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.