Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport

J Clin Invest. 1991 Oct;88(4):1272-81. doi: 10.1172/JCI115431.


To study the route by which plasma insulin enters cerebrospinal fluid (CSF), the kinetics of uptake from plasma into cisternal CSF of both insulin and [14C]inulin were analyzed during intravenous infusion in anesthetized dogs. Four different mathematical models were used: three based on a two-compartment system (transport directly across the blood-CSF barrier by nonsaturable, saturable, or a combination of both mechanisms) and a fourth based on three compartments (uptake via an intermediate compartment). The kinetics of CSF uptake of [14C]inulin infused according to an "impulse" protocol were accurately accounted for only by the nonsaturable two-compartment model (determination coefficient [R2] = 0.879 +/- 0.044; mean +/- SEM; n = 5), consistent with uptake via diffusion across the blood-CSF barrier. When the same infusion protocol and model were used to analyze the kinetics of insulin uptake, the data fit (R2 = 0.671 +/- 0.037; n = 10) was significantly worse than that obtained with [14C]inulin (P = 0.02). Addition of a saturable component of uptake to the two-compartment model improved this fit, but was clearly inadequate for a subset of insulin infusion studies. In contrast, the three-compartment model accurately accounted for CSF insulin uptake in each study, regardless of infusion protocol (impulse infusion R2 = 0.947 +/- 0.026; n = 10; P less than 0.0001 vs. each two-compartment model; sustained infusion R2 = 0.981 +/- 0.003; n = 5). Thus, a model in which insulin passes through an intermediate compartment en route from plasma to CSF, as a part of a specialized transport system for the delivery of insulin to the brain, best accounts for the dynamics of this uptake process. This intermediate compartment could reside within the blood-CSF barrier or it may represent brain interstitial fluid, if CNS insulin uptake occurs preferentially across the blood-brain barrier.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Blood-Brain Barrier
  • Dogs
  • Infusions, Intravenous
  • Insulin / blood
  • Insulin / cerebrospinal fluid
  • Insulin / pharmacokinetics*
  • Inulin / pharmacokinetics
  • Male
  • Models, Biological


  • Insulin
  • Inulin