IGF-I Mediated Recruitment of Glucose Transporters from Intracellular Membranes to Plasma Membranes in L6 Muscle Cells

  • Philip J. Bilan
  • Toolsie Ramlal
  • Amira Klip
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 293)


IGF-I has long been known to have mitogenic effects on isolated skeletal tissue (Salmon and Daughaday, 1957) and insulin-like metabolic effects on isolated adipose tissue and muscle tissue (Froesch et al., 1966; Poggi et al., 1979). Stimulation of glucose utilization by IGF-I has been observed in vivo in rats and humans (Zapf et al., 1986; Guler et al., 1987). Moreover, Giacca et al. (1990) have demonstrated that skeletal muscle is the preferred site for the stimulation of glucose utilization by IGF-I in completely insulin-deficient diabetic dogs. Simultaneously, Moxely III et al. (1990) demonstrated that in vivo, IGF-I stimulates hexose uptake directly into rat muscles. These specific effects of IGF-I on skeletal muscle are consistent with the observation that skeletal muscle expresses abundant amounts of IGF-I receptors (Livingston et al., 1988, Dohm et al., 1990), whereas adipose tissue has very low numbers of IGF-I receptors (Rechler and Nissley, 1985; Sinha et al., 1990). Skeletal muscle is also the primary site of action for the stimulation of glucose utilization by insulin in vivo (Defronzo et al., 1981). Although IGF-I and insulin have common biological actions, IGF-I and insulin receptors may function independently. For example, rat 1 fibroblasts expressing a mutant insulin receptor with an inactive tyrosine kinase are unresponsive to insulin stimulation of glucose uptake but can still respond to IGF-I through their endogenous IGF-I receptors (McClain et al., 1990). Secondly, Lammers et al. (1989) demonstrated that chimeric receptors consisting of the extracellular insulin receptor domain and the intracellular IGF-I receptor domain were ten times more responsive to insulin for stimulation of DNA synthesis than was the native insulin receptor. This suggested that the intracellular kinase of the IGF-I receptor is more active than the insulin receptor kinase and is thus inherently different from its insulin receptor counterpart. Hence, IGF-I and insulin and their receptors share common responses but can trigger them independently.


Insulin Receptor Membrane Fraction Internal Membrane Plasma Membrane Fraction Plasma Membrane Marker 
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  1. Baldwin, S.A., Baldwin, J.M., and Lienhard, G.E., 1982, Monosaccharide transporter of the human erythrocyte. Characterization of an improved preparation, Biochemistry, 21: 3836–3842.PubMedCrossRefGoogle Scholar
  2. Beguinot, F., Kahn, C.R., Moses, A.C., and Smith, R.J., 1985, Distinct biologically active receptors for insulin, insulin-like growth factor I and insulin-like gorwth factor II in cultured skeletal muscle cells, J. Biol. Chem., 260: 15892–15898.PubMedGoogle Scholar
  3. Beguinot, F., Kahn, C.R., Moses, A.C., and Smith R.J., 198 6, The development of insulin receptors and responsiveness is an early marker of differentiation in the muscle cell line L6, Endocrinology, 118: 446–455.PubMedCrossRefGoogle Scholar
  4. Bilan, P.J., and Klip, A., 1990, Glycation of the human erythrocyte glucose transporterin vtiro and its functional consequences, Bjochem. J., 268: 661–667.Google Scholar
  5. Birnbaum, M.J., 1989, Identification of a novel gene encoding an insulin-responsive glucose transporter protein, Cell, 57: 305–315.PubMedCrossRefGoogle Scholar
  6. Bradford, M.M., 1976, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Anal. Biochem.,72: 248–254.PubMedCrossRefGoogle Scholar
  7. Burant, C.F., Treutelar, M.K., Allen, K.D., Sens, D.A., and Buse, M.G., 1987, Comparison of insulin and insulin-like growth factor I receptors from rat skeletal muscle and L6 myocytes, Biochem. Biophys. Res. Commnn.,147: 100–107.CrossRefGoogle Scholar
  8. Calderhead, D.M., Kitagawa, K., Lienhard, G.E., and Gould G.W., 1990, Translocation of the brain-type glucose transporter largely accounts for insulin stimulation of glucose transport in BC3H-1 myocytes, Biochem. J., 269: 597–601.PubMedGoogle Scholar
  9. Defronzo, R.A., Ferranninni, E., Sato, Y., Felig, P., and Wahren, J., 1981, Synergistic interaction between exercise and insulin on peripheral glucose uptake, J. Clin. Invest., 68: 1468–1474.PubMedCrossRefGoogle Scholar
  10. Dohm, C.L., Elton, C.W., Raju, M.S., Mooney, N.D., Dimarchi, R., Pories, W.J., Flickinger, E.G., Atkinson, S.M. Jr., and Caro, J.F., 1990, IGF-I-Stimulated glucose transport in human skeletal muscle and IGF-I resistance in obesity and NIDDM, Diabetes, 39: 1028–1032.PubMedCrossRefGoogle Scholar
  11. Douen, A.G., Ramlal, T., Rastogi, S., Bilan, P.J., Cartee, G.D., Vranic, M., Holloszy, J.O., and Klip, A., 1990, Exercise induces recruitment of the insulin-responsive glucose transporter, J. Biol. Chem., 265:13427.PubMedGoogle Scholar
  12. Froech, E.R., Muller, W.A., Burgi, H., Waldvogel, M., and Labhart, A., 1966, Nonsuppressable insulin-like activity of human serum. I. Physicochemical properties, extraction and partial purification, Biochim. Biophys. Acta, 121: 360–374.Google Scholar
  13. Fushiki, T., Wells, J.A., Tapscott, E.B., and Dohm, G.L., 1989, Changes in glucose transporters in muscle in reponse to exercise, Am.J. Physiol., 256: E580-E587.Google Scholar
  14. Giacca, A., Gupta, R., Efendic, S., Hall, K., Skottner, A., Lickley, L., and Vranic, M., 1990, Differential effects of IGF-I and insulin of glucoregulation and fat metabolism in depancreatized dogs, Diabetes, 39: 340–347.PubMedCrossRefGoogle Scholar
  15. Guler, H.P., Zapf, J., and Froesch, E.R., 1987, Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults, N. Engl. J. Med., 317: 137–140.PubMedCrossRefGoogle Scholar
  16. Holman, G.D., and Rees, W.D., 1987, Photolabelling of the hexose transporter at external and internal sites: Fragmentation patterns and evidence for a conformational change, Biochim. Biophys. Acta, 897: 395–405.PubMedCrossRefGoogle Scholar
  17. James, D.E., Brown, R. Navarro, J., and Pilch, P.F., 1988, Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein, Nature, 333: 183–185.PubMedCrossRefGoogle Scholar
  18. James, D.E., Strube, M., and Mueckler, M., 1989, Molecular cloning and characterization of an insulin-regulatable glucose transporter, Nature, 338: 83–87.PubMedCrossRefGoogle Scholar
  19. Kidokoro, Y., 1975, Developmental Changes of membrane electrical properties in a rat skeletal muscle cell line, J. Physiol.(London)r 244: 129– 143.Google Scholar
  20. Klip, A., Li, G., and Walker, D., 1983, Insulin binding to differentiating muscle cells in culture, Can. J. Biochem. Cell Biol., 61: 644–649.PubMedCrossRefGoogle Scholar
  21. Klip, A., Li, G., and Logan, W.J., 1984, Induction of sugar uptake response to insulin by serum depetion in fusing L6 myoblasts, Am. J. Physiol., 247: E291–E296.PubMedGoogle Scholar
  22. Koivisto, U.-M., Martinez-Valdez, H., Bilan, P.J., Burdett, E., Ramlal, T., and Klip, A., Differential regulation of GLUT-1 and GLUT-4 transport systems by glucose and insulin in L6 muscle cells in culture, J. Biol. Chem. (in press) .Google Scholar
  23. Laemmli, U.K., 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature, 227, 680–685.PubMedCrossRefGoogle Scholar
  24. Lammers, R., Gray, A., Schlessinger, J., and Ullrich, A., 1989, Differential signalling potential of insulin and IGF-I receptor cytoplasmic domains, EMBO J.8: 1369–1375.PubMedGoogle Scholar
  25. Livingston, N., Pollare, T., Lithell, H., and Arner, P., 1988, Characterization of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects, Diabetolocria. 31: 871–877.Google Scholar
  26. Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., 1951, Protein measurement with the folin phenol reagent, J. Biol. Chem., 193: 265– 275.PubMedGoogle Scholar
  27. McClain, D.A., Maegawa, H., Thies, R.S., and Olefsky, J.M., 1990, Dissection of the growth versus metabolic effects of insulin and insulin-like growth factor-I in transfected cells expressing kinase-defective human insulin receptors, J. Biol. Chem., 265: 1678–1682.PubMedGoogle Scholar
  28. Moxley III, R.T., Arner, P., Moss, A., Skottner, A., Fox, M., James, D., Livingston, J.N., 1990, Acute effects of insulin-like growth factor I and insulin on glucose metabolism in vivo, Am. J. Physiol., 259: E561–E567.PubMedGoogle Scholar
  29. Poggi, C., Le Marchand-Brustel, Y., Zapf, J., Froesch, E.R., and Freychet, P., 1979, Effects and binding on insulin-like growth factor I (IGF I) in the isolated soleus muscle of lean and obese mice: Comparison with insulin, Endocrinology, 105: 723–730.PubMedCrossRefGoogle Scholar
  30. Ramlal, T., Sarabia, V., Bilan, P.J., and Klip, A., 1988, Insulin-mediated translocation of glucose transporters from intracellular membranes to plasma membranes: Sole mechanism of stimulation of glucose transport in L6 muscle cells, Biochem. Biophys. Res. Commun., 157: 1329–1335.PubMedCrossRefGoogle Scholar
  31. Rechler, M.M., and Nissley, S.P., 1985, The nature and regulation of the receptors for insulin-like growth factors, Ann. Rev. Physiol., 47: 425–442.CrossRefGoogle Scholar
  32. Ross, M., Francis, G.L., Szabo, L., Wallace, J.C., and Ballard, F.J., 1989, Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1, Biochem. J., 258: 267–272.PubMedGoogle Scholar
  33. Salmon, W.D. Jr., and Daughaday, W.H., 1957, A hormonally controlled serum factor which stimulates sulfate incorporation by cartilagein vivo. J. Lab. Clin. Med., 49: 825–836.PubMedGoogle Scholar
  34. Shainberg, A., Yagil, G., and Yaffe, D., 1971, Alteration of enzymatic activities during muscle differentiation in vitro, Dev. Biol., 25: 1–29.PubMedCrossRefGoogle Scholar
  35. Simpson, I.A., and Cushman, S.W., 1988, Hormonal regulation of mammalian glucose transport, Annu. Rev. Biochem., 55: 1059–1089.CrossRefGoogle Scholar
  36. Sinha, M.K., Buchanan, C. Leggett, N., Martin, L., Khazanie, P.G., DiMarchi, R., Pories, W.J., and Caro, J.F., 1989, Mechanism of IGF-I-stimulated glucose transport in human adipocytes: Demontration of specific IGF-I receptors not involved in stimulation of glucose transport, Diabetes, 38: 1217–1225.PubMedCrossRefGoogle Scholar
  37. Walker, P.S., Ramlal, T., Sarabia, V., Koivisto, U.-M., Bilan, P.J., Pessin, J.E., and Klip, A., 1990, Glucose transport activity in L6 muscle cells is regulated by the coordinate control of subcellular glucose transproter distribution, biosynthesis and mRNA transcription,J. Biol. Chem.. 265: 1516–1523.PubMedGoogle Scholar
  38. Widdas, W.F., 1988, Old and new concepts of the membrane transport for glucose in cells, Biochim. Biophys. Acta, 947: 385–404.PubMedGoogle Scholar
  39. Yaffe, D., 1968, Retention of differentiation potentialities during prolonged cultivation of myogenic cells, Proc. Natl. Acad. Sci. U.S.A.. 61: 477–483.PubMedCrossRefGoogle Scholar
  40. Yasumoto, K., Iwami, K., Fushiki, T., and Mitsuda, H., 1978, Purification and enzymatic properties of γ-glutamyl transferase from bovine colostrum, J. Biochem., 84: 1227–1236.PubMedGoogle Scholar
  41. Zapf, J., Hauri, C. Waldvogel, M., and Froesch, E.R., 1986, Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats, J. Clin. Invest., 77: 1768–1775.PubMedCrossRefGoogle Scholar
  42. Zorzano, A., Wilkinson, W., Kotliar, N., Thoidis, G., Wadzinski, B.E., Ruoho, A.E., and Pilch, P.F., 1989, Insulin-regulated glucose uptake in rat adipocytes mediated by two transporter isoforms present in at least two vesicle populations, J. Biol. Chem., 264: 1235–1263.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Philip J. Bilan
    • 1
  • Toolsie Ramlal
    • 1
  • Amira Klip
    • 1
  1. 1.Division of Cell BiologyThe Hospital for Sick ChildrenTorontoCanada

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