Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GLUT

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101958

Synonyms

Historical Background

The need for a specific transporter to mediate cellular glucose transport across the lipophilic cell membrane was first proposed in 1948 based on the observed saturable and isomer-specific nature of glucose uptake in human erythrocytes (LeFevre 1948). Continued work in this area led to the discovery an integral membrane protein with the ability to mediate glucose transport across the erythrocyte (Kasahara and Hinkle 1977). Cloning of this transporter in the HepG2 human hepatoma cell line in 1985 (Mueckler et al. 1985) and rat brain in 1986 (Birnbaum et al. 1986) led to the name “HepG2/rat brain/human erythrocyte transporter.” cDNA cloning of a glucose transporter abundantly expressed in the liver (and to a lesser extent in the kidney and intestine) occurred several years later (Fukumoto et al. 1988), and in the following year the first report of cDNA cloning of the glucose transporter predominantly expressed in rat muscle and adipose tissue was published (James et al. 1989). Since that time, 14 mammalian glucose transporter isoforms have been identified in humans. These proteins have been given the name “GLUT.”

Structure and Function of GLUT Class Members

GLUT proteins are integral membrane proteins that passively transport substances across the plasma membrane using energy derived from chemical or electrochemical gradients. Encoded by the solute-linked carrier family 2A gene (SLC2A), specific GLUT isoforms are derived from 14 SLC2A member genes that are located on nine separate chromosomes in humans. GLUTs have been grouped into three classes based on sequence homology and structural similarity. Class I GLUT transporters include GLUT1 (the HepG2/rat brain/human erythrocyte transporter), GLUT2 (originally named the rat liver transporter), GLUT3, and GLUT4 (originally known as the rat muscle/fat transporter) and the most recently identified GLUT14, believed to be a duplicon of GLUT3 (Wu and Freeze 2002). GLUT5, GLUT7, GLUT9, and GLUT11 belong to Class II GLUT transporters, which transport fructose as well as glucose, but do not transport galactose or the non-metabolizable glucose analogue 2-deoxy-d-glucose. GLUT9 is unique in this class as it also transports urate (a product of purine metabolism) and is considered a principal mediator of renal urate handling in humans (Bobulescu and Moe 2012). The least characterized of all GLUTs are the Class III transporters, including GLUT6, GLUT8, GLUT10, GLUT12, and GLUT13 (also known as HMIT). While the physiological role for Class III transporters is still being elucidated, it is known that GLUT13 is an H+/myoinositol co-transporter predominantly expressed in the brain. Glucose transport activity has not yet been detected for GLUT13 (Zhao and Keating 2007).

Amino acid sequences of the 14 GLUT proteins vary considerably, with GLUT proteins sharing 14 to 63% of their amino acid sequence (Zhao and Keating 2007). Despite disparities in the primary structure, GLUT isoforms are predicted to share several tertiary structural arrangements. Most of the knowledge on GLUT structure has been learned through extensive studies of GLUT1. Hydropathy and X-ray crystallography analysis of GLUT1 have revealed a protein structure containing 12-transmembrane (TM) α-helices that are divided into four symmetrical three α-helical bundles connected by a long intracellular loop between TM helix 6 and TM helix 7 (Fig. 1). The 12-TM α-helices are arranged to form a central aqueous pore for substrate transport (Deng et al. 2014). All GLUT isoforms share the 12-TM α-helical structure, as well as the intracellular position of the carboxyl and amino termini (Marger and Saier 1993).
GLUT, Fig. 1

Crystal structure of human full-length GLUT1 protein. Perspectives are presented from the side (top images) and cytoplasm (bottom images). In the top and bottom left images, segments of the same color represent the four 3-helix repeats, with extracellular and intracellular helices represented in blue and orange, respectively. The top and bottom right images were constructed using a molecular graphics system and are meant to represent a cut-open view of the surface of the transporter to help visualize the inward-facing cavity. IC intracellular helix (Image reprinted with permission from Deng et al. 2014)

Substrate transport is initiated when hydroxyl groups within GLUT substrates interact with hydrophilic amino acids in the transporter’s extracellular binding site. This results in a conformational change in the transporter, pushing the substrate through the central pore of the GLUT protein. Release of the substrate reverses the conformational change and returns the binding site to the outside of the cell (Joost et al. 2002). A more detailed alternating access model describes four major conformational states associated with substrate transport: (1) an empty outward open transporter state, (2) a ligand-bound and occluded transporter state, (3) an inward open state, and (4) a ligand-free and occluded state. This proposed transport mechanism assumes that GLUT transporters have a substrate cavity and binding site, as well as one intracellular and one extracellular configuration opening. The crystal structure of GLUT1 is consistent with and supports this alternating access mechanism (Long and Cheeseman 2015).

Tissue Expression and Physiological Roles of GLUT Transporters

All GLUT proteins (with the exception of GLUT13) have been shown to transport various hexoses, albeit with varying kinetic characteristics and transport efficiencies (Table 1). Although a single GLUT isoform may be present in several tissues, GLUTs are predominantly expressed in tissues in a manner that matches their kinetic characteristics with tissue-specific glucose requirements or the role of that tissue in glucose handling. For example, ubiquitous expression of the high-affinity transporter GLUT1 facilitates a constant rate of basal glucose uptake in all tissues. GLUT3, which also has a high affinity for glucose, is expressed in neurons to ensure constant glucose delivery to these cells that rely heavily on glucose for energy (Stringer et al. 2015). Overall, most GLUTs are high-affinity, low-capacity transporters. The exception is GLUT2, which displays low-affinity, high-capacity transport for glucose. These kinetic characteristics make GLUT2 especially efficient at transporting glucose at high concentrations, making GLUT2 the ideal glucose transporter for cells involved in glucose sensing, such as pancreatic β-cells and hepatocytes. β-Cells, which must adjust insulin secretion based on blood glucose concentrations, express GLUT2 to ensure glucose entry into these cells is directly proportional to blood glucose concentrations. The liver, the first organ to receive glucose absorbed from the intestinal tract, must respond to elevated portal glucose concentrations encountered during the postprandial state with rapid, continual uptake of glucose. Expression of a low-affinity, high-capacity transporter such as GLUT2 facilitates this (Stringer et al. 2015). Potential physiological roles for the less-characterized GLUT transporters have been reviewed elsewhere (Long and Cheeseman 2015).
GLUT, Table 1

Selected characteristics of GLUT transporters

GLUT isoform

Substrates

KMa,b(mM)

Main sites of expression

GLUT1

3-O-methylglucose (3-O-MG),

2-deoxy-d-glucose (2-DG), glucose

3–7

Global expression across all tissues

GLUT2

Glucose, galactose, fructose, mannose, glucosamine

17

Liver, kidney, small intestine, pancreas

GLUT3

Glucose, galactose, mannose, maltose, xylose, dehydroascorbic acid (DHAA)

1.4

Brain, neurons

GLUT4

Glucose, DHAA, glucosamine

5–6

Adipose tissue, skeletal muscle

GLUT5

Fructose

~6c

Liver, small intestine, testis

GLUT6

 

ND

Brain, spleen, leukocytes

GLUT7

Glucose, fructose

0.3

Small intestine, colon, testis

GLUT8

Glucose

2

Testis, blastocyst, brain, muscle, adipose tissue

GLUT9

Glucose, fructose, urate

0.61

Liver, kidney

GLUT10

Glucose, 2-DG, galactose

0.3

Liver, pancreas

GLUT11

Glucose, fructose

0.1

Heart, skeletal muscle

GLUT12

Glucose, 3-O-MG, 2-DG, fructose, galactose

n/dd

 

GLUT13

Myo-inositol

n/d

Brain

GLUT14

Glucose

n/d

Testis, small intestine, liver, kidney

aKM = Michaelis Menten constant; substrate concentration at which reaction rate is half maximum rate

bKM is presented for glucose or 2-deoxy-d-glucose

cKM for fructose transport

dn/d = not determined

Intracellular Trafficking of GLUT Proteins

GLUT proteins must be situated within the plasma membrane to effectively transport substrates across the cell membrane. However, some GLUT proteins are recycled between the membrane and intracellular compartments, and GLUT proteins can undergo subcellular trafficking in response to signal transduction pathways. The best studied of these pathways is the control of GLUT4 translocation by the hormone insulin in skeletal muscle and adipose tissue, the tissues accounting for the majority of postprandial glucose disposal. In unstimulated cells, more than 90% of GLUT4 is found within intracellular storage vesicles (Zaid et al. 2008). When insulin is released in the postprandial state and binds to its receptors present on skeletal muscle cells and adipocytes, GLUT4-containing vesicles are shuttled from intracellular stores to the plasma membrane to facilitate the movement of glucose from plasma into the cells. The signaling pathways governing this translocation are complex, but are similar in skeletal muscle and adipose tissue and involve major insulin signaling intermediates, insulin receptor substrate-1 and phosphatidylinositol 3-kinase (PI3K), and Akt. Signaling from these proteins activates Akt substrate of 160 kDa (AS160) and TBC1D1, two Rab-GTPase-activating proteins required for several steps of GLUT4 trafficking including vesicle formation, vesicle transport across cytoskeletal tracks, and membrane fusion (Sakamoto and Holman 2008). Atypical protein kinase C (PKC) and Rac (a GTP-binding protein) also participate in GLUT4 translocation via effects on microtubule and microfilament dynamics (Zaid et al. 2008).

Insulin-independent mechanisms for GLUT4 translocation are also present within adipose tissue and skeletal muscle. In adipocytes, PI3K-independent pathways involving the Rho GTPase family member, TC10α, regulate release of GLUT4-containing vesicles from the Golgi apparatus and attachment of GLUT4 vesicles to the plasma membrane (Stringer et al. 2015). Exercise-induced contraction of skeletal muscle promotes GLUT4 translocation through complex signaling involving upstream signaling intermediates including AMP-activated protein kinase, Ca2+, nitric oxide, and reactive oxygen species, as well as downstream signaling intermediates such as GTPases, Rab, and SNARE proteins (Richter and Hargreaves 2013).

Until recently, GLUT2 in the intestine was believed to be constitutively expressed within the basolateral membrane of enterocytes. However, several studies have documented a PKC-βII-dependent rapid trafficking of GLUT2 to the apical membrane. The translocation of GLUT2 is likely a response to high luminal glucose concentrations observed after a meal and occurs to ensure rapid post-meal intestinal glucose uptake (Stringer et al. 2015). Subcellular trafficking of GLUT3, GLUT8, and GLUT12 has also been observed, although the signaling pathways regulating intracellular movement of these transporters have yet to be completely elucidated (Long and Cheeseman 2015).

Pathological Conditions Associated with GLUT Dysfunction

Defects in several of the SLC2A family member genes have been documented and can lead to pathological states. GLUT1 deficiency syndrome is a rare autosomal dominant haplo-insufficiency disorder, where multiple deletions, missense, and frame shift mutations in the SLC2A1 gene may cause a loss of functional GLUT1 protein (Klepper and Leiendecker 2007). As GLUT1 facilitates glucose transport across the blood-brain barrier, GLUT1 deficiency syndrome results in impaired glucose transport into the brain, hypoglycorrhachia (low glucose concentrations in cerebrospinal fluid), and low cerebrospinal fluid lactate concentration. As a result, the consequences of GLUT1 deficiency syndrome are largely neurological in nature and manifest early in life. Patients will often present with neurological symptoms including confusion, lethargy, drowsiness, and speech impairments. Varying degrees of cognitive impairment have been described, ranging from learning disabilities to severe mental retardation (Klepper and Leiendecker 2007). GLUT1 deficiency syndrome can be treated with adherence to a high-fat, carbohydrate-restricted ketogenic diet. The benefit of a ketogenic diet for treatment of GLUT1 deficiency syndrome is twofold, as this diet provides an alternative fuel source for the brain and also has anticonvulsant actions. A ketogenic diet should be prescribed as soon as possible whenever GLUT1 deficiency syndrome is suspected (Klepper 2008).

Fanconi-Bickel syndrome is the pathological state associated with mutations in the SLC2A2 gene that leads to loss of functional GLUT2 protein. Due to its autosomal recessive pattern of inheritance, the majority of patients with this syndrome are homozygous for SLC2A2 mutations. Due to the roles of GLUT2 in the pancreas and liver, patients with Fanconi-Bickel syndrome often experience hepatic glycogen and lipid infiltration and postprandial hyperglycemia. Renal complications are also often observed and may include renal tubular nephropathy with glucosuria, phosphaturia, amino aciduria intermittent proteinuria, and hyperuricemia. Patients also often experience intestinal malabsorption and diarrhea (Thorens 2015).

Summary

GLUT proteins are expressed in every tissue of the human body and are critical mediators in the movement of substrates, particularly hexoses, across the cell membrane. Thus, GLUTs provide cells access to vital fuel sources. Originally recognized in the late 1940s, research on GLUT proteins has led to the discovery of 14 GLUT isoforms, each with a unique pattern of tissue expression and kinetic properties. Although GLUT isoforms have been grouped into three classes based on structural and functional similarities, all GLUTs appear to share a common 12-TM α-helical structure with a central aqueous pore spanning the membrane through which substrates are transported. Despite similarities in three-dimensional structure, amino acid sequences of each GLUT peptide are different, and this is what accounts for differences in substrate binding and transport kinetics between GLUT isoforms. Tissue expression of GLUT isoforms is based on kinetic properties of the GLUT and the glucose requirements of that tissue. GLUTs are subject to subcellular translocation that can be regulated by signal transduction pathways, and the best researched of these pathways is the control of GLUT4 translocation by insulin. However, GLUT3, GLUT8, and GLUT12 are also subject to subcellular translocation, although much less is known about the pathways dictating intracellular movement of these isoforms. In general, much research has focused on characterizing the physiological roles of Class I and Class II GLUTs, but the structural characteristics, kinetic properties, and physiological roles for many of the remaining GLUT transporters remain largely unknown.

References

  1. Birnbaum MJ, Haspel HC, Rosen OM. Cloning and characterization of a cDNA encoding the rat brain glucose-transporter protein. Proc Natl Acad Sci U S A. 1986;83:5784–8.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19:358–71.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, et al. Crystal structure of the human glucose transporter GLUT1. Nature. 2014;510:121–5.PubMedCrossRefGoogle Scholar
  4. Fukumoto H, Seino S, Imura H, Seino Y, Eddy RL, Fukushima Y, et al. Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose transporter-like protein. Proc Natl Acad Sci U S A. 1988;85:5434–8.PubMedCrossRefPubMedCentralGoogle Scholar
  5. James DE, Strube M, Mueckler M. Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature. 1989;338:83–7.PubMedCrossRefGoogle Scholar
  6. 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. Am J Physiol Endocrinol Metab. 2002;282:E974–6.PubMedCrossRefGoogle Scholar
  7. Kasahara M, Hinkle PC. Reconstitution and purification of the d-glucose transporter from human erythrocytes. J Biol Chem. 1977;252:7384–90.PubMedPubMedCentralGoogle Scholar
  8. Klepper J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia. 2008;49 Suppl 8:46–9.Google Scholar
  9. Klepper J, Leiendecker B. GLUT1 deficiency syndrome – 2007 update. Dev Med Child Neurol. 2007;49:707–16.PubMedCrossRefGoogle Scholar
  10. LeFevre PG. Evidence of active transfer of certain non-electrolytes across the human red cell membrane. J Gen Physiol. 1948;31:505–27.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Long W, Cheeseman CI. Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health Cytoskeleton. 2015;7. doi:10.2147/CHC.S60484.Google Scholar
  12. Marger MD, Saier Jr MH. A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem Sci. 1993;18:13–20.PubMedCrossRefGoogle Scholar
  13. Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, et al. Sequence and structure of a human glucose transporter. Science. 1985;229:941–5.PubMedCrossRefGoogle Scholar
  14. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93:993–1017.PubMedCrossRefGoogle Scholar
  15. Sakamoto K, Holman GD. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am J Physiol Endocrinol Metab. 2008;295:E29–37.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Stringer DM, Zahradka P, Taylor CG. Glucose transporters: cellular links to hyperglycemia in insulin resistance and diabetes. Nutr Rev. 2015;73:140–54.PubMedCrossRefGoogle Scholar
  17. Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58:221–32.PubMedCrossRefGoogle Scholar
  18. Wu X, Freeze HH. GLUT14, a duplicon of GLUT3, is specifically expressed in testis as alternative splice forms. Genomics. 2002;80:553–7.PubMedCrossRefGoogle Scholar
  19. Zaid H, Antonescu CN, Randhawa VK, Klip A. Insulin action on glucose transporters through molecular switches, tracks and tethers. Biochem J. 2008;413:201–15.PubMedCrossRefGoogle Scholar
  20. Zhao FQ, Keating AF. Functional properties and genomics of glucose transporters. Curr Genomics. 2007;8:113–28.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Kinesiology and Applied HealthUniversity of WinnipegWinnipegCanada