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

Abstract

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.Keywords: Glucose uptake, GLUT, insulin action, diabetes.The entry of glucose into cells is a crucial step in lifesupporting 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 (SGLT 1 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 [5][6][7]. 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 conserve...

Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells

“…Experimental K m values obtained were 0.63 (3.5 mM), 0.31 (1.7 mM), and 0.39 g/l (2.1 mM) for hCMEC/D3, IMR90, and CTR65M BMEC monolayers, respectively. Such K m values were similar to GLUT1 and GLUT3 K m values as reported in the literature (12).…”

Non-radioactive 2-deoxy-2-fluoro-D-glucose inhibits glucose uptake in xenograft tumours and sensitizes HeLa cells to doxorubicin in vitro

“…This could be explained by differential affinities between the compounds for the GLUT1 transporter. Gorovits et al [ 46 ] found that the GLUT1 Km value for glucose is 1-2mM, while its Km for 2DG is 6.9mM [ 47 ]. Of note, 19 FDG is more structurally similar to glucose than 2DG is to glucose [ 48 ], suggesting that the Km for 19 FDG may be similar to glucose, resulting in GLUT1 having a higher affinity for 19 FDG than for 2DG.…”

Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions

“…Glucose influx occurs through apical Na ϩ -glucose cotransporters that reabsorb glucose and concentrate glucose in tubules (26). Glucose efflux follows through basolateral facilitative glucose transporters (8). The family of hexose transporters (GLUT) proteins consists of several members with different characteristic elements that define their physiological function.…”

“…The family of hexose transporters (GLUT) proteins consists of several members with different characteristic elements that define their physiological function. GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5 were described as hexose transporters in the kidney (3,8,11,35). GLUT8, a recently identified member of the extended GLUT family has been localized to several tissues including kidney, testis, blastocysts, brain, muscle, and adipocytes and may contribute to maintenance of normal serum glucose (6,14,27).…”