What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies


  • Naira Gorovits,

    1. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461
    Search for more papers by this author
  • Maureen J. Charron

    Corresponding author
    1. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461
    • Dept. of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2852; Fax: 718-430-8676
    Search for more papers by this author


Glucose uptake by all cells in the organism by glucose transport proteins is among the most essential processes in life. The process of glucose uptake into tissues is performed by glucose transporters. This review focuses on the biology of facilitative glucose transporters (GLUTs). The knowledge that has accumulated for more than a decade with respect to the regulation of GLUT expression and function in various experimental conditions points to the great potential for GLUTs to be utilized as targets for designing therapies for treatment of diseases related to impaired regulation of glucose homeostasis including type 2 diabetes.

The entry of glucose into cells is a crucial step in life-supporting processes since glucose is the main monosaccharide in nature that provides carbon and energy for almost all cells. The passage of glucose into cells depends on different parameters, including expression of the appropriate glucose transporters in the target tissues and hormonal regulation of their function. Single cell eucaryotes such as Saccharomyces cerevisiae possess 20 genes encoding glucose or glucose-like transporters and express the glucose transporters most appropriate for the amount of glucose available [1]. In mammalian cells a tight regulation of blood glucose levels is needed to meet the energetic demands of the brain, a tissue that uses glucose as its primary energy source [2, 3]. Adequate glucose flux into tissues provides maintenance of glucose homeostasis that is critical in well being. Transport of glucose across the plasma membrane is accomplished by two families of glucose transporters: sodium-glucose co-transporters (SGLT11 1–3), mainly expressed in the apical membrane of renal and intestinal absorptive epithelial cells that transport glucose against its concentration gradient and utilize ATP (for a review, see Ref. 4), and facilitative glucose transporters (GLUTs) that are expressed in all cells that transport glucose down a concentration gradient [57]. Until now the search for the mammalian facilitative glucose transporters has yielded 12 carriers including GLUT1–5 and the recently discovered GLUT6–12. GLUT1–4 share greater than 40% homology [8], and GLUT5, which is a fructose transporter, exhibits 42, 40, 38, and 41.6% identity with GLUT1, GLUT2, GLUT3, and GLUT4, respectively [9]. All GLUTs have been predicted to have 12 membrane-spanning domains (helices) connected by hydrophilic loops, the first of which is exofacial and contains an N-glycosylation site in GLUT1–5 (Fig. 1) [8, 10]. Both the amino and carboxyl termini of GLUTs reside on the cytoplasmic side of the cell membrane [11]. The carboxyl termini of all GLUTs have unique amino acid sequences that have been utilized for development of reagents. The common sensitivity of the GLUT family to the inhibitory action of the fungal metabolite cytochalasin B has been reported widely and is utilized in studies of hexose transporters [12]. Substrate selectivity of GLUTs is dictated by conserved amino acid motifs, one of which is the QLS motif in helix 7 that is crucial for D-glucose specificity in GLUT1, GLUT3, and GLUT4 (Fig. 1) (for a review, see Ref. 13). Other residues common to the members of canonical GLUT family and important in recognizing glucose are arginine (R) and glycine (G) in intracellular domains 4 and 10, tryptophan (W) in helix 10, GR(R/K) sequences between helices 2 and 3 as well as between helices 8 and 9 [1416]. Models of GLUTs suggest that five of the transmembrane helices form an aqueous pore providing a channel for substrate passage (for a review, see Ref. 13). It is believed that, upon sugar binding, GLUTs undergo reorientation from an exofacial to an endofacial conformation followed by the release of the substrate into the cell (for a review, see Ref. 13). Lack of a crystal structure leaves the precise structure of GLUTs hypothetical. The following review will focus on what is known about the function and regulation of GLUT family members.


GLUT1 is a high affinity (Km = 1–2 mM, Table I) glucose transporter that is ubiquitously expressed in most mammalian tissues. It provides basal glucose transport and, most importantly, transport of glucose through the blood-brain barrier, erythrocytes, and neuronal cell membranes [17]. Additionally GLUT1 has been localized to oocytes and trophectoderm in mouse preimplantation embryos [1820]. Inhibition of GLUT1 expression using antisense oligo(deoxy)nucleotides has been shown to result in apoptosis in preimplantation murine blastocysts [21], showing its importance in mammalian development. Expression of GLUT1 in rat skeletal muscle has been analyzed by immunofluorescence, and it was found in the perineural sheath but not in the muscle fibers [22, 23]. Later, in support of these findings, a minor role for GLUT1 in skeletal muscle basal glucose transport was demonstrated, and several studies determined a prevailing role for GLUT4 over GLUT1 in skeletal muscle (Ref. 24 and for a review, see Ref. 25). Studies using transgenic mice that overexpress GLUT1 exclusively in skeletal muscle demonstrated significantly reduced fasting and fed blood glucose levels, enhanced ability to dispose of a glucose load, and elevated skeletal muscle basal glucose transport activity when compared with non-transgenic siblings [2628]. GLUT1 protein expression in skeletal muscle has been shown to correlate with glycemia and to decrease in heart due to high levels of non-esterified fatty acids [29, 30]. Expression of GLUT1 was analyzed in GLUT4-null mice as it could play a role in the compensatory glucose transport activity in these animals (see below and Ref. 31). No alteration in GLUT1 expression could be measured in skeletal muscle tissue, one of the main sites of the compensatory glucose transport activity [32].


GLUT2 is a low affinity (Km = 15–20 mM) glucose transporter expressed in adult liver, kidney, intestinal epithelium, and pancreatic β-cells [17, 33]. In early mouse embryos, GLUT2 is expressed from the eight-cell stage onward and is located on trophectoderm membranes facing the blastocyst cavity [18, 19]. Because of its high Km, GLUT2 transports glucose in amounts proportional to its circulating levels [34] and, thus, allows sensing and appropriate response by liver and pancreas, major organs that regulate glycemia. The ability of GLUT2 to transport fructose was discovered in studies using Xenopus oocytes and assigned to the HVA motif in helix 7. This motif is also present in the fructose transporter (GLUT5) instead of the QLS motif of the high affinity glucose transporters GLUT1, GLUT3, and GLUT4 (Refs. 16 and 34 and for a review, see Ref. 13). Most recently high affinity (Km = 0.8 mM) glucosamine transport has been demonstrated by hepatocytes and Xenopus oocytes expressing GLUT2 [35], suggesting the possible involvement of GLUT2 in impaired glucose metabolism following glucosamine infusion (Ref. 36 and for a review, see Ref. 37. Regulation of hepatic GLUT2 expression by hyperglycemia and hyperinsulinemia have pointed to a role for GLUT2 in regulation of glucose homeostasis [38]. Data from in vitro studies have stressed the importance of GLUT2 in overall pancreatic islet development and insulin gene expression as both are impaired in β-cells in which expression of the gene for GLUT2was ablated. GLUT2 knockout mice develop abnormal glucose tolerance, hyperglycemia, and hypoinsulinemia yet die within a few days after birth, demonstrating that GLUT2 is a crucial molecule in maintenance of glucose homeostasis [39].


GLUT3 is a high affinity (Km = 1–2 mM) glucose transporter that has been described primarily as the brain and neuronal glucose transporter [4042]. Lower levels of GLUT3 protein have been detected by immunohistochemical and immunoblot analysis in human fetal and adult myocardium, placenta, and liver [40, 43]. GLUT3 has been also proposed to play a role during cell fusion and muscle regeneration [44]. Expression of GLUT3 in muscle has been questioned and attributed to contamination of muscle samples with nerves [12, 45]. However, immunofluorescence and immunohistochemical localization of GLUT3 in normal human skeletal muscle demonstrated that GLUT3 protein is distributed throughout the muscle. GLUT3 was shown to be expressed predominantly in slow twitch fibers although at a low level [46] and was mainly localized to the plasma membrane-enriched fractions [47]. The presence of GLUT3 together with GLUT1 and GLUT4 at the plasma membrane could contribute to basal glucose uptake. Moreover GLUT3 has been localized to the apical membranes of the inner cell mass and trophectoderm in differentiating mouse embryos [20]. GLUT3-mediated transport of maternal glucose on the apical trophectoderm was confirmed using antisense oligo(deoxy)nucleotides to specifically block protein expression. Since blastocyst formation will occur in the absence of glucose, glucose transport via GLUT3 may not be essential for blastocyst formation. However, it has been suggested that GLUT3 expression in the blastocyst is required for differentiation [20]. Studies on GLUT3 expression and regulation are complicated by interspecies variations in sequence, and thus, GLUT3 expression in mouse muscle is yet to be reported.


The insulin-stimulated, high affinity (Km = 5 mM) glucose transporter protein GLUT4 is expressed predominantly, but not exclusively, in all insulin-sensitive tissues: skeletal muscle, adipose tissue, and heart [4850]. The transporter is not expressed in mouse preimplantation embryos or in early postimplantation development [19]. GLUT4 is unique in that it is the only insulin-responsive GLUT that has been characterized so far. In the basal state, the vast majority of GLUT4 resides in an intracellular compartment (Refs. 22 and 51 and for reviews, see Refs. 52 and 53). Studies in which mutation of dynamin (a GTPase involved in the finals steps of clathrin-coated vesicle formation) blocked internalization of GLUT4 followed by its accumulation at the plasma membrane in primary rat adipose cells, 3T3-L1 adipocytes, and Chinese hamster ovary cells [5456] implicated dynamin in the endocytosis of GLUT4. In addition, these studies have suggested that GLUT4 vesicles exist in at least two distinct intracellular compartments: one that is responsive to insulin and a second that undergoes constitutive recycling. However, multiple lines of evidence point to the majority of GLUT4-containing vesicles as being distinct from the recycling endosomal compartment [5759]. The intracellular retention of GLUT4 under basal conditions is dictated by the dileucine motif located in the COOH terminus of the transporter [60].

GLUT4 Vesicle Trafficking—

The final step of the insulin signaling cascade is the fusion of GLUT4-containing vesicles with the plasma membrane. This translocation of the vesicles and incorporation of GLUT4 into the cellular surface requires interactions between several adaptor proteins. GLUT4 vesicles are enriched in the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (v-SNARE), vesicle-associated membrane protein 2 (VAMP2), insulin-regulated aminopeptidase (IRAP), sortilin, and Rab4 [6167] (Fig. 2). Several studies have suggested the plasma membrane target t-SNARE, syntaxin 4 (Syn4), to be the docking protein for the GLUT4 vesicle [6871]. The interaction between VAMP2 and Syn4 is regulated by the binding of a synaptosomal protein with a molecular mass of 23 kDa (SNAP23) and Munc18c and Synip proteins that bind Syn4 [7174]. In the basal state, Synip inhibits the interaction of VAMP2 with Syn4-SNAP23-tSNARE in the plasma membrane, and thus, the steady state recycling of GLUT4 favors sequestration of the majority of GLUT4 to the intracellular compartment. Insulin stimulates dissociation of Synip from Syn4, permitting binding of VAMP2 with Syn4, which is followed by the docking and fusion of the GLUT4 vesicle with the plasma membrane (for a review, see Ref. 75). The importance of GLUT4 for proper vesicle trafficking has been addressed by Jiang et al. [76]. The study demonstrated that the trafficking of IRAP is altered in tissues from GLUT4-null mice resulting in its constitutive targeting to the plasma membrane and highlighting the role of GLUT4 in localization/function of other proteins.

Stimuli and Signaling Elements Involved in GLUT4 Translocation—

Stimuli leading to the increase in translocation of GLUT4 to the plasma membrane include insulin, contraction, and hypoxia [48, 50, 51, 7780] (Fig. 3). Undoubtedly GLUT4 translocation to the plasma membrane from the intracellular pool leads to an increase in 2-deoxy-D-glucose uptake [50, 51, 80, 81]. Correspondingly the importance of GLUT4 in the maintenance of glucose homeostasis has been determined. In addition, a defect in its distribution or function has been implicated in the development of type 2 diabetes [82, 83]. For example, a 90% impairment of insulin-stimulated GLUT4 translocation to the plasma membrane of skeletal muscle of type 2 diabetic subjects compared with normal controls was demonstrated utilizing a biotinylated photoaffinity label [84]. A study utilizing adipose cells from lean or obese Zucker rats of different ages has demonstrated decreased GLUT4 content and an abolished insulin-stimulated translocation of GLUT4 to the plasma membrane in cells from old and obese animals [85]. In the rat model of streptozotocin (STZ)-induced diabetes, the decrease in insulin-stimulated glucose uptake was measured 7 days following the induction of insulinopenia and diabetes. This precedes the decrease in expression of GLUT4 that occurred on day 14 [22]. These results suggested that the impaired translocation of GLUT4 to the plasma membrane or its altered intrinsic activity could contribute to the decreased insulin effect on glucose uptake [22].

Insulin-stimulated translocation of GLUT4 to the plasma membranes requires phosphatidylinositol 3-kinase (PI3K) activity [86] (Fig. 3). However, the activity of PI3K alone is not sufficient to cause a GLUT4-mediated increase in glucose transport, suggesting that additional stimuli are important for GLUT4 translocation. A PI3K-independent translocation of GLUT4 occurs during exercise through the signaling of AMP-activated protein kinase (AMPK) (Fig. 3) [87, 88] and has been proposed to involve a pool of GLUT4 that is different from the one that is mobilized by insulin stimulation [89]. AMPK has been demonstrated to be activated by conditions that lead to an elevation in the intracellular AMP/ATP ratio where AMP causes direct allosteric activation of AMPK making it a better substrate for AMPK kinase [90, 91]. AMPK switches off anabolic processes (decreasing ATP consumption) and activates catabolic pathways (increasing ATP production) [92]. An increase in muscle AMPK activity has been demonstrated to rapidly follow exercise training or electrically stimulated contractions [9395]. Studies utilizing mice expressing dominant-inhibitory AMPK in skeletal muscle have shown a complete attenuation of hexose transport by skeletal muscle [96]. Importantly exercise-induced hexose transport was partially preserved in these muscles suggesting the existence of an AMPK-independent signaling pathway [96]. Furthermore the AMPKα2 knockout mouse model exhibits hyperglycemia and hypoinsulinemia [97]. Moreover it has been suggested that AMPK signaling involves activation of nitric-oxide synthase in cell cultures and rat skeletal muscle [98]. Nitric-oxide synthase activation leads to production of nitric oxide (NO), which acts through the activation of soluble guanylate cyclase to increase the rate of cGMP formation [99, 100]. An increased GLUT4 translocation to the cell surface and elevation in glucose transport has been demonstrated in isolated rat skeletal muscle using a NO donor, sodium nitroprusside, that increases cGMP concentration independent of insulin, PI3K, and calcium/contraction [101103] suggesting a novel pathway for glucose transport activation.

The beneficial effects of a single bout of exercise on GLUT4 translocation has been demonstrated in subjects with type 2 diabetes [104]. The requirement of GLUT4 for hypoxia/exercise-stimulated glucose transport was demonstrated in extensor digitorum longus (EDL) and soleus muscles derived from GLUT4-deficient (GLUT4-null) mice [105]. In this study, GLUT4ablation prevented an increase in glucose uptake following hypoxia, and muscle-specific transgenic complementation of GLUT4in EDL muscle restored the hypoxia-stimulated glucose uptake, further demonstrating the essentiality of GLUT4 for this stimulus. Thus, GLUT4 is mediating glucose uptake in response to insulin, hypoxia, or exercise in responsive tissues.

Role of GLUT4 in Glucose Homeostasis—

Transgenic and gene knockout mouse models have provided important insight into the role of GLUT4 in tissue and whole body glucose metabolism. Hyperglycemia has been identified as a harmful factor that causes abnormalities of GLUT4 expression and translocation in skeletal muscle of streptozotocin diabetic rats [29, 106]. The overexpression of GLUT4 in the muscle of transgenic mice leads to enhanced insulin-stimulated glucose disposal (Ref. 107 and for a review, see Ref. 108). In addition, overexpression of GLUT4 in skeletal muscle, heart, and adipose tissue prevents the detrimental effect of hyperglycemia due to feeding a high fat diet [109]. The GLUT4 gene was selectively disrupted in heart [110], adipose [111], and muscle tissue [112] using Cre/LoxP gene targeting. Heart-restricted GLUT4 knockout mice do not exhibit any alterations in whole body glucose homeostasis but do have significant cardiac hypertrophy [110]. Mice that lack GLUT4 only in adipose tissue exhibit no increase in adipose cell glucose uptake in response to insulin and whole body glucose intolerance and hyperinsulinemia [111]. Muscle-specific GLUT4 knockout mice develop mild insulin resistance and glucose intolerance. Mice heterozygous for the muscle-specific GLUT4 deletion exhibit a rather intermediate phenotype [112]. Combined these studies demonstrate a crucial role for GLUT4 not only in tissues where it is expressed but also in whole body insulin action. Mice with whole body heterozygous ablation of GLUT4 (GLUT4+/− mice) display a diabetic phenotype with severely reduced whole body insulin-stimulated glucose uptake and disposal [113]. Diabetic GLUT4+/− mice develop enlarged adipose cells, fatty livers, hypertension, and cardiovascular complications often found in type 2 diabetic patients. Until 2–4 months of age, male GLUT4+/− mice express normal levels of GLUT4 in both skeletal muscle and adipose tissue. After 5 month of age, the majority of GLUT4+/− males develop a diabetic phenotype along with a decrease in GLUT4 content: ∼50, 26, and 46% in adipose tissue, EDL, and soleus muscles, respectively, when compared with wild type age-matched controls. In accordance with this findings, glucose uptake into EDL and soleus muscles of diabetic GLUT4+/− mice is decreased 34 and 38% as compared with controls [113]. The transgenic complementation of GLUT4 into skeletal muscles of GLUT4+/− mice restores both skeletal muscle and whole body insulin action [114, 115]. Surprisingly complete ablation of GLUT4 in mice (GLUT4-null) resulted in mice that have normal circulating glucose and insulin levels [31]. GLUT4-null mice, however, have impaired insulin tolerance, dramatically reduced adipose tissue size and content, and profound cardiac hypertrophy. Overall the unexpected non-diabetic phenotype of GLUT4-null mice has suggested a compensatory mechanism or unmasking of a novel glucose transporter activity. Indeed in vitro analysis demonstrated a 2.3-fold increase in basal glucose uptake in GLUT4-null male and normal basal levels with a significant increase following insulin stimulation in GLUT4-null female oxidative soleus muscles [116]. The possibility that overexpression of GLUT1 and/or ectopic expression of other canonical GLUTs occurred in GLUT4-null soleus muscle was ruled out [32, 116]. As a result, expression of a novel GLUT4-independent glucose transport activity was proposed [32, 108, 116]. At present, expression and regulation of three new members of the glucose transporter family (GLUT8, GLUT11, and GLUT12) are under investigation as potential compensatory transporters in GLUT4-null oxidative muscle.


GLUT5 is a facilitative fructose transporter (Km = 10–13 mM) that is highly expressed in the cells of the brush-border and basolateral membranes of the small intestines where it mediates passage of sugars from the lumen into the cells Refs. 117 and 118 and for a review, see Ref. 4). Lower levels of GLUT5 are detected in erythrocytes, kidney, spermatozoa, skeletal muscle, and adipose tissue from humans and rats [9, 119123]. The expression of GLUT5 in human muscle has been linked to the ability of muscle to utilize fructose for glycolysis and glycogenesis independent of GLUT4 and GLUT1 (Ref. 124 and for a review, see Ref. 125). Recently the gene for mouse GLUT5 was isolated, and mRNA for GLUT5 was detected in small intestine, kidney, and testis [126]. No GLUT5 was detected in mouse skeletal muscle [32]. GLUT5 is not labeled by cytochalasin B [117], and thus, cytochalasin B exposure does not inhibit GLUT5-mediated fructose transport in different tissues [123, 127, 128], suggesting that glucose and fructose are unlikely to share a common transporter (for a review, see Ref. 125). Indeed GLUT5 does not possess one of the glucose recognition motifs, QLS in helix 7 (for a review, see Ref. 13). Recent development of high affinity ligands and photoaffinity labels for GLUT5 will provide further insight into GLUT5 function and regulation by various stimuli [129].


GLUT6 (previously referred to as GLUT9), a proposed sugar anion transporter, has been detected in brain, spleen, and leukocytes [130]. GLUT6 has a low affinity for glucose (Km = 5 mM) and cytochalasin B [130]. The subcellular targeting of GLUT6 resulted in the retention of the protein in the intracellular compartments in COS-7 and rat adipose cells in which hemagglutinin-tagged GLUT6 was expressed [131]. The only N-glycosylation site of GLUT6 has been found in the exoplasmic loop between transmembrane (TM) helices 9 and 10 [130]. A marked increase in GLUT6 in the plasma membrane of cells has been demonstrated following mutation of a dileucine (LL) motif located at the amino terminus [131]. Also inhibition of general endocytosis by co-expression of dominant negative dynamin resulted in the accumulation of GLUT6 in the plasma membrane. This is consistent with GLUT6 recycling between the intracellular compartment and plasma membrane in COS-7 and rat adipose cells. Similar results have been obtained following genetic manipulation of another putative glucose transporter protein, GLUT8 (see below). The contribution of GLUT6 to insulin-stimulated glucose transport is most likely negligible since no significant translocation of the transporter to the plasma membrane could be observed following insulin stimulation [131]. In addition, neither osmotic shock using sorbitol nor the treatment with phorbol myristate acetate were efficient in causing the translocation of GLUT6 to the cell surface. Substrate specificity of GLUT6 remains to be determined.


The designation GLUT7 has been assigned previously to a now withdrawn sequence and, according to a new nomenclature proposed recently, has been assigned to a novel gene that is adjacent to the GLUT5 gene. A cDNA of GLUT7 was assembled utilizing information from genomic sequence, and it was shown that the deduced amino acid sequence of GLUT7 is 58% identical to GLUT5. The substrate specificity of the putative GLUT7 protein and the pattern of its gene expression are yet to be identified (for a review, see Ref. 6).


GLUT8 was the first in a series of novel glucose transport proteins cloned in recent years [132134]. The protein sequence of GLUT8 demonstrates 22, 25, and 23% identity with GLUT1, GLUT3, and GLUT4, respectively, and contains 12 putative transmembrane domains. Like GLUT6, GLUT8 lacks a glycosylation site in exoplasmic loop 1 and harbors only one N-glycosylation site in the exoplasmic loop between TM helices 9 and 10 [132]. A LL motif in the NH2 terminus was proposed to serve as an internalization signal. GLUT8 mRNA is widely expressed in tissues including brain (cerebellum, brainstem, hippocampus, and hypothalamus), adrenal gland, spleen, brown adipose tissue, white adipose tissue, placenta, muscle, heart, and liver. The concentration of GLUT8mRNA is greatest in testis [132136] where its expression has been linked to circulating gonadotropins. Estrogen treatment suppressed GLUT8 expression in testis [133], and no expression of GLUT8 mRNA could be detected in testis of prepubertal (12 days) mice. However, there was a gradual up-regulation of expression of the gene for GLUT8 as the mice matured [137]. More recently GLUT8 was immunolocalized to the acrosome in sperm suggesting that GLUT8 may be important in maintaining reproductive function and/or fertility [138]. Utilizing immunohistochemistry and emulsion autoradiographic analysis, GLUT8 has been detected in rat hippocampal neurons and localized to the cytoplasm of neuronal cell bodies [135]. The absence of other glucose transporters and increased expression of GLUT8 mRNA in STZ diabetes in this subset of neurons highlighted a possible contribution of GLUT8 in supporting glucose requirements of hippocampal neuronal cell bodies and their cognitive function [135]. Importantly localization of GLUT8 in the hippocampus demonstrated that it is mainly an intracellular protein. In vitro studies demonstrated that GLUT8 expressed in Xenopus oocytes transports glucose with high affinity (Km = ∼2 mM) in a cytochalasin B-inhibitable manner [132134]. Moreover addition of fructose or galactose to the incubation medium resulted in significant, yet partial, inhibition of glucose uptake demonstrating that fructose and galactose might serve as substrates for GLUT8 [132]. No plasma membrane translocation of GLUT8 could be observed in Xenopus oocytes, COS-7 cells, HEK-293T cells, or isolated fat cells unless the dileucine motif in the amino terminus was mutated [131, 132]. The contribution of GLUT8 to insulin-, osmotic shock (sorbitol)-, or phorbol myristate acetate-stimulated glucose transport in these cells is negligible since no significant translocation of the transporter to the plasma membrane could be observed following stimulation by these compounds [131]. The first clue for GLUT8 intracellular regulation was obtained from the immunogold electron microscopy study of hippocampal neurons from rats subjected to glucose challenge. This study demonstrated redistribution of GLUT8 to the endoplasmic reticulum pointing to its possible role in targeting glucose intracellularly [139]. On the other hand, GLUT8 is responsible for insulin-stimulated glucose transport in blastocysts [134] where it is crucial for embryonic development and survival. Embryos exposed to GLUT8 antisense oligo(deoxy)nucleotides demonstrated increased apoptosis in nuclei [140]. GLUT8 gene expression decreased following glucose deprivation or hypoxia in cultured, differentiated 3T3-L1 adipocytes; however, the conditions tested were beyond the physiologic range [137]. GLUT8 expression in liver is restricted to a single layer of hepatocytes surrounding central veins similar to GLUT1 [141]. The highly glycolytic nature of pericentral hepatocytes suggests GLUT8 involvement in substrate shuttling through the glycolytic pathway [141]. The zonation of GLUT8 expression is altered in type 1 and type 2 diabetic mice models further pointing to GLUT8 involvement in hepatocyte adaptation to altered glucose homeostasis [141]. The history of GLUT8 has just begun, and exploration of its function and regulation in the multiple sites where it is expressed will be the focus of future research.


The putative glucose transporter GLUT9 has been cloned from a human skeletal muscle library [142]. GLUT9 exhibits the highest (44.5% identical amino acid residues) sequence similarity to GLUT5. Its mRNA is highly expressed in kidney and liver with lower levels of expression in placenta, lung, peripheral blood leukocytes, heart, and skeletal muscle. The protein contains signature sugar transporter motifs and characteristics of the facilitative glucose transport family [142]; however, GLUT9 substrate specificity is not known nor has its regulation been characterized.


GLUT10 is a high affinity (Km = 0.3 mM) glucose transporter that exhibits 31–35% identity to human GLUT1–GLUT8 proteins with the highest sequence similarity to GLUT8 [143]. GLUT10, like other members of the GLUT family, contains 12 putative membrane-spanning domains with two major hydrophilic loops: one intracellular between TM domains 6 and 7 and the second one exofacial between TM domains 9 and 10. Putative N-glycosylation sites of GLUT10 were described between TM domains 8 and 9 and on the cytoplasmic carboxyl terminus [143]. High levels of GLUT10 mRNA were demonstrated in liver and pancreas, and low mRNA levels were detected in heart, skeletal muscle, placenta, kidney, lung, brain, liver, and pancreas [143, 144]. GLUT10 mRNA has also been detected in salivary gland, thyroid, adrenal gland, ovary, prostate, and skin utilizing reverse transcription-PCR analysis of human mRNA [143]. Screening of the mouse EST data base resulted in two ESTs from mammary gland and one EST from a mixed tissue library [143]. When expressed in Xenopus oocytes, GLUT10-mediated 2-deoxy-D-glucose uptake with a high affinity (Km = 0.3 mM) and was inhibited by galactose but not fructose [143]. The glucose transporting properties and proximity of the genomic locus of GLUT10 to a known type 2 diabetes locus implicated it as a candidate gene for diabetes [143, 144]. The development of necessary reagents for studying its expression and regulation will shed light on its involvement in the progression or prevention of diabetes and its complications.


The next member of the glucose transporter family to be cloned and characterized was the human sugar transporter GLUT11 [145]. GLUT11 consists of 12 exons and transcribes into a 7.2-kb message exclusively in human heart and skeletal muscle. An additional transcript was detected at 3.6 kb. GLUT11 contains 12 putative membrane-spanning domains with an expected N-glycosylation site in exofacial loop 1 and motifs and conserved residues that have previously been shown to be essential for sugar transporter function. GLUT11, however, does not have a QLS motif in helix 7. It exhibits 42 and 35% amino acid identity with GLUT5 and GLUT1. A GLUT11-specific immunoreactive protein of 45 kDa was detected in the fraction containing both plasma membranes and microsomes of the human heart. Reconstituted vesicles from COS-7 cells overexpressing GLUT11 demonstrated a 2–3-fold increase in glucose transport followed by marked inhibition of glucose transport in the presence of 5 mM fructose. The close relationship between GLUT11 and GLUT5 and its fructose sensitivity pointed to its possible function as a fructose transporter and suggested that muscle tissue specificity makes GLUT11 a candidate for the compensatory glucose transport activity described in GLUT4-null soleus muscle [116, 145]. The murine homolog of GLUT11 has not yet been identified.


The putative glucose transporter protein GLUT12 has been identified in MCF-7 breast cancer cells [146]. GLUT12 exhibits 29 and 40% amino acid identity with GLUT4 and GLUT10, respectively. GLUT12 mRNA is highly expressed in human heart, skeletal muscle, and prostate with lower levels in brain, placenta, and kidney. Immunoblot analysis of several human tissues has demonstrated expression of GLUT12 in skeletal muscle, adipose tissue, and small intestine [146]. It possesses dileucine motifs at the NH2 and COOH termini, several sites for sugar transport, and novel N-linked glycosylation sites [146]. Immunohistochemistry and immunofluorescence microscopy analysis of GLUT12 in MCF-7 cells revealed a perinuclear localization under acute insulin stimulation. Redistribution of GLUT12 to the plasma membrane of MCF-7 cells following chronic exposure to insulin has indicated its potential for insulin-responsive glucose transport [146]. The potential role of GLUT12 in glucose transport in mouse tissues is to be addressed in the future because a murine homolog has not as yet been identified.


This review highlights the key features of all known facilitative glucose transporter proteins. The precise function and regulation of the canonical glucose transporters GLUT1–5 have been the subject of investigation for many years. These studies resulted in the knowledge that these proteins are crucial for appropriate uptake of hexoses into various tissues, one of the essential steps in regulation of glucose homeostasis. Transgenic and knockout mouse models have provided crucial insight into the whole body and tissue-specific role of GLUT4 in preserving glucose homeostasis and preventing diabetes. While substrate specificity and regulation of GLUT1–5 function has been substantially clarified, only a handful of reports related to the novel glucose transporters GLUT6–12 have been published. Future research will address the substrate specificity, function, and regulation of these glucose transporters in response to different stimuli. Undoubtedly genetic manipulation of each of the new GLUTs will contribute to revealing the cellular and whole body role in sugar metabolism. A more detailed knowledge of the function and regulation of the novel glucose transporter proteins may provide important clues and targets for developing therapeutic agents to improve glucose disposal and treat diseases of insulin resistance such as type 2 diabetes and obesity, two major problems present in the United States.

Figure FIGURE 1..

Schematic representation of the canonical facilitative glucose transporters. Twelve hydrophobic transmembrane domains (TM rectangles) are connected by hydrophilic loops. Carboxyl and amino termini of the protein are oriented intracellularly. Conserved amino acid residues are shown individually and are discussed in the text. G, glycine; R, arginine; W, tryptophan; L, leucine; S, serine; N, asparagine; Q, glutamine; K, lysine.

Figure FIGURE 2..

Schematic of GLUT4 trafficking. GLUT4 resides in two distinct intracellular compartments. GLUT4 from recycling endosomes constitutively recycles between plasma membrane and the intracellular compartment. Also GLUT4 recycles between the endosomal compartment and specialized GLUT4 vesicles that in addition to GLUT4 contain IRAP, Rab4, and sortilin. GLUT4 vesicles translocate to the plasma membrane following stimulation by insulin, hypoxia, or exercise. Fusion of the vesicles with the plasma membrane depends on the interaction of SNARE proteins VAMP2 and Syn4.

Figure FIGURE 3..

Pathways leading to GLUT4 translocation and increase in glucose uptake. Increase in glucose uptake by skeletal muscle is a result of GLUT4 translocation to the plasma membrane that occurs following activation of at least one of the three pathways indicated. While insulin activates the PI3K-Akt pathway, hypoxia and exercise signal through AMPK. AMPK is necessary for GLUT4-mediated glucose uptake in response to hypoxia, whereas the exercise-stimulated pathway of glucose uptake may involve other, yet identified signaling elements. Exercise and hypoxia stimulation of glucose uptake via GLUT4 is independent of the insulin signaling pathway. Therefore patients with type 2 diabetes and other insulin-resistant states are recommended to use exercise to increase their glucose disposal.

Table Table I. Characteristics of facilitative glucose transporters
TransporterNo. of amino acid residuesTissues expressing high levelsSubstrate and affinityFunctionRefs.
GLUT1492Erythrocytes, blood-brain barrier, neuronal cell membranes, ubiquitousGlucose 1–2 mMBasal glucose uptake1730
GLUT2524Liver, kidney and intestinal epithelium, pancreatic β-cellsGlucose 15–20 mM Glucosamine 0.8 mMGlucose sensing and transport by liver and pancreas1719, 34, 35, 39
GLUT3496NeuronsGlucose 1–2 mMBasal glucose uptake20, 4047
GLUT4509Skeletal muscle, heart, adipose cellsGlucose 5 mMInsulin-stimulated glucose uptake48103
GLUT5501Brush-border and basolateral membranes of intestinal epithelium spermFructose 10–13 mMTransport of sugars from intestinal lumen into the cells and into sperm104118
GLUT6507Brain, spleen, leukocytesGlucose 5 mM (to be confirmed)Not known119, 120
GLUT7Not knownNot determinedNot knownNot known121
GLUT8477Testis, brain, liverGlucose 2 mMNot known122130
GLUT9540Kidney, liverNot knownNot known131
GLUT10541Liver, pancreasGlucose 0.3 mMNot known132, 133
GLUT11496Heart, skeletal muscleNot knownNot known134
GLUT12617Heart, skeletal muscle, prostateNot knownNot known135


  1. 1

    The abbreviations used are: SGLT, sodium-glucose co-transporter; GLUT, glucose transporter; SNARE, soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor; v-SNARE, vesicle SNARE; t-SNARE, target SNARE; VAMP2, vesicle-associated membrane protein 2; IRAP, insulin-regulated aminopeptidase; Syn4, syntaxin 4; SNAP23, soluble NSF attachment protein of 23 kDa; STZ, streptozotocin; PI3K, phosphatidylinositol 3-kinase; AMPK, AMP-activated protein kinase; EDL, extensor digitorum longus; TM, transmembrane; EST, expressed sequence tag.