Skip to main content
Log in

Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier

  • Peptide Drug Design, Pharmacology, And Delivery In Health And Disease
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Glucagon-like peptide-1 (GLP-1) reduces insulin requirement in diabetes mellitus and promotes satiety. GLP-1 in the periphery (outside the CNS) has been shown to act on the brain to reduce food ingestion. As GLP-1 is readily degraded in blood, we focused on the interactions of [Ser8]GLP-1, an analog with similar biological effects and greater stability, with the blood-brain barrier (BBB). The influx of radiolabeled [Ser8]GLP-1 into brain has several distinctive characteristics:

  1. 1.

    A rapid influx rate of 8.867±0.798 × 104 mL/g-min as measured by multiple-time regression analysis after iv injection in mice.

  2. 2.

    Lack of self-inhibition by excess doses of the unlabeled [Ser8]GLP-1 either iv or by in situ brain perfusion, indicating the absence of a saturable transport system at the BBB.

  3. 3.

    Lack of modulation by short-term fasting and some other ingestive peptides that may interact with GLP-1, including leptin, glucagon, insulin, neuropeptide Y, and melanin-concentrating hormone.

  4. 4.

    No inhibition of influx by the selective GLP-1 receptor antagonist exendin(9–39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain.

Similarly, there was no efflux system for [Ser8]GLP-1 to exit the brain other than following the reabsorption of cerebrospinal fluid (CSF). The fast influx was not associated with high lipid solubility. Upon reaching the brain compartment, substantial amounts of [Ser8]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser8]GLP-1 was compared with that of GLP-1 in a blood-free brain perfusion system; radiolabeled GLP-1 had a more rapid influx than its analog and neither peptide showed the self-inhibition indicative of a saturable transport system. Therefore, we conclude that [Ser8]GLP-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Banks W. A., Fasold M. B., and Kastin A. J. (1997) Measurement of efflux rates from brain to blood, in Methods of Molecular Biology, Neuropeptide Protocols, Vol. 73 (Irvine G. B. and Williams C. H., eds.), Humana Press Inc., Totowa, NJ, pp. 353–360.

    Google Scholar 

  • Banks W. A. and Kastin A. J. (1989) Quantifying carrier-mediated transport of peptides from the brain to the blood, in Methods in Enzymology, Vol. 168, Conn, P. M. (ed.), Academic Press, San Diego, pp. 652–660.

    Google Scholar 

  • Creutzeldt W. O. C., Kleine N., Willms B., Orskov C., Holst J. J., and Nauck M. A. (1996) Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide 1 (7–36) amide type 1 diabetic patients. Diabetes Care 19, 580–586.

    Article  Google Scholar 

  • Dauch P., Masuo Y., Vincent J. P., and Checler F. (1993) A survey of the cerebral regionalization and ontogeny of eight exo- and endopeptidases in murines. Peptides 14, 593–599.

    Article  PubMed  CAS  Google Scholar 

  • Elias C. F., Kelly J. F., Lee C. E., et al. (2000) Chemical characterization of leptin-activated neurons in the rat brain. J. Comp. Neurol. 423, 261–281.

    Article  PubMed  CAS  Google Scholar 

  • Flint A., Raben A., Astrup A., and Holst J. J. (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515–520.

    Article  PubMed  CAS  Google Scholar 

  • Goldstone A. P., Mercer J. G., Gunn I., et al. (1997) Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents. FEBS Lett. 415, 134–138.

    Article  PubMed  CAS  Google Scholar 

  • Gutzwiller J.-P., Drewe J., Goke B., et al. (1999) Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am. J. Physiol. 276, R1541-R1544.

    PubMed  CAS  Google Scholar 

  • Hansen L., Deacon C. F., Orskov C., and Holst J. J. (1999) Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140, 5356–5363.

    Article  PubMed  CAS  Google Scholar 

  • Jin S. L., Han V. K., Simmons J. G., Towle A. C., Lauder J. M., and Lund P. K. (1988) Distribution of glucagon-like peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study. J. Comp. Neurol. 271, 519–532.

    Article  PubMed  CAS  Google Scholar 

  • Kanse S. M., Kreymann B., Ghatei M. A., and Bloom S. R. (1988) Identification and characterization of glucagon-like peptide-1 7–36 amide-binding sites in the rat brain and lung. FEBS Lett. 241, 209–212.

    Article  PubMed  CAS  Google Scholar 

  • Kastin A. J. and Akerstrom V. (1999a) Nonsaturable entry of neuropeptide Y into the brain. Am. J. Physiol. 276, E479-E482.

    PubMed  CAS  Google Scholar 

  • Kastin A. J. and Akerstrom V. (1999b) Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J. Pharmacol. Exp. Ther. 289, 219–223.

    PubMed  CAS  Google Scholar 

  • Kastin A. J., Akerstrom V., Hackler L., and Zadina J. E. (2000) Phe13,Tyr19-Melanin-concentrating hormone and the blood-brain barrier: role of protein binding. J. Neurochem. 74, 385–391.

    Article  PubMed  CAS  Google Scholar 

  • Kastin A. J. and Akerstrom V. (1999) Entry of CART into brain is rapid but not inhibited by excess CART or leptin. Am. J. Physiol. 277, E901-E904.

    PubMed  CAS  Google Scholar 

  • Kastin A. J., Akerstrom V., and Hackler L. (2000) Agouti-related protein (83–132) aggregates and crosses the blood-brain barrier slowly. Metabolism 49, 1444–1448.

    Article  PubMed  CAS  Google Scholar 

  • Kastin A. J., Hahn K., and Zadina J. E. (2001) Regional differences in peptide degradation by rat cerebral microvessels: a novel regulatory mechanism for communication between blood and brain. Life Sci. 69, 1305–1312.

    Article  PubMed  CAS  Google Scholar 

  • Kieffer T. J., McIntosh C. H. S., and Pederson R. A. (1995) Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136, 3585–3596.

    Article  PubMed  CAS  Google Scholar 

  • Kreymann B., Ghatei M. A., Burnet P., et al. (1989) Characterization of glucagon-like peptide-1-(7–36) amide in the hypothalamus. Brain Res. 502, 325–331.

    Article  PubMed  CAS  Google Scholar 

  • Larsen P. J., Tang-Christensen M., Holst J. J., and Orskov C. (1997) Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77, 259–270.

    Article  Google Scholar 

  • Mercer J. G., Moar K. M., Findlay P. A., Hoggard N., and Adam C. L. (1998) Association of leptin receptor (OB-Rb), NPY and GLP-1 gene expression in the ovine and murine brainstem. Regul. Pept. 75–76, 271–278.

    Article  PubMed  Google Scholar 

  • Naslund E., Barkeling B., King N., et al. (1999) Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int. J. Obesity 23, 304–311.

    Article  CAS  Google Scholar 

  • Ritzel U., Leonhardt U., Ottleben M., et al. (1998) A synthetic glucagon-like peptide-1 analog with improved plasma stability. J. Endocrinol. 159, 93–102.

    Article  PubMed  CAS  Google Scholar 

  • Shimizu I., Hirota M., Ohboshi C., and Shima K. (1987) Identification and localization of glucagon-like peptide-1 and its receptor in rat brain. Endocrinology 121, 1076–1082.

    Article  PubMed  CAS  Google Scholar 

  • Tang-Christensen M., Larsen P. J., Goke R., et al. (1996) Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am. J. Physiol. 271, R848-R856.

    PubMed  CAS  Google Scholar 

  • Toft-Nielsen M. B., Madsbad S., and Holst J. J. (1999) Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 22, 1137–1143.

    Article  PubMed  CAS  Google Scholar 

  • Tritos N. A., Vincent D., Gillette J., Ludwig D. S., Flier E. S., and Maratos-Flier E. (1998) Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes 47, 1687–1692.

    Article  PubMed  CAS  Google Scholar 

  • Turton M. D., O’Shea D., Gunn I., et al. (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kastin, A.J., Akerstrom, V. & Pan, W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci 18, 7–14 (2002). https://doi.org/10.1385/JMN:18:1-2:07

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:18:1-2:07

Index Entries

Navigation