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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.

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