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Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport.
Open accessAbstract
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.
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“The simulation results demonstrated that insulin concentration dynamics in the blood and that in the CSF are characteristic of two- or three-compartmental model, and are consistent with the results reported by Schwartz and coworkers [40], where dynamics of CSF insulin was described by a three-compartment model.”
From A mathematical model of brain glucose homeostasis (2009) · cites this paper as [40]
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Metadata
- Authors
- Schwartz, M. W., Bergman, R. N., Kahn, S. E., Taborsky, G. J., Fisher, L. D., Sipols, A. J., Woods, S. C., Steil, G. M., & Porte, D.
- Affiliations
- University of Washington (US)
- University of Southern California (US)
- United States Department of Veterans Affairs (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1991-10-01
- Volume
- 88
- Issue
- 4
- Pages
- 1272-1281
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC295596
- OpenAlex
- W1967708672
- Cited by
- 183
- References
- 27
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 3 · 2013: 6 · 2012: 5
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (1f32dk008025-01, 2r01dk012829-36)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, DK-17047, DK-08025, P30DK017047)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- insulin, cerebrospinal fluid, blood-CSF barrier, intermediate compartment, inulin, two-compartment model, three-compartment model, saturable transport, blood-brain barrier
- MeSH terms
- Animals, Biological Transport, Blood-Brain Barrier, Dogs, Infusions, Intravenous, Insulin, Inulin, Male, Models, Biological
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