Brain Capillary Endothelial Transport of Insulin

  • William M. Pardridge

Abstract

The most immediate short-term action of insulin on cells is the increase in plasma membrane glucose transporter activity in such tissues as fat, skeletal muscle, and heart.1 Although insulin does not cause a short-term increase in glucose transport into brain,2,3 it does have important long-term actions on brain at the physiologic concentrations occurring in plasma, i.e., 1–10 ng/ml (25–250 μU/ml). For example, physiologic concentrations of insulin increase the glutamate-induced firing rate of cholinergic retinal neurons in tissue culture,4 and increase the coupling across nascent synapses of superior cervical ganglion cells or sympathetic neurons in primary tissue culture.5,6 In vivo studies have shown that the hypothalamic injection of picomolar quantities of insulin increases the firing rate of rat sympathetic nerves innervating brown fat,7 and that the chronic intraventricular infusion of insulin in baboons enhances the suppressive effect of intravenous cholecystokinin-8 on meal size.8

Keywords

Insulin Receptor Wheat Germ Agglutinin Insulin Binding Brain Capillary Brain Insulin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Pilkis, S. J., and Park, C. R.., 1974, Mechanism of action of insulin, Annu. Rev. Pharmacol. 14:365–388.CrossRefGoogle Scholar
  2. 2.
    Betz, A. L., Gilboe, D. D., Yudilevich, D. L., and Drewes, L. R., 1973, Kinetics of unidirectional glucose transport into the isolated dog brain, Am. J. Physiol. 225:586–592.PubMedGoogle Scholar
  3. 3.
    Daniel, P. M., Love, E. R., and Pratt, O. E., 1975, Insulin and the way the brain handles glucose, J. Neurochem. 25:471–476.PubMedCrossRefGoogle Scholar
  4. 4.
    Puro, D. G., and Agardh, E., 1984, Insulin-mediated regulation of neuronal maturation, Science 225:1170–1172.PubMedCrossRefGoogle Scholar
  5. 5.
    Kessler, J. A., Spray, D. C., Saez, J. C., and Bennett, M. V. L., 1984, Determination of synaptic phenotype: Insulin and cAMP independently initiate development of electrotonic coupling between cultured sympathetic neurons, Proc. Natl. Acad. Sci. USA 81:6235–6239.PubMedCrossRefGoogle Scholar
  6. 6.
    Wolinsky, E. J., Patterson, P. H., and Willard, A. L., 1985, Insulin promotes electrical coupling between cultured sympathetic neurons, J. Neurosci. 5:1675–1679.PubMedGoogle Scholar
  7. 7.
    Sakaguchi, T., and Bray, G. A., 1987, Intrahypothalamic injection of insulin decreases firing rate of sympathetic nerves, Proc. Natl. Acad. Sci. USA 84:2012–2014.PubMedCrossRefGoogle Scholar
  8. 8.
    Figlewicz, D. P., Stein, L. J., West, D., Porte, Jr., D., and Woods, S. C., 1986, Intracisternal insulin alters sensitivity to CCK-induced meal suppression in baboons, Am. J. Physiol. 250:R856–R860.Google Scholar
  9. 9.
    Giddings, S. J., Chirgwin, J., and Permutt, M. A., 1985, Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues, Diabetologia 28:343–347.PubMedCrossRefGoogle Scholar
  10. 10.
    Weindl, A., 1973, Neuroendocrine aspects of circumventricular organs, in: Frontiers in Neuroendocrinology (W. F. Ganong and L. Martini, eds.), Oxford University Press, London, p. 3.Google Scholar
  11. 11.
    Brightman, M. W., 1977, Morphology of blood-brain interfaces, Exp. Eye Res. 25(Suppl.):1–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Crone, C., 1971, The blood-brain barrier—Facts and questions, in: Ion Homeostasis of the Brain (B. K., Siesjo and S. C, Sorenson, eds.), Copenhagen, Munksgaard, p. 52.Google Scholar
  13. 13.
    Pardridge, W. M., 1983, Neuropeptides and the blood-brain barrier, Annu. Rev. Physiol. 45:73–82.PubMedCrossRefGoogle Scholar
  14. 14.
    Pardridge, W. M., 1989, Strategies for drug delivery through the blood-brain barrier, Neurobiol. Aging 10:636–637.PubMedCrossRefGoogle Scholar
  15. 15.
    Pardridge, W. M., and Frank, H. J. L., 1983, Mechanisms of peptide transport from blood to brain, in: Neuroendocrine Perspectives II (E. E. Muller and R. M. Macleod, eds.), Elsevier/North-Holland, Amsterdam, p. 107.Google Scholar
  16. 16.
    Covell, D. G., Narang, P. K., and Poplack, D. G., 1985, Kinetic model for disposition of 6-mercaptopurine in monkey plasma and cerebrospinal fluid, Am. J. Physiol. 248:R147–R156.Google Scholar
  17. 17.
    Spector, R., and Berlinger, W. H., 1982, Localization and mechanism of thymidine transport in the central nervous system, J. Neuorchem. 39:837–841.CrossRefGoogle Scholar
  18. 18.
    Cornford, E. M., and Oldendorf, W.H., 1975, Independent blood-brain barrier transport systems for nucleic acid precursor, Biochim. Biophys. Acta 394:211–219.PubMedCrossRefGoogle Scholar
  19. 19.
    Terasaki, T., and Pardridge, W. M., 1988, Restricted transport of AZT and dideoxynucleosides through the blood-brain barrier, J. Infect. Dis. 158:630–632.PubMedCrossRefGoogle Scholar
  20. 20.
    Woods, S. C., and Porte, D., 1977, Relationship between plasma and cerebrospinal fluid insulin levels of dogs, Am. J. Physiol. 233:E331–E334.Google Scholar
  21. 21.
    Wallum, B. J., Taborsky, G. J., Porte, Jr., D., Figelwicz, D. P., Jacobson, L., Beard, J. C., Ward, W. K., and Dorsa, D., 1987, Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man, J. Clin. Endocrinol. Metab. 64:190–194.PubMedCrossRefGoogle Scholar
  22. 22.
    Stein, L. J., Dorsa, D. M., Baskin, D. G., Figlewicz, D. P., Ikeda, H., Frankmann, S. P., Greenwood, M. R. C., Porte, Jr., D., and Woods, S. C., 1983, Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats, Endocrinology 113:2299–2301.PubMedCrossRefGoogle Scholar
  23. 23.
    Baskin, D. G., Woods, S. C., West, D. B., van Houten, M., Posner, B. I., Dorsa, D. M., and Porte, Jr., D., 1983, Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid, Endocrinology 113:1818–1825.PubMedCrossRefGoogle Scholar
  24. 24.
    Young, W. S., Kuhar, M. J., Roth, J., and Brownstein, M. J., 1980, Radiohistochemical localization of insulin receptors in the adult and developing rat brain, Neuropeptides 1:15–22.CrossRefGoogle Scholar
  25. 25.
    Baskin, D. G., Brewitt, B., Davidson, D. A., Corp, E., Paquetta, T., Figlewicz, D. P., Lewellen, T. K., Graham, M. K., Woods, S. G., and Dorsa, D. M., 1986, Quantitative autoradiographic evidence for insulin receptors in the choroid plexus of the rat brain, Diabetes 35:246–249.PubMedCrossRefGoogle Scholar
  26. 26.
    Werther, G. A., Hogg, A., Oldfield, B. J., McKinley, M. J., Figdor, R., Allen, A. M., and Mendelsohn, F. A. O., 1987, Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry, Endocrinology 21:1562–1570.CrossRefGoogle Scholar
  27. 27.
    Hynes, M. A., Brooks, P. J., Van Wyk, J. J., and Lund, P. K., 1988, Insulin-like growth factor II messenger ribonucleic acids are synthesized in the choroid plexus of the rat brain, Mol. Endocrinol. 2:47–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Aldred, A. R., Dickson, P. W., Marley, P. D., and Schreiber, G., 1987, Distribution of transferrin synthesis in brain and other tissues in the rat, J. Biol. Chem. 262:5293–5297.PubMedGoogle Scholar
  29. 29.
    Pardridge, W. M., Eisenberg, J., and Yang, J., 1985, Human blood-brain barrier insulin receptor, J. Neurochem. 44:1771–1778.PubMedCrossRefGoogle Scholar
  30. 30.
    Pardridge, W. M., 1986, Receptor-mediated peptide transport through the blood-brain barrier, Endocrine Rev. 7:314–330.CrossRefGoogle Scholar
  31. 31.
    Duffy, K. R., and Pardridge, W. M., 1987, Blood-brain barrier transcytosis of insulin in developing rabbits, Brain Res. 420:32–38.PubMedCrossRefGoogle Scholar
  32. 32.
    Kumagai, A. K., Eisenberg, J., and Pardridge, W. M., 1987, Absorptive-mediated endocytosis of cationized albumin and a β-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport, J. Biol. Chem. 262:15214–15219.PubMedGoogle Scholar
  33. 33.
    Triguero, D., Buciak, J. B., Yang, J., and Pardridge, W. M., 1989, Blood-brain barrier transport of cationized immunoglobulin G. Enhanced delivery compared to native protein, Proc. Natl. Acad. Sci. USA 86:4761–4765.PubMedCrossRefGoogle Scholar
  34. 34.
    Pardridge, W. M., Triguero, D., and Buciak, J. B., 1989, Transport of histone through the blood-brain barrier, J. Pharmacol. Exp. Ther. 251:821–826.PubMedGoogle Scholar
  35. 35.
    Fishman, J. B., Rubin, J. B., Handrahan, J. V., Connor, J. R., and Fine, R. E., 1987, Receptor-mediated transcytosis of transferrin across the blood-brain barrier, J. Neurosci. Res. 18:299–304.PubMedCrossRefGoogle Scholar
  36. 36.
    Pardridge, W. M., Eisenberg, J., and Yang, J., 1987, Human blood-brain barrier transferrin receptor, Metabolism 36:892–895.PubMedCrossRefGoogle Scholar
  37. 37.
    Duffy, K. R., Pardridge, W. M., and Rosenfeld, R. G., 1988, Human blood-brain barrier insulin-like growth factor receptor, Metabolism 37:136–140.PubMedCrossRefGoogle Scholar
  38. 38.
    Chabrier, P. E., Boubert, P., and Braquet, P., 1987, Specific binding of atrial natriuretic factor in brain microvessels, Proc. Natl. Acad. Sci. USA 84:2078–2081.PubMedCrossRefGoogle Scholar
  39. 39.
    Frank, H. J. L., and Pardridge, W. M., 1981, A direct in vitro demonstration of insulin binding to isolated brain microvessels, Diabetes 30:757–761.PubMedCrossRefGoogle Scholar
  40. 40.
    Frank, H. J. L., Pardridge, W. M., Morris, W. L., Rosenfeld, R. G., and Choi, T. B., 1986, Binding and internalization of insulin and insulin-like growth factors by isolated brain microvessels, Diabetes 35:654–661.PubMedCrossRefGoogle Scholar
  41. 41.
    Bar, R. S., Boes, M., and Sandra, A., 1988, Vascular transport of insulin to rat cardiac muscle. Central role of the capillary endothelium, J. Clin. Invest. 81:1225–1231.PubMedCrossRefGoogle Scholar
  42. 42.
    Milici, A. J., Watrous, N. E., Stukenbrok, H., and Palade, G. E., 1987, Transcytosis of albumin in capillary endothelium, J. Cell Biol. 105:2603–2609.PubMedCrossRefGoogle Scholar
  43. 43.
    Walsh, R. J., Slaby, F. J., and Posner, B. I., 1987, A receptor-mediated mechanism for the transport of prolactin from blood to cerebrospinal fluid, Endocrinology 120:1846–1851.PubMedCrossRefGoogle Scholar
  44. 44.
    King, G. L., and Johnson, S. M., 1985, Receptor-mediated transport of insulin across endothelial cells, Science 227:1583–1586.PubMedCrossRefGoogle Scholar
  45. 45.
    Rasio, E. A., 1969, Preliminary Communications: The displacement of insulin from blood capillaries, Diabetologia 5:416–419.PubMedCrossRefGoogle Scholar
  46. 46.
    Hinkle, P. M., and Kinsella, P. A., 1982, Rapid temperature-dependent transformation of the thyrotropin-releasing hormone-receptor complex in rat pituitary tumor cells, J. Biol. Chem. 257:5462–5470.PubMedGoogle Scholar
  47. 47.
    Boni-Schnetzler, M., Scott, W., Waugh, S. M., DiBella, E., and Pilch, P. F. 1987, The insulin receptor. Structural basis for high affinity ligand binding, J. Biol. Chem. 262:8395–8401.PubMedGoogle Scholar
  48. 48.
    White, M. F., Haring, H.-U., Kasuga, M., and Kahn, C. R., 1984, Kinetic properties and sites of autophosphorylation of the partially purified insulin receptor from hepatoma cells, J. Biol. Chem. 259: 255–264.PubMedGoogle Scholar
  49. 49.
    Lowe, W., and LeRoith, D., 1986, Insulin receptors from guinea pig liver and brain: Structural and functional studies, Endocrinology 118:1669–1677.PubMedCrossRefGoogle Scholar
  50. 50.
    Heidenreich, K.A., Zahniser, N. R., Berhanu, P., Brandenburg, D., and Olefsky, J. M., 1983, Structural differences between insulin receptors in the brain and peripheral target tissues, J. Biol. Chem. 258:8527–8530.PubMedGoogle Scholar
  51. 51.
    Haskell, J. F., Meezan, E., and Pillion, D. J., 1985, Identification of the insulin receptor of cerebral microvessels, Am. J. Physiol. 248:E115–E125.Google Scholar
  52. 52.
    Lowe, W. L., Boyd, F. T., Clarke, D. W., Raizada, M. K., Hart, C., and LeRoith, D., 1986, Development of brain insulin receptors: Structural and functional studies of insulin receptors from whole brain and primary cell cultures, Endocrinology 119:25–35.PubMedCrossRefGoogle Scholar
  53. 53.
    Heidenreich, K. A., Brandenburg, D., 1986, Oligosaccharide heterogeneity of insulin receptors. Comparison of N-linked glycosylation of insulin receptors in adipocytes and brain, Endocrinology 118:1835–1842.PubMedCrossRefGoogle Scholar
  54. 54.
    Gammeltoft, S., Kowalski, A., Fehlmann, M., and van Obberghen, 1984, Insulin receptors in rat brain: Insulin stimulates phosphorylation of its receptor β-subunit, FEBS Lett. 172:87–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Haskell, J. F., Meezan, E., and Pillion, D. J., 1984, Identification and characterization of the insulin receptor of bovine retinal microvessels, Endocrinology 115:698–704.PubMedCrossRefGoogle Scholar
  56. 56.
    Shemer, J., and LeRoith, D., 1987, The interaction of brain insulin receptors with wheat germ agglutinin, Neuropeptides 9:1–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Grunberger, G., Lowe, W. L., McElduff, A., and Glick, R. P., 1986, Insulin receptor of human cerebral gliomas. Structure and function, J. Clin. Invest. 77:997–1005.PubMedCrossRefGoogle Scholar
  58. 58.
    Roth, R. A., Morgan, D. O., and Beaudoin, J., 1986, Purification and characterization of the human brain insulin receptor, J. Biol. Chem. 261:3753–3757.PubMedGoogle Scholar
  59. 59.
    Rosenfeld, R. G., Pham, H., Keller, B. T., Borchardt, R. T., and Pardridge, W. M., 1987, Demonstration and structural comparison of receptors for insulin-like growth factor-I and -II (IGF-I and -II) in brain and blood-brain barrier, Biochem. Biophys. Res. Commun. 149:159–166.PubMedCrossRefGoogle Scholar
  60. 60.
    Szabo, A. J., and Szabo, O., 1975, Influence of the insulin-sensitive central nervous system glucoregulator receptor on hepatic glucose metabolism, J. Physiol. (London) 253:121–133.Google Scholar
  61. 61.
    Van Houten, M., and Posner, B. I., 1979, Insulin binds to brain blood vessels in vivo, Nature 282:623–625.PubMedCrossRefGoogle Scholar
  62. 62.
    Pillion, D. J., Haskell, J. F., and Meezan, E., 1982, Cerebral cortical microvessels: An insulin-sensitive tissue, Biochem. Biophys. Res. Commun. 104:686–692.PubMedCrossRefGoogle Scholar
  63. 63.
    Albrecht, J., Wroblewska, B., Mossakowski, M. J., 1982, The binding of insulin to cerebral capillaries and astrocytes of the rat, Neurochem. Res. 7:489–494.PubMedCrossRefGoogle Scholar
  64. 64.
    Goodner, C. J., and Berrie, M. A., 1977, The failure of rat hypothalamic tissues to take up labeled insulin in vivo or to respond to insulin in vitro, Endocrinology 101:605–612.PubMedCrossRefGoogle Scholar
  65. 65.
    Triguero, D., Buciak, J. B., and Pardridge, W. M., 1990, Capillary depletion method for quantifying blood-brain barrier transcytosis of circulating peptides and plasma proteins, J. Neurochem. 54:1882–1888.PubMedCrossRefGoogle Scholar
  66. 66.
    Frank, H. J. L., Pardridge, W. M., and Jankovic-Vokes, T., 1986, Insulin binding to the blood-brain barrier in the streptozotocin diabetic rat, J. Neurochem. 47:405–411.PubMedCrossRefGoogle Scholar
  67. 67.
    Frank, H. J. L., Jankovic-Vokes, T., and Pardridge, W. M., 1985, Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits, Diabetes 34:728–733.PubMedCrossRefGoogle Scholar
  68. 68.
    Pardridge, W. M., Yang, J., and Eisenberg, J., 1985, Blood-brain barrier protein phosphorylation and dephosphorylation, J. Neurochem. 45:1141–1147.PubMedCrossRefGoogle Scholar
  69. 69.
    Baskin, D. G., Porte, D., Guest, K., and Dorsa, D. M., 1983, Regional concentrations of insulin in the rat brain, Endocrinology 112:898–903.PubMedCrossRefGoogle Scholar
  70. 70.
    Havrankova, J., Roth, J., and Brownstein, M. J., 1979, Concentrations of insulin and of insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents, J. Clin. Invest. 64:636–642.PubMedCrossRefGoogle Scholar
  71. 71.
    Broadwell, R. D., Balin, B. J., and Salcman, M., 1988, Transcytotic pathway for blood-borne protein through the blood-brain barrier, Proc. Natl. Acad. Sci. USA 85:632–635.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • William M. Pardridge
    • 1
  1. 1.Department of Medicine, Division of Endocrinology, and Brain Research InstituteUCLA School of MedicineLos AngelesUSA

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