Glucose transport

The oxidation of glucose represents a major source of metabolic energy for mammalian cells. Because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by special carrier proteins called glucose transporters[1][2][3][4][5][6][7]. These are integral membrane proteins located in the plasma membrane that bind glucose and transfer it across the lipid bilayer. The rate of glucose transport is limited by the number of glucose transporters on the cell surface and the affinity of the transporters for glucose. There are two classes of glucose carriers described in mammalian cells: the Na+-glucose cotransporters (SGLTs) and the facilitative glucose transporters (GLUTs)[1-7].

There are two families of glucose transporters

The Na+-glucose cotransporter or symporter is expressed by specialized epithelial (brush border) cells of the small intestine and the proximal tubule of the kidney and mediates an active, Na+-linked transport process against an electrochemical gradient[1-3] . It actively transports glucose from the lumen of the intestine or the nephron against its concentration gradient by coupling glucose uptake with that of Na+, which is being transported down its concentration gradient. The Na+ gradient is maintained by the active transport of Na+ across the basolateral (antiluminal) surface of the brush border cells by membrane-bound Na+-K+- ATPase[1-3,7].

The second class of glucose carriers is the facilitative glucose transporters (GLUTs) of which there are 14 genes in the human genome[1,4-7] . These proteins mediate a bidirectional and energy-independent process of glucose transport in most tissues and cells where glucose is transported down its concentration gradient by facilitative diffusion[1].

There are 12 members of the human SGLT family

There are twelve members of the human SGLT family in the human genome, including cotransporters for sugars, anions, vitamins, and short-chain fatty acids[2] . The sugar transporters include SGLT1, SGLT2, SGLT4 and SGLT5, while SGLT3 functions as a glucose sensor [2,7] . Discussion here will be confined to SGLT1, SGLT 2 and SGLT 3.

Human SGLT1 was first cloned and characterised from the small intestine and is a 664 amino acid protein[8]. A secondary structure model is shown in Figure 1 and the experimentally determined 3D structure shown in Figure 2.

Figure 1. Secondary structure model of human SGLT1[2] Reprinted with permission from American Physiological Society (Click for enlarged view)
Figure 1. Secondary structure model of human SGLT1[2] Reprinted with permission from American Physiological Society (Click for enlarged view)
Figure 1 depicts a secondary structure model of human SGLT1[2] . This model shows the sequence of the 664 residues arranged in 14 transmembrane helices with both the NH2 and COOH termini facing the extracellular side of the plasma membrane. A single N-glycosylation site occurs at Asn (N) 248. Highlighted are the locations of the helical domains based on the vSGLT structure[9].

Figure 2. The structure of vSGLt [9] Reprinted with permission from AAAS (Click for enlarged view)
Figure 2. The structure of vSGLt [9] Reprinted with permission from AAAS (Click for enlarged view)
Figure 2 depicts a topology model showing the 14 TM from the NH2 terminal (TM-1) to the COOH terminal (TM13). The blue and red trapeziums represent the inverted topology of TM1-TM5 and TM6-TM10. B: a side view of the 3-dimensional structure viewed from the membrane plane. The location of the bound sugar is shown as black and red spheres. Residues involved in sugar binding and gating and Na+ binding are shown on TM as circles. The two discontinuities represent the disordered regions of the protein. Source: redrawn from Faham et al. 2008 [9].

SGLT1 is a glucose transporter that has poor affinity for galactose[2]. It is expressed in the intestine, trachea, kidney, heart, brain, testis and prostate[2]. It actively transports glucose from the lumen of the intestine or the nephron against its concentration gradient by coupling glucose uptake with that of Na+, which is being transported down its concentration gradient. The Na+ gradient is maintained by the active transport of Na+ across the basolateral (antiluminal) surface of the brush border cells by membrane-bound Na+-K+- ATPase[1,4]. The model for glucose transport across the small intestine is that glucose is first accumulated within the epithelium by a Na+-glucose cotransporter (SGLT1) in the brush-border membrane and then is transported out of the cell across the basolateral membrane by a facilitated sugar transporter GLUT2[2,3]. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion[10].

SGLT2 is expressed in the kidney, brain, liver, thyroid, muscle and heart[2]. It is a glucose transporter that transports galactose poorly[2].The kidneys play a major role in the regulation of plasma glucose levels and increasing attention is being given to renal glucose transporters as drug targets in the treatment of patients with diabetes mellitus. Each day, `180 g of D-glucose are filtered from plasma by the kidneys, and this is all normally reabsorbed back into the blood in the proximal tubules. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine[11]. The model for glucose transport across the tubule is similar to that proposed for the small intestine but with SLGT2 not SLGT1 as the major player. The presently accepted dogma for the kidney is that the bulk of the filtered glucose is reabsorbed in the proximal convoluted tubule by the low-affinity, high-capacity SGLT2, and that the remainder is reabsorbed by the high-affinity cotransporter SGLT1[2].

SGLT3 is expressed in human skeletal muscle and small intestine. Immunofluorescence microscopy indicated that in the small intestine the protein was expressed in cholinergic neurons in the submucosal and myenteric plexuses, but not in enterocytes. Functional studies have shown that human SGLT3 is incapable of sugar transport, leading to the conclusion that SGLT3 is not a Na+/glucose cotransporter but instead a glucose sensor in the plasma membrane of cholinergic neurons, skeletal muscle, and other tissues[12].

There are 14 members of the facultative glucose transporter family

There are 14 GLUT genes in the human genome of which 11 have been shown to catalyze sugar transport[1,7] . The individual isotypes exhibit different substrate specificity, kinetic characteristics, and expression profiles, thereby allowing a tissue-specific adaptation of glucose uptake through regulation of their gene expression[1,4]. Furthermore, some transporters such as GLUT4 and GLUT8 are regulated by their subcellular distribution. The presence of GLUT1 and GLUT3 mRNA in all human tissues suggests that these facilitative glucose transporter isoforms mediate basal glucose uptake[1,4]. In addition to catalyzing glucose entry into cells, some isotypes (GLUT2) seem to be involved in the mechanisms of glucosensing of pancreatic beta-cells, neuronal, or other cells, thereby playing a major role in the hormonal and neural control[1]. The characteristics of four facultative transporters, GLUT1, GLUT2, GLUT3 and GLUT4 will be discussed here to illustrate the differences exhibited across the family.

GLUT1 - The basal glucose transporter (erythrocyte-type transporter GLUT1) has been extensively studied. It is expressed in most tissues with the highest levels of expression in fetal tissues including the placenta[1,5]. In adult humans the highest levels are found in brain microvessels, kidney and colon, but very low in liver and skeletal muscle[5]. GLUT1 is a high-affinity glucose transporter with a Km for glucose of around 3-7 mM[13]. The Km value for GLUT proteins is the concentration of blood glucose at which transport into the cell takes place at half its maximum rate. A Km of 3-7 mM is below or equal to the average blood glucose concentration of 5-7 mM, enabling tissues to take up glucose at a significant rate, regardless of the amount present in the blood. GLUT1 is a 492 amino acid protein, predicted on the basis of sequence analysis to span the plasma membrane 12 times (transmembrane segments M1 to M12) with the N- and C-termini located on the cytoplamsic side of the membrane[14]. The model (Figure 3) indicates there is a 33 amino acid extracellular loop between M1 and M2, that contains a single N-linked glycan, and a large 65 residue hydrophilic segment between M6 and M7[14]. The crystal structure of GLUT1 has been solved and is shown in Figure 4[15].

Figure 3. GLUT1 sequence and putative topology[14] Reprinted with permission from AAAS  (Click for enlarged view)
Figure 3. GLUT1 sequence and putative topology[14] Reprinted with permission from AAAS (Click for enlarged view)
Figure 3. GLUT1 sequence and putative topology. Amino acids are shown using the 1 letter code. The 12 transmembrane regions (TMs) are colored as in Figure 4 A and B below. Some amino acids are numbered. Individual amino acids that are coloured purple are amino acids, which when mutagenized to cysteine result in ≥90% inhibition of GLUT1; coloured orange - putative substrate-binding sites predicted by docking studies; coloured blue, amino acids implicated in substrate discrimination; black, sites at which mutations cause GLUT1 deficiency syndrome. Some amino acids fall into multiple categories. Source: Mueckler et al [14].

Figure 4. Glucose transporter 1 (GLUT1) structure [15] Reprinted by permission from Macmillan Publishers Ltd (Click for enlarged view)
Figure 4. Glucose transporter 1 (GLUT1) structure [15] Reprinted by permission from Macmillan Publishers Ltd (Click for enlarged view)
Figure 4. Glucose transporter 1 (GLUT1) structure. The structure of full-length human GLUT1 containing two point mutations (N45T, E329Q) was determined in an inward-open conformation. The side (panel A) and cytoplasmic (panel B) views are shown. The corresponding transmembrane segments in the four 3-helix repeats are coloured the same. The extracellular and intracellular helices are coloured blue and orange, respectively. A slab of cut-open view of the surface electrostatic potential is shown on the right to facilitate visualization of the inward-facing cavity. IC indicates intracellular helix. Source: Deng et al [15].

GLUT2 - Liver plays a huge role in glucose homeostasis. Biochemical and molecular biological studies showed that liver as well as pancreatic β cells, small intestine and kidney have a distinct glucose transporter GLUT2 which is a high-capacity, low-affinity glucose transporter with a Km, around 15-20 mM[1,13]. With these cell types the amount of incoming glucose is proportional to the amount of glucose in the blood. The presence of GLUT2 ensures that glucose is taken up rapidly by the liver only when it is abundant and enables pancreatic β cells to monitor blood glucose levels directly, and regulate insulin secretion. The presence of GLUT2 in the small intestine and the kidney reflects its role in the transport of glucose across the serosal surface of the epithelial cells which line the intestine and the nephron, after glucose absorption across their luminal surface via the sodium-linked glucose transporter SLGT1[5]. Molecular cloning revealed that human GLUT2 is a 524 amino acid protein with 55.5% sequence identity to human GLUT1 and a predicted transmembrane topology identical to that suggested for GLUT1 (Figure 3)[5].

GLUT3 – GLUT3 is considered to be a neuron-specific glucose transporter since its protein is mainly detected in the brain[1]. However, its mRNA is widely distributed in human tissues[1]. It is a 496 residue protein with 64% and 52% sequence identity with GLUT1 and GLUT2 respectively and a transmembrane topology similar to GLUT1[5]. GLUT3 is a high-affinity glucose transporter with a Km for glucose of around 2 mM[1,13], much less than the average blood glucose concentration of 5-7 mM, enabling most tissues to take up glucose at a constant rate, regardless of the amount present in the blood. GLUT2 also transports galactose (Km 8.5 mM), mannose, maltose, xylose and dehydroascorbic acid [1].

GLUT4 - Muscle and fat cells express a third type of glucose transporter, the high-affinity, insulin-responsive GLUT4, with a Km around 5 mM. The level of this transporter on the surface of these cells is rapidly regulated by insulin. In the absence of insulin, GLUT4 is sorted from the endosome to either a perinuclear storage compartment or specialized GLUT4 storage vesicles (GSVs)[16]. Cycling between the endosome and these two compartments leads to retention of GLUT4 inside the cell under basal conditions. A slow rate of cycling between the GSV compartment and the plasma membrane does occur, although GSVs do not efficiently engage with the plasma membrane in the basal state[17]. In addition, some GLUT4 traffics to the PM in the basal state via a constitutive, transferrin receptor (TR)-containing, general trafficking pathway between the endosome and the plasma membrane[17]. Insulin signaling stimulates GSV recruitment to and fusion with the plasma membrane.

When insulin binds to the insulin receptor it initiates a signaling cascade that leads to the translocation of GLUT4 glucose transporter vesicles to the plasma membrane. Fusion of GLUT4 storage vesicles with the plasma membrane in response to insulin results in an increase in the amount of GLUT4 on the cell surface, thereby increasing the transport of glucose into the cell. Insulin signaling also inhibits GLUT4 endocytosis ensuring a longer duration of GLUT4 residence in the plasma membrane.

Perspective: proteins involved in vesicle fusion

The process of insulin-stimulated GLUT4 translocation involves homologues of many of the proteins involved in nerve cell transmission and other types of cellular transport[18]. These proteins include NSF (N-ethylmaleimide–sensitive factor), SNAP (soluble NSF attachment protein) and the SNARE protein complex which is the receptor for SNAP and NSF (hence the name SNARE, derived from SNAP receptor)[18]. The SNARE complex consists of three membrane proteins proposed to bridge the exocytic vesicle to the plasma membrane: syntaxin-1 and SNAP-25, emanating from the presynaptic plasma membrane, and vesicle-associated membrane protein (VAMP; also called synaptobrevin), located in the synaptic vesicle[18]. The synaptic SNARE proteins are the targets for botulinum and tetanus toxins, exquisitely specific proteases that block synaptic vesicle fusion[18]. Other proteins involved in vesicle fusion include the SM (Sec/Munc) proteins which regulate the process[18]. SM proteins associate with SNARE proteins in multiple ways, including as clasps binding both the v-SNARE and t-SNARE components of zippering SNARE complexes. It now seems likely that SM proteins organize trans-SNARE complexes (i.e., SNAREpins) spatially and temporally[18].

As Thomas Südhof and James Rothman write at the end of their review [18]: Intracellular membrane fusion in eukaryotes is executed by a conserved and universal fusion machinery composed of SNARE and SM proteins. Fusion results from the thermodynamic coupling of protein folding (assembly of v-SNAREs with t-SNAREs, spatially and temporally organized by SM proteins) to bilayer perturbation. Energy made available from folding is productively channeled into the bilayer so that, on balance, fusion is the favored, spontaneous reaction. Nonetheless, fusion is tightly regulated in a spatial and temporal manner, most strikingly at the synapse, where the regulation of fusion enables information processing by the brain. We are just beginning to understand how this regulation works, but in the case of the synapse we have learned some of the molecular details through the recent elucidation of the interplay among complexin, SNAREs, and synaptotagmin. There are a plethora of proteins and compounds that fragmentary evidence suggests may regulate synaptic and other fusion processes—including the large families of Rab GTPases, tethering proteins, and phosphoinositides—but the underlying principles are likely the same, driven by the simple mechanism we have described[18]. The 2013 Nobel Prize in Physiology or Medicine was awarded jointly to James E. Rothman, Randy W. Schekman and Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic.[19]


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  11. ^ Jabbour SA et al,. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract 2008; 62:1279-84.

  12. ^ Diez-Sampedro A et al., A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci U S A. 2003; 100:11753-8

  13. ^ Burant CF, Bell GI, Mammalian facilitative glucose transporters: evidence for similar substrate recognition sites in functionally monomeric proteins. Biochemistry 1992; 31:10414-20.

  14. ^ Muekler M et al., Sequence and structure of a human gluvose transporter. Science 1985; 299:941-5.

  15. ^ Deng D et al., Crystal structure of the human glucose transporter GLUT1. Nature 2014;510:121-125

  16. ^ Blot V, McGraw TE. Molecular mechanisms controlling GLUT4 intracellular retention. Mol Biol Cell 2008; 19:3477–3487.

  17. ^ Xiong W, Jordens I, Gonzalez E, McGraw TE. GLUT4 is sorted to vesicles whose accumulation beneath and insertion into the plasma membrane are differentially regulated by insulin and selectively affected by insulin resistance. Mol Biol Cell 2010; 21:1375–1386.

  18. ^ Südhof TC, Rothman JE, Membrane fusion: grappling with SNARE and SM proteins. Science 2009; 323:474-477.

  19. ^ Press release: 2013 Nobel Prize in Physiology or Medicine


  1. Gauranga Dhar
    Gauranga Dhar added a compliment on 3 October 2014 at 06:36PM
    Very good review on SGLTs and GLUTs
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