scholarly journals Insulin transport across the blood-brain barrier can occur independently of the insulin receptor

2018 ◽  
Vol 596 (19) ◽  
pp. 4753-4765 ◽  
Author(s):  
Elizabeth M. Rhea ◽  
Christian Rask-Madsen ◽  
William A. Banks
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Insulin Transport ◽  
Blood Brain

scholarly journals The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain

2018 ◽  
Vol 315 (4) ◽  
pp. E531-E542 ◽  
Author(s):  
Maria Hersom ◽  
Hans C. Helms ◽  
Christoffer Schmalz ◽  
Thomas Å. Pedersen ◽  
Stephen T. Buckley ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Insulin Transport ◽  
Blood Brain ◽  
The Brain ◽  
Receptor Inhibitor

Insulin and its receptor are known to be present and functional in the brain. Insulin cerebrospinal fluid concentrations have been shown to correlate with plasma levels of insulin in a nonlinear fashion, indicative of a saturable transport pathway from the blood to the brain interstitial fluid. The aim of the present study was to investigate whether insulin was transported across brain endothelial cells in vitro via an insulin receptor-dependent pathway. The study showed that the insulin receptor was expressed at both the mRNA and protein levels in bovine brain endothelial cells. Luminally applied radiolabeled insulin showed insulin receptor-mediated binding to the endothelial cells. This caused a dose-dependent increase in Akt-phosphorylation, which was inhibited by coapplication of an insulin receptor inhibitor, s961, demonstrating activation of insulin receptor signaling pathways. Transport of insulin across the blood-brain barrier in vitro was low and comparable to that of a similarly sized paracellular marker. Furthermore, insulin transport was not inhibited by coapplication of an excess of unlabeled insulin or an insulin receptor inhibitor. The insulin transport and uptake studies were repeated in mouse brain endothelial cells demonstrating similar results. Although it cannot be ruled out that culture-induced changes in the cell model could have impaired a potential insulin transport mechanism, these in vitro data indicate that peripheral insulin must reach the brain parenchyma through alternative pathways rather than crossing the blood-brain barrier via receptor mediated transcytosis.

Selective Alteration in Blood-Brain Barrier and Insulin Transport in Iron-Deficient Rats

1988 ◽  
Vol 50 (5) ◽  
pp. 1434-1437 ◽  
Author(s):  
Dorit Ben-Shachar ◽  
S. Yehuda ◽  
J. P. M. Finberg ◽  
I. Spanier ◽  
M. B. H. Youdim
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Insulin Transport ◽  
Blood Brain ◽  
Iron Deficient

scholarly journals Nitric Oxide Isoenzymes Regulate Lipopolysaccharide-Enhanced Insulin Transport across the Blood-Brain Barrier

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1514-1523 ◽  
Author(s):  
William A. Banks ◽  
Shinya Dohgu ◽  
Jessica L. Lynch ◽  
Melissa A. Fleegal-DeMotta ◽  
Michelle A. Erickson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Mrna Levels ◽  
Insulin Transport ◽  
Blood Brain ◽  
Inducible Nos

Insulin transported across the blood-brain barrier (BBB) has many effects within the central nervous system. Insulin transport is not static but altered by obesity and inflammation. Lipopolysaccharide (LPS), derived from the cell walls of Gram-negative bacteria, enhances insulin transport across the BBB but also releases nitric oxide (NO), which opposes LPS-enhanced insulin transport. Here we determined the role of NO synthase (NOS) in mediating the effects of LPS on insulin BBB transport. The activity of all three NOS isoenzymes was stimulated in vivo by LPS. Endothelial NOS and inducible NOS together mediated the LPS-enhanced transport of insulin, whereas neuronal NOS (nNOS) opposed LPS-enhanced insulin transport. This dual pattern of NOS action was found in most brain regions with the exception of the striatum, which did not respond to LPS, and the parietal cortex, hippocampus, and pons medulla, which did not respond to nNOS inhibition. In vitro studies of a brain endothelial cell (BEC) monolayer BBB model showed that LPS did not directly affect insulin transport, whereas NO inhibited insulin transport. This suggests that the stimulatory effect of LPS and NOS on insulin transport is mediated through cells of the neurovascular unit other than BECs. Protein and mRNA levels of the isoenzymes indicated that the effects of LPS are mainly posttranslational. In conclusion, LPS affects insulin transport across the BBB by modulating NOS isoenzyme activity. NO released by endothelial NOS and inducible NOS acts indirectly to stimulate insulin transport, whereas NO released by nNOS acts directly on BECs to inhibit insulin transport.

Diet and TNF-α differentially regulate the insulin receptor and its transporter at the blood–brain barrier

Appetite ◽  
2009 ◽  
Vol 52 (3) ◽  
pp. 817
Author(s):  
L. Asarian ◽  
S.M. Robinson ◽  
N. Geary ◽  
W. Langhans ◽  
W.A. Banks
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Tnf Α

scholarly journals Triglycerides cross the blood–brain barrier and induce central leptin and insulin receptor resistance

2017 ◽  
Vol 42 (3) ◽  
pp. 391-397 ◽  
Author(s):  
W A Banks ◽  
S A Farr ◽  
T S Salameh ◽  
M L Niehoff ◽  
E M Rhea ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Mathematical Models of Blood-Brain Barrier Transport of Monoclonal Antibodies Targeting the Transferrin Receptor and the Insulin Receptor

2021 ◽  
Vol 14 (6) ◽  
pp. 535
Author(s):  
William M. Pardridge ◽  
Tom Chou
Keyword(s):  
Monoclonal Antibodies ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Plasma Concentrations ◽  
Mass Action ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Blood Brain

We develop and analyze mathematical models for receptor-mediated transcytosis of monoclonal antibodies (MAb) targeting the transferrin receptor (TfR) or the insulin receptor (IR), which are expressed at the blood-brain barrier (BBB). The mass-action kinetic model for both the TfR and IR antibodies were solved numerically to generate predictions for the concentrations of all species in all compartments considered. Using these models, we estimated the rates of MAb endocytosis into brain capillary endothelium, which forms the BBB in vivo, the rates of MAb exocytosis from the intra-endothelial compartment into brain extracellular space, and the rates of receptor recycling from the endothelial space back to the luminal endothelial plasma membrane. Our analysis highlights the optimal rates of MAb association with the targeted receptor. An important role of the endogenous ligand, transferrin (Tf) or insulin, in receptor-mediated-transport (RMT) of the associated MAb was found and was attributed to the five order magnitude difference between plasma concentrations of Tf (25,000 nM) and insulin (0.3 nM). Our modeling shows that the very high plasma concentration of Tf leads to only 5% of the endothelial TfR expressed on the luminal endothelial membrane.

Sign in / Sign up

Export Citation Format

Share Document