3. GLUT Transporter Classes

3.1. Class I GLUTs
GLUTs 1–4, and GLUT14 in human, make up the Class I family of glucose transporters. In mammalian species, the glut1/slc2a1 gene encodes the major GLUT protein of the blood–brain barrier [15]. The encoded protein is located primarily along the cell surface and in the cell membrane. GLUT1 may be responsible for constitutive or basal glucose uptake in cells and can transport a wide range of aldoses, including pentose and hexose [16,17]. On the cell surface, human GLUT1 may function as a receptor for T-cell leukemia virus I and II. Gene mutations associated with GLUT1 deficiency in humans have been linked to microcephaly and childhood epilepsy [18,19], hypoglycorrhachia [20,21], cryohydrocytosis with reduced stomatin [22], paroxysmal dystonic choreathetosis [23], episodic ataxia [22], hemiplegic migraines [24,25], spasticity and paroxysmal exertion-induced dyskinesia [26]. Overexpression of GLUT1 was shown to be an indicator for cancer [27] and to have an association with thymic carcinoma [28]. Suppression of GLUT1 by apigenin slowed overexpression of GLUT1 and had anticancer properties in mouse lung cancer cells [29]. Chicken GLUT1 shares 80% amino acid residues with humans [30]. Chicken GLUT1 has ubiquitous expression, with abundant expression in the hypothalamus, and has demonstrated response to insulin and dexamethasone [31]. According to the National Center for Biotechnology Information (NCBI) Gene Database [32], glut1/slc2a1 orthologs are conserved in 124 organisms including human, chicken, chimpanzee, cow, mouse, rat, Rhesus monkey, zebrafish and Eremothecium gossypii (fungus).
In mammals, glut2/slc2a2 encodes a glycoprotein. The encoded protein regulates bidirectional glucose transport across liver cells, pancreatic islet beta cells that store and release insulin, epithelial kidney cells and intestines. Similar to mammalian species, chickens have abundant GLUT2 expression in the liver [33], pancreatic beta cells, kidney and small intestine [34]. Due to its low affinity for glucose, GLUT2 may be a glucose sensor. glut2/slc2a2 gene mutations in humans are associated with increased disease susceptibility, including noninsulin-dependent diabetes mellitus and Fanconi–Bickel syndrome. Mutations in glut2/slc2a2 were also found to increase risk of cardiovascular disease in patients with type 2 diabetes [35,36]. Alternative gene splicing results in multiple transcript variants. Based on the NCBI Gene Database [32,37], glut2/slc2a2 orthologs have been found in 168 organisms including human, chicken, dog, chimpanzee, cow, Rhesus monkey, rat, Xenopus tropicalis (western clawed frog), Xenopus laevis (African clawed frog) and zebrafish.
Mammalian GLUT3 facilitates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose, fucose and other monosaccharides across the cell membrane. GLUT3 does not mediate fructose transport [36,38]. GLUT3 deficiency has been implicated in age of onset in Huntington’s disease [39]. Chicken GLUT3 is known to be a neuronal glucose transporter and shares 70% sequence similarity with that of humans [2]. The neuronal functions of GLUT1 and GLUT3 are similar across chickens and mammals [30,31]. In chickens, the upregulation of GLUT1 and GLUT3 is associated with the formation of tight junctions in the blood-retinal barrier [40]. Orthologs of glut3/slc2a3 are preserved across 70 organisms so far, including chicken, dog, cow, chimpanzee, mouse, rat, Rhesus monkey, X. tropicalis, X. laevis, zebrafish, fruit fly, mosquito, Caenorhabditis elegans (non-parasitic roundworm), Saccharomyces cerevisiae (yeast), Kluyveromyces lactis (yeast), rice, Magnaporthe oryzae (rice blast fungus), Neurosporra crassa (red bread mold) and Arabidopsis thaliana (flowering plant), according to the NCBI Gene Database [32,37].
It is well known that GLUT4 is the major insulin sensitive glucose transporter in mammals. The mechanism by which insulin regulates GLUT4 activity has been well studied. Upon stimulation by insulin, intracellular GLUT4 translocates to the plasma membrane, where GLUT4 facilitates cellular glucose uptake. This constitutes the major portion of insulin-stimulated glucose uptake, especially in adipose tissue, skeletal muscle and cardiac muscle tissues. Humans and most mammals rely on normal protein expression of GLUT4 for blood glucose homeostasis [41]. glut4 gene mutations in humans are associated with type 2 diabetes mellitus [42]. According to the NCBI Gene Database, glut4/slc2a4 orthologs are found in 114 organisms including dog, cow, chimpanzee, mouse, rat and Rhesus monkey [32,37]. Chickens intrinsically lack glut4 expression, and chickens are known to be naturally hyperglycemic with adipose tissue [2,43,44] and skeletal muscle tissue [45] that is poorly sensitive to insulin.
GLUT14, a duplicon of GLUT3, has been shown to have messenger RNA (mRNA) expression in the human testis [6] and, according to the NCBI Gene Database, may have a specific function related to spermatogenesis in males [46]. One study linked a polymorphism of slc2a14 to having a possible role in the development of late-onset Alzheimer’s disease in a Han Chinese population [47]. High GLUT14 expression was also found to be associated with gastric adenocarcinoma [48]. According to the NCBI Gene Database, slc2a14 orthologs are present in humans and Western gorillas [32,37]. In Oryctolagus cuniculus (rabbit), slc2a14 is known as proteins GLUT3 and SLC2A14. In Rhesus monkey, the LOC715795 gene is known as proteins SLC2A3 and SLC2A14. slc2a3b orthologs are also present in zebrafish. UniProt lists slc2a1 as the gene that encodes the GLUT14 protein in X. tropicalis, inferred from database entries.

3.2. Class II GLUTs
Class II consists of GLUTs 5, 7, 9 and 11. GLUT5 is a fructose transporter protein with expression across many species [49]. According to the NCBI Gene and Protein databanks, human GLUT5 is thought to be a cytochalasin β-sensitive carrier with expression in human testis, spermatozoa, small intestine [49], adipose tissue and skeletal muscle [50]. More recent RNA-seq analyses found human GLUT5 expression in duodenum, bone marrow and kidney [51]. GLUT5 was found to have an association with malignant clear renal cell carcinoma [52]. According to the NCBI Gene database [32,37], orthologs of glut5/slc2a5 are found so far in 123 organisms across chicken, dog, cow, chimpanzee, Rhesus monkey, mouse, rat and X. tropicalis. Chicken GLUT5 has been shown to have mRNA expression in the small intestine [53] and may be regulated by glucocorticoids [54].
GLUT7 has been identified as a high affinity transporter for glucose and fructose. GLUT7 does not transport galactose, 2-deoxyglucose or xylose [55]. Human GLUT7 has expression in the small intestine and colon, with lower expression levels in the testis and prostate [55]. Based on our searches of the NCBI Gene and Protein Database and UniProt Database [37,46,56], there are no data for GLUT7 in chickens or other avian species, suggesting that the avian lineage has lost slc2a7 during evolution. Orthologs of slc2a7 are conserved in 55 organisms across mouse, rat, chimpanzee and Rhesus monkey, according to the NCBI Gene Database.
GLUT9 is a known transporter of fructose and urate and can transport glucose at a low rate. Mammalian GLUT9 plays a regulatory role in the development and survival of cartilage chondrocytes and may have a role in urate reabsorption by proximal tubules [57,58]. One study linked gout to GLUT9 deficiency in a population of Japanese males [59]. It is assumed that chicken GLUT9 mediates uric acid uptake, although substrate specificity for this GLUT transporter has not yet been identified [33]. Liver mRNA expression of GLUT9 was shown to be greater in obese chickens, possibly due to having a larger glucose uptake capacity with greater demand and glucose load in high bodyweight chickens [33]. Based on the NCBI Gene Database [32,37], two transcript variants with distinct isoforms have been identified for glut9/slc2a9. Orthologs of glut9/slc2a9 are present in 153 organisms including chicken, dog, cow, mouse, rat, chimpanzee, X. tropicalis and X. laevis.
According to the NCBI Gene Database, GLUT11 is also known as GLUT10. GLUT11 is a transporter of glucose and fructose, but does not transport galactose in humans. GLUT11 has roughly 42% amino acid sequence similarity to GLUT5 and 35% similarity to GLUT1 [60]. Alternative splicing results in multiple transcript variants, including GLUT11-A, GLUT11-B and GLUT11-C [61]. Mammalian GLUT11-A has expression in skeletal muscle, heart and kidney. Mammalian GLUT11-B is expressed in adipose tissue, kidney and placenta. Mammalian GLUT11-C has expression in skeletal muscle, heart, adipose tissue and pancreas [62]. Based on NCBI RefSeq, there is also evidence of a fourth GLUT11 isoform, known as GLUT11-D [46]. Human glut11/slc2a11 orthologs are present in 111 organisms and conserved across chicken, dog, cow, chimpanzee, Rhesus monkey, zebrafish and X. tropicalis, based on the NCBI Gene Database [37]. Rats and mice lack the glut11/slc2a11 gene [62].

3.3. Class III GLUTs
Class III contains GLUTs 6, 8, 10, 12 and HMIT/GLUT13. According to NCBI, slc2a6 has alias GLUT6 and GLUT9 proteins in humans, mice and X. tropicalis. GLUT6 is a hexose transporter protein. Mammalian GLUT6 is highly expressed in the brain, spleen and leukocytes [63]. One study linked an upregulation of GLUT6 to endometrial cancer in women [64]. Based on the NCBI Gene Database [32,37], GLUT6/SLC2A6 orthologs are present in 169 organisms including chicken, dog, cow, mouse, chimpanzee, Rhesus monkey, zebrafish, fruit fly, mosquito, X. tropicalis and X. laevis.
Based on sequence similarity, GLUT8 has been identified as an insulin-regulated glucose transporter. According to NCBI, GLUT8 binds cytochalasin β in a glucose-inhibitable manner. Mammalian GLUT8 may be dual-specific and is inhibitable by fructose. A recent study on the mouse atria suggests that GLUT8 has a role in glucose uptake in the mammalian heart, along with GLUT4 [65]. glut8/slc2a8 orthologs are conserved across 171 organisms including chicken, dog, mouse, rat, cow, chimpanzee, Rhesus monkey, X. tropicalis, zebrafish, fruit fly, A. thaliana and rice, according to NCBI. Similar to mammals, chicken GLUT8 is a known insulin-responsive glucose transporter with ubiquitous expression in cells and higher mRNA concentrations in adipose tissue and kidney [1].
According to the NCBI Gene Database, GLUT10 plays a role in glucose homeostasis regulation. Human GLUT10 has highest mRNA expression in the liver and pancreas [66]. In humans, genetic mutations of glut10/slc2a10 are associated with arterial tortuosity syndrome, a rare connective tissue disorder [67]. Based on NCBI, glut10/slc2a10 orthologs are conserved across 166 organisms including chicken, dog, mouse, rat, chimpanzee, Rhesus monkey, cow, X. tropicalis, X. laevis and zebrafish [32,37].
According to the Gene Database at NCBI, the slc2a12 encoded protein contains alias GLUT8 and GLUT12 in humans. GLUT12 can facilitate transport of a variety of hexoses [68]. Human GLUT12 is expressed in skeletal muscle, heart and prostate, with lower mRNA expression in the brain, placenta and kidneys [69]. A recent study implicated GLUT12 expression in the frontal cortex for its role in Alzheimer’s disease, a metabolic disease which impairs the brain’s ability to utilize glucose [70]. The GLUT12 level, as well as GLUT1 level, was shown to be elevated in hypertension and diabetic neuropathy in animal studies [71]. A recent study of GLUT12 in chicken skeletal and cardiac muscle suggests that GLUT12 may act as an insulin-sensitive transporter similar to GLUT4 in mammalian species [72]. Orthologs of glut12/slc2a12 are conserved across 177 organisms including chicken, dog, mouse, rat, chimpanzee, Rhesus monkey, cow, X. tropicalis, X. laevis, zebrafish, A. thaliana and rice, based on the NCBI Gene Database [32,37].
Studies on Xenopus oocytes have helped identify GLUT13 as a proton (H+) myo-inositol cotransporter with specificity for the transport of myo-inositol, inositol triphosphate and related stereoisomers [73,74]. Mammalian HMIT/GLUT13 is predominantly expressed in glial cells and some neurons and may be responsible for myo-inositol brain metabolism regulation [73]. Intracellular function of HMIT may also be responsible for mood control [74]. Genetic alterations of HMIT may also be associated with non-small-cell lung cancer [75] and Parkinson’s disease [76]. According to the NCBI Gene Database [32,37], glut13/slc2a13 orthologs are conserved across 151 organisms including chicken, dog, cow, chimpanzee, Rhesus monkey, mouse, rat, X. tropicalis, X. laevis, zebrafish, C. elegans, S. cerevisiae, K. lactis, E. gossypii, Schizosaccharomyces pombe (fission yeast), A. thaliana and rice.