Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep;472(9):1177-1206.
doi: 10.1007/s00424-020-02433-x. Epub 2020 Aug 7.

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

Gergely Gyimesi  1 , Jonai Pujol-Giménez  1 , Yoshikatsu Kanai  2 , Matthias A Hediger  3
Affiliations
Review

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

Gergely Gyimesi et al. Pflugers Arch. 2020 Sep.

Abstract

Sodium glucose transporters (SGLTs) belong to the mammalian solute carrier family SLC5. This family includes 12 different members in human that mediate the transport of sugars, vitamins, amino acids, or smaller organic ions such as choline. The SLC5 family belongs to the sodium symporter family (SSS), which encompasses transporters from all kingdoms of life. It furthermore shares similarity to the structural fold of the APC (amino acid-polyamine-organocation) transporter family. Three decades after the first molecular identification of the intestinal Na+-glucose cotransporter SGLT1 by expression cloning, many new discoveries have evolved, from mechanistic analysis to molecular genetics, structural biology, drug discovery, and clinical applications. All of these advances have greatly influenced physiology and medicine. While SGLT1 is essential for fast absorption of glucose and galactose in the intestine, the expression of SGLT2 is largely confined to the early part of the kidney proximal tubules, where it reabsorbs the bulk part of filtered glucose. SGLT2 has been successfully exploited by the pharmaceutical industry to develop effective new drugs for the treatment of diabetic patients. These SGLT2 inhibitors, termed gliflozins, also exhibit favorable nephroprotective effects and likely also cardioprotective effects. In addition, given the recent finding that SGLT2 is also expressed in tumors of pancreas and prostate and in glioblastoma, this opens the door to potential new therapeutic strategies for cancer treatment by specifically targeting SGLT2. Likewise, further discoveries related to the functional association of other SGLTs of the SLC5 family to human pathologies will open the door to potential new therapeutic strategies. We furthermore hope that the herein summarized information about the physiological roles of SGLTs and the therapeutic benefits of the gliflozins will be useful for our readers to better understand the molecular basis of the beneficial effects of these inhibitors, also in the context of the tubuloglomerular feedback (TGF), and the renin-angiotensin system (RAS). The detailed mechanisms underlying the clinical benefits of SGLT2 inhibition by gliflozins still warrant further investigation that may serve as a basis for future drug development.

Keywords: Cancer; Diabetes; Drug delivery; Gliflozins; Glucose transport; Molecular docking; Nephroprotective; Renin-angiotensin system; SGLT1; SGLT2; SGLT2 inhibitors; SLC5 family; Tubuloglomerular feedback.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Phylogenetic tree of human SLC5 members. The physiological substrates of individual transporters are indicated (SCFA: short chain fatty acids). The phylogenetic tree was visualized with the Interactive Tree of Life (iTOL) server [95]
Fig. 2
Fig. 2
Na+-glucose cotransporter SGLT1 kinetic model. Extracellular Na+ binds first to the Na+1 and Na+2 binding sites of the empty carrier (states #1 and #2). This opens the external gate, allowing glucose to bind to the central pocket, whereupon the outer barrier closes to form the occluded state (#3). The internal barrier opens and the two Na+ ions and glucose can exit to the cytoplasm via the aqueous inner vestibule (#4). The transport cycle is then completed (#5) and the empty carrier returns to its original state (#1), ready for the next transport cycle. The transport rate of SGLT1 depends on the rate of the conformational changes needed to open and close the outer and inner barriers (step #2 to #3 and step #3 to #4, respectively)
Fig. 3
Fig. 3
Na+/glucose cotransporters in the intestine (a) and kidney (b). SGLT1, Sodium Glucose Cotransporter (gene name: SLC5A1). SGLT2, Sodium Glucose Cotransporter (gene name: SLC5A2). GLUT2, “Facilitated” (passive) Glucose Transporter (gene name SLC2A1). GLUT5, “Facilitated” (passive) Glucose Transporter (gene name SLC2A5). SGLT1 is expressed in the brush border membrane of enterocytes and in the apical membranes of kidney of epithelial cells of the proximal straight tubules (second part of S2 segments and all of S3 segments). SGLT2 is expressed in the apical membranes of the kidney early proximal tubule cells (segment S1). GLUT2 is expressed in the basolateral membranes of intestine and renal proximal tubule S1 cells. In kidney proximal tubule S3 segments, cytosolic glucose exit occurs via basolateral GLUT1. In the intestine, in the absence of GLUT2, the current concept is that an alternative basolateral exit pathway exists, according to which glucose is converted to glucose-6-phosphate, which is transported into vesicles, followed by exocytosis [168]. GLUT5 is expressed in both apical and basolateral membranes of intestinal cells
Fig. 4
Fig. 4
MAP17 model and augmentation of SGLT2 function. a Model showing MAP17 activating SGLT2 (and possibly other transporters like NHE3), via an unknown mechanism, independent of the PDZ transporter complex formation. b Augmentation of SGLT2 functional activity by co-expression with MAP17. The cRNAs for human SGLT2 and human MAP17 were obtained by in vitro transcription and injected individually or co-injected into X. oocytes. The uptake of 14C-α-MG (50 μM) was measured in ND96 buffer with 1 mM mannose 1 mM galactose [23] for 2 h and expressed as pmol/oocyte/h. The co-expression of MAP17 drastically increased SGLT2-mediated 14C-α-MG uptake. The experiment shown in Fig. 4b was performed by Ryuichi Ohgaki and Jin Chunhuan, Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University (unpublished data from the laboratory of Yoshikatsu Kanai)
Fig. 5
Fig. 5
Chemical structures of various inhibitors of the SLC5 proteins in comparison with α-d-glucose. While phlorizin is a relatively non-selective inhibitor of sodium-coupled sugar transporters, canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin are selective (250-fold, 1200-fold, 2500-fold, 360-fold, 1650-fold, 2900-fold, respectively) inhibitors of human SLC5A2 vs human SLC5A1 (see text for details)
Fig. 6
Fig. 6
Binding modes of glucose and various inhibitors to human SGLT2 (SLC5A2). The protein backbone is shown as gray ribbon. Selected individual amino acid side-chains are shown in dark cyan. Purple sphere represents the Na+ ion. Hydrogen bonds and aromatic ring stacking interactions are shown as dashed lines. Docked ligands are shown in various colors (a–e). Panel f shows a putative alternative sugar-binding site of docked α-d-glucose (yellow) compared with the canonical binding pose (pink) (see text for details)
Fig. 7
Fig. 7
Effect of SGLT2 inhibition on renal hemodynamics via the tubuloglomerular feedback (TGF) mechanism: the macula densa cells are specialized epithelial cells that form the macula densa as part of the distal tubule sensing system of the same nephron. As shown on the right, these cells detect the luminal NaCl concentration in the tubular fluid. NaCl detection occurs after its uptake by SLC12A1 (NKCC2). Elevated filtration at the glomerulus or reduced reabsorption of Na+ and water in the proximal tubule causes the tubular fluid at the macula densa to have a higher concentration of luminal NaCl. Inhibition of SGLT2-mediated Na+-coupled glucose transport significantly increases NaCl exposure at the macula densa. This is followed by increased transport activity of SLC12A1 (NKCC2) in macula densa cells. As part of the sensing mechanism, this ultimately leads to extracellular accumulation of adenosine in the juxtaglomerular interstitial space (see text for details). Adenosine can then directly act on Gi-coupled A1 receptors expressed on afferent arteriolar smooth muscle cells [63, 87], triggering vasoconstriction of the afferent arterioles to reduce GFR, as shown in Fig. 8a and b
Fig. 8
Fig. 8
Hypothesized renal hemodynamic effects of SGLT2 inhibitors: a and b beneficial effects in type 1 diabetes patients; c and d beneficial effects in type 2 diabetes patients treated with a renin-angiotensin system (RAS) blocker
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes. 2013;62:3324–3328. doi: 10.2337/db13-0604. - DOI - PMC - PubMed
    1. Adler AI, Cronshaw J, Prescott C, Patel S, Donegan E, Hayre J. NICE guidance on sotagliflozin for type 1 diabetes. Lancet Diabetes Endocrinol. 2020;8:274–275. doi: 10.1016/S2213-8587(20)30066-8. - DOI - PubMed
    1. Ansary TM, Nakano D, Nishiyama A (2019) Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the renin-angiotensin system. Int J Mol Sci 20. 10.3390/ijms20030629 - PMC - PubMed
    1. Arakawa K, Ishihara T, Oku A, Nawano M, Ueta K, Kitamura K, Matsumoto M, Saito A. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095. Br J Pharmacol. 2001;132:578–586. doi: 10.1038/sj.bjp.0703829. - DOI - PMC - PubMed
    1. Baader-Pagler T, Eckhardt M, Himmelsbach F, Sauer A, Stierstorfer BE, Hamilton BS. SGLT6 - A pharmacological target for the treatment of obesity? Adipocyte. 2018;7:277–284. doi: 10.1080/21623945.2018.1516098. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances