Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs.
We have previously shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells. Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport. Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin approximately 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma-->intermediate compartment, hypothesized to be brain interstitial fluid-->CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) +/- 1.2 x 10(-6) min-2 (P < or = 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX. As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min-1 (P < or = 0.0005) during DEX treatment. We conclude that DEX impairs CNS insulin transport. This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport process and that this process may be subject to regulation. Moreover, since increasing brain insulin transport reduces food intake and body adiposity, this observation provides a potential mechanism by which glucocorticoid excess leads to increased body adiposity.
Department of Bioengineering, University of Washington, Seattle, USA.
G D
GD
Baura
D M
DM
Foster
K
K
Kaiyala
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D
Porte
S E
SE
Kahn
M W
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Schwartz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004285:Dogs; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood* / Q000134:cerebrospinal fluid; D008297:Male; D008954:Models, Biological; D011972:Receptor, Insulin / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007328:Insulin; D003907:Dexamethasone; D011972:Receptor, Insulin