By acting in the central nervous system, circulating insulin may regulate food intake and body weight. We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment. To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 ,U/ml) (n = 10). Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma --intermediate compartment -CSF). By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (klk2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4). At physiologic plasma insulin levels (80±7.4,gU/ml), klk2 was determined to be 10.7 X 10'±+1.3 X 10-6 min2. With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 ,U/ml). The apparent KM of this saturation curve was 742 uUU/ml ( -5 nM). In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0.011±0.0019 min' and k4 = 0.046±0.021 min').We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process. (J. Clin. Invest. 1993.
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.
While creating the curriculum for this new program, she embedded multi-semester projects to increase student engagement and performance. Previously, she was a Professor of Medical Devices at Keck Graduate Institute of Applied Life Sciences, which is one of the Claremont Colleges. She received her BS Electrical Engineering degree from Loyola Marymount University, her MS Electrical Engineering and MS Biomedical Engineering degrees from Drexel University, and her PhD Bioengineering degree from the University of Washington. Between her graduate degrees, she worked as a loop transmission systems engineer at AT&T Bell Laboratories. She then spent 13 years in the medical device industry conducting medical device research and managing research and product development at several companies. In her last industry position, Dr.
While creating the curriculum for this new program, she embedded multi-semester projects to increase student engagement and performance. Previously, she was a Professor of Medical Devices at Keck Graduate Institute of Applied Life Sciences, which is one of the Claremont Colleges. She received her BS Electrical Engineering degree from Loyola Marymount University, her MS Electrical Engineering and MS Biomedical Engineering degrees from Drexel University, and her PhD Bioengineering degree from the University of Washington. Between her graduate degrees, she worked as a loop transmission systems engineer at AT&T Bell Laboratories. She then spent 13 years in the medical device industry conducting medical device research and managing research and product development at several companies. In her last industry position, Dr.
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