Open access

Introductory Chapter: Glucose Transporters

Written By

Leszek Szablewski

Submitted: 27 August 2018 Published: 18 February 2019

DOI: 10.5772/intechopen.82263

Chapter metrics overview

1,294 Chapter Downloads

View Full Metrics

1. Introduction

The major source of energy for mammalian cells is glucose. Glucose derived from the diet and synthesized within the body is transported from the circulation into target cells. The transfer of glucose across the plasma membrane is necessary. Cell membrane is composed by lipid bilayer, which is hydrophobic. Glucose has hydrophilic nature. Therefore, cell membranes act as barriers to most molecules. For water molecules and a few other small molecules, such as oxygen and carbon dioxide, the lipid bilayer is permeable. These molecules move spontaneously down their concentration gradient by diffusion. For cations such as K+, Na+, and Ca2+; anions such as Cl and HCO3; and hydrophilic molecules and macromolecules such as proteins and RNA, lipid bilayer is impermeable. Therefore, these molecules and ions need specific transport system. There are two general classes of membrane transporters: channels and carriers.

Glucose transporters belong to the major facilitator superfamily (MFS). MFS contains 74 families of membrane transporters including more than 10,000 members. These transporters transport variety of molecules.

Glucose as well as other monosaccharides cannot penetrate the lipid bilayer because they are hydrophilic in nature; therefore, they require specific carrier proteins to undergo diffusion through the bilayer. In humans, there are three families of genes that encode for glucose transporters: SLC2A, SLC5A, and SLC50A [1].

Glucose is transported across the cell membranes and tissue barriers by a sodium-independent glucose transporter (facilitated transport, GLUT proteins, and SLC2 genes), sodium-dependent glucose symporters (secondary active transport, SGLT proteins, and SLC5 genes), and glucose uniporter—SWEET protein (SLC50 genes). Most cells express more than one kind of glucose transporters. However, these membrane carrier proteins are called glucose transporters; they are involved in the transport of several different molecules, not just glucose.


2. Characteristics of glucose transporters

2.1 Characteristics of GLUT proteins

In humans, 14 members of GLUT proteins have been identified. They are encoded by the solute-linked carrier family 2, subfamily A gene family, and SLC2A [2, 3]. All GLUT proteins are predicted to contain 12 hydrophobic membrane spanning, α-helical transmembrane (TM) domains. These domains are connected by hydrophilic loop between TM6 and TM7 of the protein [4, 5, 6]. GLUTs contain a site for single glycosylation on the exofacial end, either in the large loop between TM1 and TM2 (first extracellular loop) or between TM9 and TM10 (fifth extracellular loop) [7]. As was proposed for GLUT1, helices 1, 2, 4, 5, 7, 8, 10, and 11 form an inner bundle that is stabilized by the outer helices 3, 6, 9, and 12 [8].

Based on the phylogenetic analysis of sequence similarity and characteristic elements, the GLUT family of sugar transporters is divided into three classes [4, 5, 9, 10]: an N-linked glycosylation site for GLUTs of class I and II is positioned in the first exofacial loop between TM1 and TM2, and family members of class III contain the glycosylation site between TM9 and TM10 [5].

Class I GLUTs include GLUT1–GLUT4 and GLUT14, which are 48–63% identical in humans. Class II GLUTs comprise of GLUT5, GLUT7, GLUT9, and GLUT11. These transporters are 36–40% identical. Class III GLUTs include GLUT6, GLUT8, GLUT10, GLUT12, and GLUT13 (HMIT). GLUTs in this class are only 19–41% identical.

The human GLUTs are involved in the transport of the several hexoses in addition to myoinositol, urate, glucosamine, and ascorbate [7]. All the members of the GLUT family are facilitative transporters except for GLUT13 (HMIT), which is an H+/myoinositol symporter [11].

2.2 Pseudogenes

To date, four pseudogenes of SLC2A family were described [5, 7]:

  1. SLC2A3P1 (alias GLUT6 or GLUT3 pseudogene) is located on chromosome 5q35.1 and is a retroposon of SLC2A3.

  2. SLC2A3P2 (alias GLUT3 pseudogene 2) is located on chromosome 1p31.3 and is a retroposon of SLC2A3.

  3. SLC2A3P4 (alias GLUT3 pseudogene 4) is located on chromosome 8q21.3 and is a retroposon of SLC2A3.

  4. SLC2AXP1 is located on chromosome 2q11.2 and contains internal stop sequences.

2.3 Characteristics of sodium-dependent glucose symporters

Crane [12] showed that active glucose absorption by hamster’s small intestine required sodium ions in the bathing medium. He proposed that these symporters have two binding sites: one for glucose and one for sodium [13].

The sodium-dependent glucose cotransporters belong to the gene family (SLC5A), the SGLTs, or sodium/substrate symporters family (SSSF), containing over 450 members [14, 15, 16]. In humans, 12 members of sodium-dependent glucose cotransporters have been identified. Amino acid comparison of the human sodium-dependent glucose cotransporters shows the range of identity from 57 to 71% [17]. The members of the SGLT family also share considerable homology among the proteins (21–70% amino acid identity with SGLT1) [10, 16]. These proteins contain of 580–718 amino acid residues, with a predicted mass of 60–80 kDa. There is a diversity in gene structure. In eight genes, the coding sequences are found in 14–15 exons (SLC5A1, SLC5A2, SLC5A4–SLC5A6, and SLC5A9–SLC5A11), and the coding sequence for SLC5A7 and SLC5A3 are present in exons 8 and 1, respectively. In SLC5A9–SLC5A11 and SLC5A3, there is evidence for alternative splicing. These proteins contain 14 TM α-helices (TMHs) in all but not in sodium-iodide symporter (NIS) and SMCT1, which lack TMH14 [18]. Both the hydrophilic N- and C-termini are located on the extracellular side of the cell membrane [1]. SGLTs are highly glycosylated membrane proteins; however, glycosylation is not required in the functioning of the protein. The human SLC5A genes are expressed in different tissues, and all of them code for sodium-dependent glucose cotransporter proteins, except for SGLT3 (SLC5A4), which acts as a glucose sensor [19]. These carrier proteins transport substrates such as glucose, myoinositol, and iodide; one is a Na+/Cl/choline cotransporter, and another is a glucose-activated ion channel [16].

2.4 Characteristics of SWEET glucose transporters

SWEETs transport mono- and disaccharides across vacuolar and plasma membranes. A new class of glucose transporters, SWEET, was first identified by expressing candidate Arabidopsis genes coding for polytopic membrane proteins in HEK293T cells [20]. SWEETs are ubiquitously expressed in plants. In contrast to Arabidopsis thaliana, in which up to two dozen SWEETs have been identified, animals usually have only one SWEET, except for Caenorhabditis elegans, where seven SWEET-encoding genes have been found. Homologs of the SWEETs are widespread in metazoan genomes, and there is a single homolog in human genome (SWEET1) encoded by the gene SLC50A1 [1].

Human SWEET1 (RAG1AP1), encoded by SLC50A1, comprises 221 amino acids with a molecular weight of 25 kDa. Human SWEET1 did not promote glucose uptake but instead mediated a weak efflux. Human SWEET1 when expressed in HEK293T cells was predominantly found to be localized in the Golgi with minimum expression also found in the plasma membrane. Chen et al. [20] discovered the highest level of expression in the oviduct, epididymis, and intestine, and its expression was induced in mouse mammary gland during lactation. The authors suggest that the human SWEET1 serves to supply glucose for lactose synthesis in the mammary gland. Human SWEET1 glucose transporter is the missing glucose transporter in the basolateral membrane of enterocytes where it may account for the exit of glucose from the cell into the blood in patients with Fanconi-Bickel syndrome and in mice missing the GLUT2 transporter [21, 22].


  1. 1. Wright EM. Glucose transport families SLC5 and SLC50. Molecular Aspects of Medicine. 2013;34:183-196
  2. 2. Long W, Cheeseman CI. Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton. 2015;7:167-183
  3. 3. Thorens B, Mueckler M. Glucose transporters in the 21st century. American Journal of Physiology. Endocrinology and Metabolism. 2010;298:E141-E145
  4. 4. Joost HG, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. American Journal of Physiology. Endocrinology and Metabolism. 2002;282:E974-E976
  5. 5. Joost H-G, Thorens B. The extend GLUT-family of sugar-polyol transport facilitators: Nomenclature, sequence characteristics, and potential function of its novel members. Molecular Membrane Biology. 2001;18:247-256
  6. 6. Uldry M, Thorens B. The SLC2 family of facilitative hexose and polyol transporters. Pflügers Archiv: European Journal of Physiology. 2004;447:480-489
  7. 7. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Molecular Aspects of Medicine. 2013;34:121-138
  8. 8. Mueckler M, Makepeace C. Model of the exofacial substrate-binding site and helical folding of the human Glut1 glucose transporter based on scanning mutagenesis. Biochemistry. 2009;48:5934-5942
  9. 9. Manolescu AR, Witkowska K, Kinnaird A, Cessford T, Cheeseman C. Facilitated hexose transporters: New perspectives on form and function. Physiology. 2007;22:234-240
  10. 10. Zhao F-Q , Keating AF. Functional properties and genomic of glucose transporters. Current Genomics. 2007;8:113-128
  11. 11. Uldry M, Ibberson M, Horisberger J-D, Rieder BM, Thorens B. Identification of a mammalian H+-myo-inositol symporter expressed predominantly in the brain. The EMBO Journal. 2001;20:4467-4477
  12. 12. Crane RK. Hypothesis for mechanism of intestinal active transport of sugars. Federation Proceedings. 1962;21:891-895
  13. 13. Crane RK. Na+-dependent transport in the intestine and other animal tissues. Federation Proceedings. 1965;24:1000-1006
  14. 14. Wright EM. Renal Na+/glucose cotransporters. The American Journal of Physiology. 2001;280:F10-F18
  15. 15. Wright EM, Loo DDF, Hirayama BA, Turk E. Surprising versatility of Na+/glucose cotransporters: SLC5. Physiology. 2004;19:370-376
  16. 16. Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflügers Archiv: European Journal of Physiology. 2004;447:510-518
  17. 17. Woods IS, Trayhurn P. Glucose transporters (GLUT and SGLT): Expressed families of sugar transport protein. The British Journal of Nutrition. 2003;89:3-9
  18. 18. Turk E, Wright EM. Membrane topology motifs in the SGLT cotransporter family. The Journal of Membrane Biology. 1997;159:1-20
  19. 19. Bianchi L, Diez-Sampedro A. A single amino acid change converts the sugar sensor SGLT3 into a sugar transporter. PLoS One. 2010;5:e10241
  20. 20. Chen LQ , Hou BH, Lalonde S, Takanaga H, Hartung ML, Qu XO, et al. Sugar transporters for intracellular exchange and nutrition of pathogens. Nature. 2010;468:527-532
  21. 21. Santer R, Hillebrand G, Steinmann B, Schaub J. Intestinal glucose transport: Evidence for a membrane traffic- based pathway in humans. Gastroenterology. 2003;124:34-39
  22. 22. Stumpel F, Burcelin R, Jungermann K, Thorens B. Normal kinetics of intestinal glucose absorption in the absence of GLUT2: Evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:11330-11335

Written By

Leszek Szablewski

Submitted: 27 August 2018 Published: 18 February 2019