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Gene Review

SLC2A4  -  solute carrier family 2 (facilitated...

Homo sapiens

Synonyms: GLUT-4, GLUT4, Glucose transporter type 4, insulin-responsive, Solute carrier family 2, facilitated glucose transporter member 4
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Disease relevance of SLC2A4


Psychiatry related information on SLC2A4

  • Taken together, the results suggest that feeding behavior influences GLUT4 gene expression pattern through changes in sympathetic activity, especially during long-term starvation periods [6].
  • Based on the possible dependency of GLUT4 expression on volume, we hypothesize that the reduced GLUT4 expression in obesity and type 2 diabetes may partly be compensated for by physical activity [7].

High impact information on SLC2A4


Chemical compound and disease context of SLC2A4


Biological context of SLC2A4


Anatomical context of SLC2A4

  • In muscle and fat cells, insulin stimulates the delivery of the glucose transporter GLUT4 from an intracellular location to the cell surface, where it facilitates the reduction of plasma glucose levels [21].
  • Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action [22].
  • Perhaps consistent with a less efficient insulin signaling, a twofold reduction in GLUT4, glycogen synthase, and leptin mRNA expression was observed in omental adipose tissue [23].
  • Here, we report that an Eps15 homology (EH) domain-containing protein, EHD1, controls the normal perinuclear localization of GLUT4-containing membranes and is required for insulin-stimulated recycling of these membranes in cultured adipocytes [24].
  • GLUT4 trafficking between endosomes and trans-Golgi network was regulated via an acidic targeting motif in the carboxy terminus of GLUT4, because a mutant lacking this motif was retained in endosomes [25].

Associations of SLC2A4 with chemical compounds

  • This indicates that mitochondrial dysfunction decreases insulin-stimulated SLC2A4 translocation and glucose uptake [26].
  • Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383 [1].
  • Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment [27].
  • Reporter studies in H9C2 cardiomyotubes showed that HL in vitro, induced by high levels of arachidonic (AA) stearic, linoleic, and oleic acids (24 h, 200 mum) repressed transcription from the GLUT4 promoter; AA also repressed transcription from the PPARgamma1 and PPARgamma2 promoters [19].
  • The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA [2].

Physical interactions of SLC2A4

  • These data demonstrate that exercise increases MEF2 and GEF DNA binding and imply that these transcription factors could be potential targets for modulating GLUT4 expression in human skeletal muscle [28].
  • Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects [29].
  • Together these data demonstrated that MEF2 binding activity is necessary for regulation of the GLUT4 gene promoter in muscle and adipose tissue [30].
  • These findings strongly suggest that EHD2 interacts with GLUT4 in rat adipocytes and may play a key role in insulin-induced GLUT4 recruitment to the plasma membrane [31].
  • Heterologous expression of rab4 reduces glucose transport and GLUT4 abundance at the cell surface in oocytes [32].

Co-localisations of SLC2A4


Regulatory relationships of SLC2A4

  • Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes [24].
  • Activation of AMPK is an attractive strategy to enhance glucose transport through increased cell surface GLUT4 content in insulin-resistant skeletal muscle [29].
  • In contrast, insulin- and AICAR-stimulated responses on glucose transport and cell-surface GLUT4 content were impaired in subjects with type 2 diabetes [29].
  • We recently reported that the Krüppel-like zinc finger transcription factor KLF15 can induce adipocyte maturation and GLUT4 expression [34].
  • These data strongly suggest that the MEF2A-MEF2D heterodimer is selectively decreased in insulin-deficient diabetes and is responsible for hormonally regulated expression of the GLUT4 gene [35].

Other interactions of SLC2A4

  • Mechanistically, we show that nephrin allows the GLUT1- and GLUT4-rich vesicles to fuse with the membrane of this cell [36].
  • Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells [37].
  • Similarly, small interfering RNA-mediated depletion of endogenous EHD1 protein also markedly dispersed perinuclear GLUT4 in cultured adipocytes [24].
  • RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable [38].
  • Moreover, EHD1 is shown to interact through its EH domain with the protein EHBP1, which is also required for insulin-stimulated GLUT4 movements and hexose transport [24].

Analytical, diagnostic and therapeutic context of SLC2A4


  1. Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. Kusari, J., Verma, U.S., Buse, J.B., Henry, R.R., Olefsky, J.M. J. Clin. Invest. (1991) [Pubmed]
  2. Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation. Buse, J.B., Yasuda, K., Lay, T.P., Seo, T.S., Olson, A.L., Pessin, J.E., Karam, J.H., Seino, S., Bell, G.I. Diabetes (1992) [Pubmed]
  3. Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. Mioni, R., Chiarelli, S., Xamin, N., Zuliani, L., Granzotto, M., Mozzanega, B., Maffei, P., Martini, C., Blandamura, S., Sicolo, N., Vettor, R. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  4. A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. van Harmelen, V., Ryd??n, M., Sj??lin, E., Hoffstedt, J. J. Lipid Res. (2007) [Pubmed]
  5. Deregulated simultaneous expression of multiple glucose transporter isoforms in malignant cells and tissues. Binder, C., Binder, L., Marx, D., Schauer, A., Hiddemann, W. Anticancer Res. (1997) [Pubmed]
  6. Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats. Zanquetta, M.M., Nascimento, M.E., Mori, R.C., D'Agord Schaan, B., Young, M.E., Machado, U.F. Metab. Clin. Exp. (2006) [Pubmed]
  7. GLUT4 expression at the plasma membrane is related to fibre volume in human skeletal muscle fibres. Gaster, M., Vach, W., Beck-Nielsen, H., Schrøder, H.D. APMIS (2002) [Pubmed]
  8. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Abel, E.D., Peroni, O., Kim, J.K., Kim, Y.B., Boss, O., Hadro, E., Minnemann, T., Shulman, G.I., Kahn, B.B. Nature (2001) [Pubmed]
  9. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Zisman, A., Peroni, O.D., Abel, E.D., Michael, M.D., Mauvais-Jarvis, F., Lowell, B.B., Wojtaszewski, J.F., Hirshman, M.F., Virkamaki, A., Goodyear, L.J., Kahn, C.R., Kahn, B.B. Nat. Med. (2000) [Pubmed]
  10. Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population. O'Rahilly, S., Krook, A., Morgan, R., Rees, A., Flier, J.S., Moller, D.E. Diabetologia (1992) [Pubmed]
  11. GLUT-4 NH2 terminus contains a phenylalanine-based targeting motif that regulates intracellular sequestration. Piper, R.C., Tai, C., Kulesza, P., Pang, S., Warnock, D., Baenziger, J., Slot, J.W., Geuze, H.J., Puri, C., James, D.E. J. Cell Biol. (1993) [Pubmed]
  12. Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues. Rudich, A., Konrad, D., Török, D., Ben-Romano, R., Huang, C., Niu, W., Garg, R.R., Wijesekara, N., Germinario, R.J., Bilan, P.J., Klip, A. Diabetologia (2003) [Pubmed]
  13. Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia. Dimitrakoudis, D., Vranic, M., Klip, A. J. Am. Soc. Nephrol. (1992) [Pubmed]
  14. Glucose transporters and transport kinetics in retinoic acid-differentiated T47D human breast cancer cells. Rivenzon-Segal, D., Rushkin, E., Polak-Charcon, S., Degani, H. Am. J. Physiol. Endocrinol. Metab. (2000) [Pubmed]
  15. Muscle GLUT4 in cirrhosis. Holland-Fischer, P., Andersen, P.H., Lund, S., Pedersen, S.B., Vinter-Jensen, L., Nielsen, M.F., Kaal, A., Dall, R., Schmitz, O., Vilstrup, H. J. Hepatol. (2007) [Pubmed]
  16. Liver X receptor agonists ameliorate TNFalpha-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression. Fern??ndez-Veledo, S., Nieto-Vazquez, I., Rondinone, C.M., Lorenzo, M. Diabetologia (2006) [Pubmed]
  17. Regulation of the human GLUT4 gene promoter: interaction between a transcriptional activator and myocyte enhancer factor 2A. Knight, J.B., Eyster, C.A., Griesel, B.A., Olson, A.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  18. Separation of insulin signaling into distinct GLUT4 translocation and activation steps. Funaki, M., Randhawa, P., Janmey, P.A. Mol. Cell. Biol. (2004) [Pubmed]
  19. Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. Armoni, M., Harel, C., Bar-Yoseph, F., Milo, S., Karnieli, E. J. Biol. Chem. (2005) [Pubmed]
  20. Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Carlson, C.J., Koterski, S., Sciotti, R.J., Poccard, G.B., Rondinone, C.M. Diabetes (2003) [Pubmed]
  21. Regulated transport of the glucose transporter GLUT4. Bryant, N.J., Govers, R., James, D.E. Nat. Rev. Mol. Cell Biol. (2002) [Pubmed]
  22. Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. McGee, S.L., Hargreaves, M. Diabetes (2004) [Pubmed]
  23. Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Lefebvre, A.M., Laville, M., Vega, N., Riou, J.P., van Gaal, L., Auwerx, J., Vidal, H. Diabetes (1998) [Pubmed]
  24. Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes. Guilherme, A., Soriano, N.A., Furcinitti, P.S., Czech, M.P. J. Biol. Chem. (2004) [Pubmed]
  25. GLUT4 recycles via a trans-Golgi network (TGN) subdomain enriched in Syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif. Shewan, A.M., van Dam, E.M., Martin, S., Luen, T.B., Hong, W., Bryant, N.J., James, D.E. Mol. Biol. Cell (2003) [Pubmed]
  26. Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells. Lim, J.H., Lee, J.I., Suh, Y.H., Kim, W., Song, J.H., Jung, M.H. Diabetologia (2006) [Pubmed]
  27. Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Robinson, K.A., Sens, D.A., Buse, M.G. Diabetes (1993) [Pubmed]
  28. Exercise increases MEF2- and GEF DNA-binding activity in human skeletal muscle. McGee, S.L., Sparling, D., Olson, A.L., Hargreaves, M. FASEB J. (2006) [Pubmed]
  29. 5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Koistinen, H.A., Galuska, D., Chibalin, A.V., Yang, J., Zierath, J.R., Holman, G.D., Wallberg-Henriksson, H. Diabetes (2003) [Pubmed]
  30. Myocyte enhancer factor 2 (MEF2)-binding site is required for GLUT4 gene expression in transgenic mice. Regulation of MEF2 DNA binding activity in insulin-deficient diabetes. Thai, M.V., Guruswamy, S., Cao, K.T., Pessin, J.E., Olson, A.L. J. Biol. Chem. (1998) [Pubmed]
  31. EHD2 interacts with the insulin-responsive glucose transporter (GLUT4) in rat adipocytes and may participate in insulin-induced GLUT4 recruitment. Park, S.Y., Ha, B.G., Choi, G.H., Ryu, J., Kim, B., Jung, C.Y., Lee, W. Biochemistry (2004) [Pubmed]
  32. Heterologous expression of rab4 reduces glucose transport and GLUT4 abundance at the cell surface in oocytes. Mora, S., Monden, I., Zorzano, A., Keller, K. Biochem. J. (1997) [Pubmed]
  33. Expression of a synapsin IIb site 1 phosphorylation mutant in 3T3-L1 adipocytes inhibits basal intracellular retention of Glut4. Muretta, J.M., Romenskaia, I., Cassiday, P.A., Mastick, C.C. J. Cell. Sci. (2007) [Pubmed]
  34. The Krüppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis. Banerjee, S.S., Feinberg, M.W., Watanabe, M., Gray, S., Haspel, R.L., Denkinger, D.J., Kawahara, R., Hauner, H., Jain, M.K. J. Biol. Chem. (2003) [Pubmed]
  35. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. Mora, S., Pessin, J.E. J. Biol. Chem. (2000) [Pubmed]
  36. Nephrin is critical for the action of insulin on human glomerular podocytes. Coward, R.J., Welsh, G.I., Koziell, A., Hussain, S., Lennon, R., Ni, L., Tavaré, J.M., Mathieson, P.W., Saleem, M.A. Diabetes (2007) [Pubmed]
  37. Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. Quon, M.J., Butte, A.J., Zarnowski, M.J., Sesti, G., Cushman, S.W., Taylor, S.I. J. Biol. Chem. (1994) [Pubmed]
  38. Retinol-binding protein 4 in human obesity. Janke, J., Engeli, S., Boschmann, M., Adams, F., B??hnke, J., Luft, F.C., Sharma, A.M., Jordan, J. Diabetes (2006) [Pubmed]
  39. Need for GLUT4 activation to reach maximum effect of insulin-mediated glucose uptake in brown adipocytes isolated from GLUT4myc-expressing mice. Konrad, D., Bilan, P.J., Nawaz, Z., Sweeney, G., Niu, W., Liu, Z., Antonescu, C.N., Rudich, A., Klip, A. Diabetes (2002) [Pubmed]
  40. Polymorphic human insulin-responsive glucose-transporter gene on chromosome 17p13. Bell, G.I., Murray, J.C., Nakamura, Y., Kayano, T., Eddy, R.L., Fan, Y.S., Byers, M.G., Shows, T.B. Diabetes (1989) [Pubmed]
  41. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1. Al-Khalili, L., Forsgren, M., Kannisto, K., Zierath, J.R., Lönnqvist, F., Krook, A. Diabetologia (2005) [Pubmed]
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