The facilitative transport of glucose across the plasma membrane in the mammalian cells is performed series of glucose transport proteins (GLUTs). These GLUTs involve similar structure and functions but their distributions in the mammalian tissue differ. From those GLUTs, GLUT4 is attracted an attention since it was shown dependence to insulin stimuli for the translocation of plasma membrane. In addition, as a key determinant in glucose homeostasis, GLUT4 comprises various cellular signaling mechanisms that is important for the human diseases such as cancer and insulin resistance. Here, we report the collection of several studies that included (a) structure and function of mammalian GLUTs, (b) signaling mechanisms and membrane trafficking pathways play role in the GLUT4 system and (c) the influence of GLUT4 on human diseases and its therapeutic implications. Future directions were also discussed.
The function of glucose is to provide important energy source in the generation of ATP through glycolysis and act as precursor for the glycoproteins, triglycerides and glycogen synthesis. As a polar molecule, glucose does not easily diffuse across the hydrophobic plasma membrane, and thus, specific carrier molecules are required to mediate uptake of the distinct sugars. For instance, energy dependent Na+/glucose cotransporter identified as mammalian facilitated glucose carrier in the intestinal brush border (Hediger, Coady, Ikeda, & Wright, 1987) and involved in the movement of Na+ down its electrochemical gradient which uptakes glucose. On the other hand, all mammalian cells comprise at least a member of the facilitative glucose transporter gene family. This system composed of glucose transporters (GLUTs) allows bidirectional transport of glucose with passive diffusion merely down to concentration gradient thereby acting as the supply of circulating glucose that is available for metabolism. In this review article, we will dwell on (a) structure and function of mammalian GLUTs, (b) GLUT4 as key determinant in glucose homeostasis and (c) the impact of GLUT4 on human diseases such as cancer and insulin resistance.
Until now, thirteen members of the mammalian GLUTs (GLUT1-12 and H+/myo-inositol transporter HMIT) have been identified. Three groups of GLUTs were classified considering sequence homology and structural similarity. While Class I included GLUT1-4, class II GLUTs comprised GLUT5, GLUT7, GLUT9 and GLUT11, whereas Class III included GLUT6, GLUT8, GLUT10, GLUT12 and HMIT. Sequence alignment data showed that at least 28% similarity between GLUT1 and the other GLUTs (Bell et al., 1990).
GLUTs included 12 hydrophobic α helical domains in which protein transverse itself 12 times with the its N- and C- terminus both located in cytosol (see Figure 1). Although there is high degree of sequence homology between GLUTs across the transmembrane helices, variability was shown among N- and C- terminus and loop sequences (Olson & Pessin, 1996).
GLUT4 is one of the thirteen members of mammalian GLUTs encoded in human genome and involved in ATP-independent hexose transport across the plasma membrane through facilitative diffusion mechanism (Murata, Hruz, & Mueckler, 2002). GLUT4 and other sugar transporter proteins demonstrate distinctions in terms of their respective substrate specificities (i.e., GLUT4 played role in the glucose transportation while GLUT5 played role in fructose transportation, see Table 1). However, main difference observed in GLUT4 is its unique characteristics in which it is redistributed to the plasma membrane in the presence of insulin while in the unstimulated state, intracellular disposition is seen (Bryant, Govers, & James, 2002). In addition, the unique sequences in the N- terminus such as phenylalanine residues and C- terminus such as dileucine and acidic motifs of GLUT4 govern its kinetics during the exocytosis and endocytosis in the recycling trafficking system. Therefore, GLUT4 demonstrates an important characteristic in the trafficking of membrane and insulin signaling mechanisms.
Figure 1: Representation of GLUT4 Glucose Transporter Protein
Unique N-terminus and divergent COOH-terminus regions located in cytosol played important role in rapid internalization and sorting of GLUT4 in intracellular membranes.
The facilitative glucose transporters are distributed within different tissues to maintain whole body glucose homeostasis. There is substantial degree of overlap in the tissue expression of distinct GLUT isoforms, but main tissue localization of GLUTs could be differed. For instance, GLUT1 mainly expressed in endothelial cells and brain in which glucose transport across the blood brain barrier to the central nervous system occurs (Mueckler et al., 1985; Pardridge, Boado, & Farrell, 1990). On the other hand, the GLUT2 protein is mainly found on the basolateral surfaces of liver cells, pancreatic β cells and kidney (Thorens, Sarkar, Kaback, & Lodish, 1988). In contrast to other GLUTs localized in various tissues, GLUT3 and HMIT are only found in the brain, and highly expressed in neuronal tissue (Nagamatsu et al., 1992; Uldry et al., 2001). The GLUT4 system mainly localized in muscle and adipose tissue that play important role in whole body glucose homeostasis (Rea & James, 1997). The tissue localization of other GLUTs and their type of transport were illustrated in table 1.
The major role of GLUT4 in whole-body glucose homeostasis was support by several genetically modified mouse models. For instance, Stenbit et al., (1997) investigated the different impacts of GLUT4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. Their findings indicated that GLUT4 null mice has impaired basal deoxy-glucose uptake in EDL muscles, but compensatory mechanisms such as GLUT1 intrinsic activity may have promoted survival of these mice.
Table 1: Different GLUT isoforms Located in Distinct Tissues for Transportation of Hexoses
But, heterozygous GLUT4+/- mice showed reduced GLUT4 protein and glucose uptake in muscle and adipose tissue and these mice demonstrated insulin resistance and vulnerability to type II diabetes (Li, Houseknecht, Stenbit, Katz, & Charron, 2000) which is consistent with the main role of GLUT4 in glucose disposition. GLUT4 overexpression studies in the skeletal muscle of GLUT4+/- mice showed that transgenic mice normalized insulin sensitivity and glucose tolerance (Tsao et al., 1999). This data were consistent with other research, when GLUT4 is also overexpressed in adipose tissue of GLUT4+/- mice, transgenic mice became sensitive to insulin and glucose tolerant (Tozzo, Shepherd, Gnudi, & Kahn, 1995). However, conditional depletion of GLUT4 in adipose tissue and skeletal muscle resulted in decreased insulin responsiveness (Zisman et al., 2000) and insulin resistance (Abel et al., 2001), respectively.
Insulin and exercise was shown to stimulate GLUT4 recruitment to the surface of muscle and adipose cells (Herman & Kahn, 2006) but signaling mechanism involved in the regulation of GLUT4 differed. Activation of the insulin receptor tyrosine kinase triggers canonical insulin signaling pathway which result in phosphorylation of tyrosine in insulin receptors substrate proteins and recruitment of phospho-inositol-3-kinase (PI-3K). PI-3K involved in the conversion of phosphatidylinositol (4,5)P2 to phosphatidylinositol (3,4,5)P3 (PIP3). Later, PIP3 leads to activation the Akt via the PDK1 and Rictor/mTOR (Sarbassov, Guertin, Ali, & Sabatini, 2005). From the Akt isoforms, not Akt1 and Akt3 but Akt2 involved in GLUT4 trafficking in adipose and muscle tissue and controlled glucose output in the liver through insulin signaling (Bae, Cho, Mu, & Birnbaum, 2003; Cho et al., 2001). The GTPase activating protein TBC1D4 designated as AS160 is the substrate of Akt2 involved in GLUT4 trafficking and mutation in AS160 in the calmodulin binding region did not impact on GLUT4 translocation (Kane & Lienhard, 2005). On the other hand, AS160 mutant which had deficiency in Akt-specific phosphorylation sites resulted in the inhibition of insulin stimulated GLUT4 translocation (Sano et al., 2003). In addition, AS160 knockdown studies also demonstrated that insulin signals to GLUT4 exocytosis both AS160 dependent and independent mechanisms suggesting that other unknown Akt substrates may contribute GLUT4 regulation by means of insulin (Eguez et al., 2005). There are also considerable amount of evidences in which atypical PKCλ/ζ modulates downstream of PI-3K signaling relay insulin signals in the GLUT4 translocation (Farese, Sajan, & Standaert, 2005).
Apart from those mechanisms, muscle contraction was also suggested to involve in GLUT4 translocation. When muscles are contracted (i.e., during exercise), increase in intracellular Ca2+ concentration and [AMP]/[ATP] ratio were observed. For instance, elevated levels of [Ca2+] result in activation of CaMKII and protein kinase C (Rose & Richter, 2005). In addition, Ca2+/Calmodulin also activates the AMPK signaling pathways in HeLa and A549 cell lines through the downstream protein kinases CaMKKα and CaMKKβ (Hurley et al., 2005). Cantó et al., (2006) found that increased Ca2+ levels mediate a metalloproteinase-dependent release of neuregulins which involved in tyrosine stimulation of ErbB4 receptors. Since ErbB4 activation is important mechanism for Ca2+-derived effects of glucose transport, inhibition of ErbB4 resulted in impairments in glucose uptake. Moreover, Wijesekara et. al., (2006) investigated membrane depolarization on GLUT4 cycling and come up with the data showing K+ depolarization result in reduction in GLUT4 endocytosis largely independent of PI-3K, Akt, AMPK activity. Thus, not only insulin signaling pathways but also mechanisms involved in muscle contraction also involved in GLUT4 translocation.
In unstimulated adipocytes and muscle cells, glycosylated and newly synthesized GLUT4 participated recycling pathway in intracellular membranes (Cushman & Wardzala, 1980). In the presence of insulin, GLUT4 redistributed in the plasma membrane (Cushman & Wardzala, 1980). Blot and McGraw, (2006) showed cholesterol-dependent uptake of glucose through GLUT4 in adipocytes. Their findings indicate that two main pathways involved in GLUT4 internalization: (1) AP-2-independent and clathrin-independent mechanisms are responsible for major GLUT4 internalization which does not require GLUT4 motifs and (2) clathrin-dependent and AP-2-dependent mechanisms required GLUT4 trafficking motifs (i.e., FQQI). Morphological studies showed that 60% of all the GLUT4 expressed in atrial cardiomyocytes is localized to secretory granules that included atrial natriuretic factor. There is strong evidence in which GLUT4 enters secretory granules at the trans-golgi network possibly from endosomes (Slot et al., 1997). Moreover, the transport of GLUT4 from endosomes to trans-golgi network was shown regulated by the acidic targeting motif distal to the dileucine signal in the COOH-terminus of GLUT4 (Shewan et al., 2000). The trans-golgi network is the key sorting station in which protein sorting decision was made. AP-1 and AP-2 are coat-protein complexes localized in the trans-golgi network and involved in transportation of proteins into and out of this organelle. Moreover, apart from AP-2 (Blot & McGraw, 2006), AP-1 vesicles are also play role in sorting of GLUT4 to endosomes (Martin et al., 2000). GLUT4 recycled between endosomes and trans-golgi network, but more secretory pool was shown to move GLUT4 directly to the cell surface in the presence of insulin (Hashiramoto & James, 2000). Moreover, GLUT4 also present in the GLUT4 storage vesicles (GSVs) which slowly fuse with endosomes and trans-golgi-endosomal recycling occurs.
Until now, we have come up with important studies that shows action of insulin in the translocation of GLUT4 on plasma membrane. But which step does insulin control to increase GLUT4 translocation in the cell surface? Inoue et al., (1999) was the first group who showed docking and fusion of intracellular GLUT4 vesicles with the cell surface in vitro. Results from this study provided important data about which sub-cellular compartments are influenced by the action of insulin that leading to an increased GLUT4 translocation. Basically, insulin modulated targets in the plasma membrane and the vesicle suggesting that more than one signaling pathways are involved in GLUT4 transport. For instance, while Akt is activated at the cell membrane, PKCζ is activated at the endosomes. Thus, different cellular locations may involve interaction with the substrates of distinct cellular kinases, when GLUT4 signaling pathway should be considered. Apart from these, Inoue et al., (2003) showed that the exocyst complex is required for targeting of GLUT4 to the plasma membrane by insulin. A tyrosine phosphorylation event only occurred in the plasma membrane leads to activation of G protein TC10. Later, TC10 interacts with the Exo70 region of exocyst complex. In the presence of insulin, Exo70 translocated to the plasma membrane, activated TC10 and result in assemble of Sec6 and Sec8 multiprotein complexes. Furthermore, this event was shown take role in lipid rafts suggesting that TC10/exocyst complex/SAP97 axis took role in the tethering of GLUT4 vesicles on the plasmam membrane in adipocytes.
The insulin resistance in the obesity and type II diabetes is characterized by the impairments in the kinase activity and receptor concentration. PI-3K activity and glucose translocation and activity of intracellular enzymes are also impaired (Pessin & Saltiel, 2000). Garvey et al., (1998) investigated the impact of GLUT4 intracellular translocation on insulin resistance. Their findings indicate that impaired GLUT4 translocation strongly associates with human insulin resistance. In addition, translocation defects also seen with an abnormality in GLUT4 subcellular localization occurred in basal muscle. Insulin resistance was associated where the GLUT4 is accumulated in denser membrane vesicles. Thus, this data demonstrated that insulin is not able to recruit GLUT4 plasma membrane since GLUT4 trafficking is impaired and GLUT4 is accumulated in denser membrane vesicles. More recently, Pinto-Junior et al., (2018), questioned how advanced glycation end products (i.e., albumin) induces insulin resistance and investigated the role of GLUT4 expression in skeletal muscle in this process. Their data revealed that advanced glycation end products impair glucose homeostasis by increasing stress in the endoplasmic reticulum, activating inflammatory pathways and repressing GLUT4 expression. In vivo treatment of advanced glycation end products increases GRP78 chaperone involved in ER stress activation. Moreover, albumin activated NFKβ1 protein in skeletal muscle. They also showed that activated NFKβ1 protein binds to NFKβ binding sites in GLUT4 gene. Furthermore, as mentioned, there are strong association with insulin resistance and the action of GLUT4, there are substantial amount of research focused on regulating GLUT4 and ameliorating insulin resistance. Yang et al., (2018) isolated a novel proteoglycan PTP1B inhibitor from a Chinese medicinal fungus namely Ganoderma lucidum. Their novel compound upregulated GLUT4 expression and promoted GLUT4 translocation to the plasma membrane by ameliorating insulin resistance. Similar to this research, Alkhateeb, (2018) investigated the effect of oleuropein which is main constituent of leaves and fruits of olive tree. Their findings indicate that 12h of oleuropein treatment fully restored insulin-stimulated glucose transport, GLUT4 translocation and phosphorylation of AS160. In sum, targeting GLUT4 might be a good strategy to prevent insulin resistance.
Tumor cells have increased demand for nutrients and cancer cells display elevated levels of glucose uptake and consumption (Ganapathy, Thangaraju, & Prasad, 2009). GLUTs involved in facilitative glucose uptake across the cell surface. Previous reports indicated that cancer cells have higher expression of GLUTs (Barron, Tsiani, & Tsakiridis, 2012). Cheng et al., (2013) studied constitutive plasma membrane localization of GLUT4 in multiple myeloma cells which is fatal plasma cell malignancy demonstrating elevated level of glucose consumption. Intriguingly, a novel AS160 splice variant version 2 phosphorylated in multiple myeloma cell lines and GLUT4 is removed from the cell surface by expression of full length AS160 protein. They come up with data showing constitutive GLUT4 activation in multiple myeloma cells promotes Warburg effect in tumor cells. The ectopic expression of full length AS160_v2 is enough to impair GLUT4 plasma membrane residence was shown as characteristics of multiple myeloma cells. Moreover, McBrayer et al., (2012) showed that multiple myeloma cells demonstrated novel dependence on GLUT4, GLUT8 and GLUT11. These cells are dependent on GLUT4 activity for basal glucose consumption, Mcl-1 protein level maintenance, growth and survival. Targeting GLUT4 with a HIV drug named as ritonavir displayed off-target inhibitory impacts on GLUT4 and inhibited glucose consumption and cell proliferation through decreasing Mcl-1 expression (McBrayer et al., 2012).
The important function of GLUT4 in the maintenance of whole-body glucose homeostasis is currently well investigated based on the genetically engineered mouse models, and cell line knockdowns. Although several mechanisms are enlightened through the biological models, we are still at the early stages in terms of unveiling molecular mechanisms involved in GLUT4 expression in vivo. Most of the signaling mechanisms are identified but functional regulators involved in transcription, the role microRNAs and inflammatory pathways are still needed to be elucidated. Since signaling mechanisms involved in GLUT4 system may overlap each other, cross-talk between the signaling pathways and compounds targeting GLUT4 system is also be under investigation. Moreover, as exemplified in the research investigating the impact of different compounds on GLUT4 system (Alkhateeb, 2018; Yang et al., 2018), more compounds are required to be screening. In addition, as we understood the membrane recycling pathway of GLUT4 including the discovery of AS160, we are required to find more substrates which is important in the treatment of diseases such as insulin resistance and cancer. Recently, advances in the total internal reflection fluorescence microscopy (TIRF) leads to a more understanding in the impact of insulin signaling on movement of GLUT4 in very small distances and kinetics of docking and fusion in GLUT4 containing vesicles (Fish, 2009). Therefore, we are also required to develop new imaging techniques to understand what happens in the cellular environment when cell biology is questioned. Consequently, here, we demonstrated basic understanding about the action of GLUTs, especially GLUT4, from the cell biology aspect.
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