:
50.    Zhang, H., et al., A Phase I Study on the Pharmacokinetics and Pharmacodynamics of DJT1116PG, a Novel Selective Inhibitor of Sodium-glucose Cotransporter Type 2, in Healthy Individuals at Steady State. Clin Ther, 2020. 42(5): p. 892-905 e3.
51.    Choi, M.K., et al., Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin. Pharmaceutics, 2020. 12(3).
52.    Oranje, P., et al., Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2. Pharmacol Res Perspect, 2019. 7(4): p. e00504.

Solvo Transporter Book 4th Edition
Transporter Book 4th edition
  • 63 transporters
  • over 1500 references
  • comprehensive information on holistic models and proteomics for transporter research
  • changes in the regulatory landscape and scientific insights

Get the Book