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

J Mol Neurosci. Feb-Apr 2002;18(1-2):7-14. doi: 10.1385/JMN:18:1-2:07.


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. A rapid influx rate of 8.867 +/- 0.798 x 10(4) mL/g-min as measured by multiple-time regression analysis after iv injection in mice. 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. 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. 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Appetite Regulation / physiology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology*
  • Brain / drug effects
  • Brain / metabolism*
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology
  • Dose-Response Relationship, Drug
  • Food Deprivation / physiology
  • Glucagon / metabolism*
  • Glucagon / pharmacology
  • Glucagon-Like Peptide 1
  • Hypothalamic Hormones / pharmacology
  • Insulin / pharmacology
  • Leptin / pharmacology
  • Male
  • Melanins / pharmacology
  • Mice
  • Mice, Inbred ICR
  • Neuropeptide Y / pharmacology
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / pharmacology
  • Pituitary Hormones / pharmacology
  • Protein Precursors / metabolism*


  • Hypothalamic Hormones
  • Insulin
  • Leptin
  • Melanins
  • Neuropeptide Y
  • Peptide Fragments
  • Pituitary Hormones
  • Protein Precursors
  • exendin (9-39)
  • melanin-concentrating hormone
  • Glucagon-Like Peptide 1
  • Glucagon