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 cen tral nervous system (CNS) is mediated by a saturable mechanism consist ent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells, Since g lucocorticoids antagonize insulin receptor-mediated actions both perip herally and in the CNS, we hypothesized that glucocorticoids also impa ir CNS insulin transport, Nine dogs were studied both in the control c ondition and after 7 days of high-dose oral dexamethasone (DEX) admini stration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels d uring a 90-min euglycemic intravenous insulin infusion (plasma insulin similar to 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with thr ee 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 increa sed 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 insu lin 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 less than or equal to 0.001). As glucocort icoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decr eased by DEX, As expected, the model rate constant for CSF insulin rem oval decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min(-1) (P less than or equal to 0.0005) during DEX treatment, We conclude that D EX impairs CNS insulin transport, This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport proce ss and that this process may be subject to regulation, Moreover, since increasing brain insulin transport reduces food intake and body adipo sity, this observation provides a potential mechanism by which glucoco rticoid excess leads to increased body adiposity.