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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Insulin concentration dynamics in the blood and in the CSF are characteristic of a two- or three-compartmental model, and are consistent with results reported by Schwartz and coworkers.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Continuous Univariate Distributions.
Omori, Y., Johnson, N. L., Kotz, S., & Balakrishnan, N. (1995) · Journal of the American Statistical Association · doi:10.2307/2291547 · Cited by 9,085 · see citing works
Receptor-Mediated Transport of Insulin Across Endothelial Cells
King, G. L., & Johnson, S. M. (1985) · Science · doi:10.1126/science.3883490 · Cited by 474 · see citing works
Mlab — A mathematical modeling tool
Knott, G. D. (1979) · Computer Programs in Biomedicine · doi:10.1016/0010-468x(79)90075-8 · Cited by 380 · see citing works
Quantitative Aspects of the Insulin-Receptor Interaction in Liver Plasma Membranes
Kahn, C. R., Freychet, P., Roth, J., & Neville, D. M. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42825-1 · Cited by 373 · see citing works
Blood-brain barrier transcytosis of insulin in developing rabbits
Duffy, K. R., & Pardridge, W. M. (1987) · Brain Research · doi:10.1016/0006-8993(87)90236-8 · Cited by 358 · see citing works
Baskin, D. G., Figlewicz, D. P., Woods, S. C., Porte, D., & Dorsa, D. M. (1987) · Annual Review of Physiology · doi:10.1146/annurev.ph.49.030187.002003 · Cited by 344 · see citing works
Self-citationDrainage of cerebral interstitial fluid into deep cervical lymph of the rabbit
Bradbury, M. W., Cserr, H. F., & Westrop, R. J. (1981) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1981.240.4.f329 · Cited by 335 · see citing works
Receptor-Mediated Peptide Transport through the Blood-Brain Barrier*
Pardridge, W. M. (1986) · Endocrine Reviews · doi:10.1210/edrv-7-3-314 · Cited by 316 · see citing works
Insulin transport across capillaries is rate limiting for insulin action in dogs.
Yang, Y. J., Hope, I. D., Ader, M., & Bergman, R. N. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114339 · Cited by 303 · see citing works
Self-citationCerebrospinal Fluid Insulin Levels Increase During Intravenous Insulin Infusions in Man*
Wallum, B. J., Taborsky, G. J., Porte, D., Figlewicz, D. P., Jacobson, L., Beard, J. C., Ward, W. K., & Dorsa, D. M. (1987) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-64-1-190 · Cited by 254 · see citing works
Self-citationRelationship between plasma and cerebrospinal fluid insulin levels of dogs.
Woods, S. C., & Porte, D. (1977) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1977.233.4.e331 · Cited by 218 · see citing works
Self-citationModified protocols improve insulin sensitivity estimation using the minimal model
Yang, Y. J., Youn, J. H., & Bergman, R. N. (1987) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1987.253.6.e595 · Cited by 212 · see citing works
Self-citationKinetics and specificity of insulin uptake from plasma into cerebrospinal fluid.
Schwartz, M. W., Sipols, A. J., Kahn, S. E., Lattemann, D. F., Taborsky, G. J., Bergman, R. N., Woods, S. C., & Porte, D. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.259.3.e378 · Cited by 191 · see citing works
Self-citationInsulin-Mediated Regulation of Neuronal Maturation
Puro, D. G., & Agardh, E. (1984) · Science · doi:10.1126/science.6089343 · Cited by 181 · see citing works
Woods, S., Porte, D., Bobbioni, E., Ionescu, E., Sauter, J., Rohner-Jeanrenaud, F., & Jeanrenaud, B. (1985) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/42.5.1063 · Cited by 180 · see citing works
Self-citationBaskin, D. G., Woods, S. C., West, D. B., van Houten, M., Posner, B. I., Dorsa, D. M., & Porte, D. (1983) · Endocrinology · doi:10.1210/endo-113-5-1818 · Cited by 122 · see citing works
Self-citationQuantitative Autoradiographic Evidence for Insulin Receptors in the Choroid Plexus of the Rat Brain
Baskin, D. G., Brewitt, B., Davidson, D. A., Paquette, T. L., Figlewicz, D. P., Lewellen, T. K., Graham, M. K., Woods, S. G., & Dorsa, D. M. (1986) · Diabetes · doi:10.2337/diab.35.2.246 · Cited by 104 · see citing works
Self-citationFrank, H. J. L., Jankovic‐Vokes, T., Pardridge, W. M., & Morris, W. L. (1985) · Diabetes · doi:10.2337/diab.34.8.728 · Cited by 92 · see citing works
Stein, L. J., Dorsa, D. M., Baskin, D. G., Figlewicz, D. P., Porte, D., & Woods, S. C. (1987) · Endocrinology · doi:10.1210/endo-121-5-1611 · Cited by 84 · see citing works
Self-citationSakaguchi, T., Takahashi, M. P., & Bray, G. A. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113584 · Cited by 84 · see citing works
Quantitation of Blood-Brain Barrier Permeability
Smith, Q. R. (1989) · Springer eBooks · doi:10.1007/978-1-4613-0701-3_4 · Cited by 64 · see citing works
Permeability of the choroid plexus of the rabbit to several solutes
Welch, K. A., & Sadler, K. M. (1966) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1966.210.3.652 · Cited by 63 · see citing works
Deoxynucleoside and vitamin transport into the central nervous system.
Spector, R., & Eells, J. T. (1984) · PubMed · Cited by 58 · see citing works
Vascular transport of insulin to rat cardiac muscle. Central role of the capillary endothelium.
Bar, R. S., Boes, M. K., & Sandra, A. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113439 · Cited by 50 · see citing works
Frank, H. J., Jankovic‐Vokes, T., Pardridge, W. M., et al. (1985) · Diabetes · doi:10.2337/diabetes.34.8.728 · Cited by 49 · see citing works
(1991) · Annals of Internal Medicine · doi:10.7326/0003-4819-115-3-238_1 · Cited by 40 · see citing works
Assies, J., SCHELLEKENS, A. P. M., & TOUBER, J. L. (1978) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1978.tb02186.x · Cited by 39 · see citing works
Insulin in the Central Nervous System
Yalow, R. S., & Eng, J. (1983) · Advances in metabolic disorders · doi:10.1016/b978-0-12-027310-2.50018-9 · Cited by 38 · see citing works
Quantitative autoradiographic evidence for insulin receptors in the choroid plexus of the rat brain
Baskin, D. G., Brewitt, B., Davidson, D. A., et al. (1986) · Diabetes · doi:10.2337/diabetes.35.2.246 · Cited by 38 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Woods, S. C., D. P. Figlewicz Lattemann, A. J. Sipols, and D. Porte, Jr. 1988. Baboons as a model for research on metabolism, feeding and the regulation of body weight. In Monographs in Primatology, Vol. 12: Nonhuman Primate Studies and Diabetes, Carbohydrate Intolerance, and Obesity.
Cited by
Sorted by citations
Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., et al. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.185 · Cited by 1,597 · see citing works
Sniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Animal models of obesity and diabetes mellitus
Kleinert, M., Clemmensen, C., Hofmann, S. M., Moore, M. C., Renner, S., Woods, S. C., Huypens, P., Beckers, J., de Angelis, M. H., Schürmann, A., et al. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.161 · Cited by 853 · see citing works
Self-citationInsulin in the brain: There and back again
Banks, W. A., Owen, J. B., & Erickson, M. A. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.07.006 · Cited by 576 · see citing works
Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease
Erickson, M. A., & Banks, W. A. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.135 · Cited by 572 · see citing works
Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Schwartz, M. W., Sipols, A. J., Marks, J. L., Sanacora, G., White, J. D., Scheurink, A., Kahn, S. E., Baskin, D. G., Woods, S. C., & Figlewicz, D. P. (1992) · Endocrinology · doi:10.1210/endo.130.6.1597158 · Cited by 555 · see citing works
Self-citationInsulin receptors and insulin action in the brain: review and clinical implications
Schulingkamp, R. J., Pagano, T. C., Hung, D., & Raffa, R. B. (2000) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(00)00040-3 · Cited by 491 · see citing works
Baura, G. D., Foster, D. M., Porte, D., Kahn, S. E., Bergman, R. N., Cobelli, C., & Schwartz, M. W. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116773 · Cited by 489 · see citing works
Self-citationThe selfish brain: Competition for energy resources
Peters, A., Schweiger, U., Pellerin, L., Hubold, C., Oltmanns, K. M., Conrad, M., Schultes, B., Born, J., & Fehm, H. L. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.03.002 · Cited by 489 · see citing works
Havel, P. J. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122601102 · Cited by 476 · see citing works
Differential Permeability of the Blood–Brain Barrier to Two Pancreatic Peptides: Insulin and Amylin
Banks, W. A., & Kastin, A. J. (1998) · Peptides · doi:10.1016/s0196-9781(98)00018-7 · Cited by 340 · see citing works
Hemostasis, endothelial stress, inflammation, and the metabolic syndrome
Grandl, G., & Wolfrum, C. (2017) · Seminars in Immunopathology · doi:10.1007/s00281-017-0666-5 · Cited by 344 · see citing works
Insulin gene expression and insulin synthesis in mammalian neuronal cells.
Devaskar, S. U., Giddings, S. J., Rajakumar, P. A., Carnaghi, L. R., Menon, R. K., & Zahm, D. S. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37214-9 · Cited by 333 · see citing works
Model for the regulation of energy balance and adiposity by the central nervous system
Schwartz, M. W., Baskin, D. G., Kaiyala, K. J., & Woods, S. C. (1999) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/69.4.584 · Cited by 323 · see citing works
Self-citationTransport of Insulin Across the Blood-Brain Barrier: Saturability at Euglycemic Doses of Insulin
Banks, W. A., Jaspan, J. B., Huang, W., & Kastin, A. J. (1997) · Peptides · doi:10.1016/s0196-9781(97)00231-3 · Cited by 318 · see citing works
Näslund, E. B., Gutniak, M., Skogar, S., Rössner, S., & Hellström, P. M. (1998) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/68.3.525 · Cited by 307 · see citing works
Energy metabolism in adult neural stem cell fate
Rafalski, V. A., & Brunet, A. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.10.007 · Cited by 280 · see citing works
Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance
Rhea, E. M., & Banks, W. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00521 · Cited by 263 · see citing works
The brain as an insulin-sensitive metabolic organ
Milstein, J. L., & Ferris, H. A. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101234 · Cited by 269 · see citing works
Strazielle, N., & Ghersi‐Egea, J. (2013) · Molecular Pharmaceutics · doi:10.1021/mp300518e · Cited by 262 · see citing works
Brain Insulin: Regulation, Mechanisms of Action and Functions
Gerozissis, K. (2003) · Cellular and Molecular Neurobiology · doi:10.1023/a:1022598900246 · Cited by 235 · see citing works
McNay, E. C., & Recknagel, A. K. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.005 · Cited by 229 · see citing works
Tschritter, O., Preissl, H., Hennige, A. M., Stumvoll, M., Porubska, K., Frost, R., Marx, H., Klösel, B., Lutzenberger, W., Birbaumer, N., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604404103 · Cited by 223 · see citing works
Adiposity signals and the control of energy homeostasis
Woods, S. C., & Seeley, R. J. (2000) · Nutrition · doi:10.1016/s0899-9007(00)00454-8 · Cited by 221 · see citing works
Self-citationBanks, W. A., Jaspan, J. B., & Kastin, A. J. (1997) · Peptides · doi:10.1016/s0196-9781(97)00198-8 · Cited by 219 · see citing works
Brain insulin signalling in metabolic homeostasis and disease
Scherer, T., Sakamoto, K., & Buettner, C. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00498-x · Cited by 205 · see citing works
Insulin Regulates Brain Function, but How Does It Get There?
Gray, S. M., Meijer, R. I., & Barrett, E. J. (2014) · Diabetes · doi:10.2337/db14-0340 · Cited by 206 · see citing works
Driedonks, T. A. P., Jiang, L., Carlson, B. W., Han, Z., Liu, G., Queen, S. E., Shirk, E. N., Gololobova, O. A., Liao, Z., Nyberg, L. H., et al. (2022) · Journal of Extracellular Biology · doi:10.1002/jex2.59 · Cited by 205 · see citing works
Consumption of a high-fat diet induces central insulin resistance independent of adiposity
Clegg, D. J., Gotoh, K., Kemp, C., Wortman, M. D., Benoit, S. C., Brown, L. M., D’Alessio, D. A., Tso, P., Seeley, R. J., & Woods, S. C. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.01.010 · Cited by 187 · see citing works
Self-citationBiological consequences of drug administration: Implications for acute and chronic tolerance
Ramsay, D. S., & Woods, S. C. (1997) · Psychological Review · doi:10.1037/0033-295x.104.1.170 · Cited by 155 · see citing works
Self-citationInsulin transport across the blood–brain barrier can occur independently of the insulin receptor
Rhea, E. M., Rask‐Madsen, C., & Banks, W. A. (2018) · The Journal of Physiology · doi:10.1113/jp276149 · Cited by 153 · see citing works
Fasting insulin and incident dementia in an elderly population of Japanese-American men
Peila, R., Rodriguez, B. L., White, L. R., & Launer, L. J. (2004) · Neurology · doi:10.1212/01.wnl.0000129989.28404.9b · Cited by 152 · see citing works
Tang‐Christensen, M., Havel, P. J., Jacobs, R. R., Larsen, P. J., & Cameron, J. L. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.2.5458 · Cited by 147 · see citing works
Effect of Diabetes Mellitus on the Permeability of the Blood–Brain Barrier to Insulin
Banks, W. A., Jaspan, J. B., & Kastin, A. J. (1997) · Peptides · doi:10.1016/s0196-9781(97)00238-6 · Cited by 145 · see citing works
Ott, V., Benedict, C., Schultes, B., Born, J., & Hallschmid, M. (2012) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01490.x · Cited by 139 · see citing works
Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice
Brown, L. M., Clegg, D. J., Benoit, S. C., & Woods, S. C. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.08.008 · Cited by 139 · see citing works
Self-citationKonishi, M., Sakaguchi, M., Lockhart, S. M., Cai, W., Li, M. E., Homan, E. P., Rask‐Madsen, C., & Kahn, C. R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710625114 · Cited by 138 · see citing works
Steil, G. M., Ader, M., Moore, D. M., Rebrin, K., & Bergman, R. N. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118572 · Cited by 138 · see citing works
Self-citationMechanisms of Insulin Action on Sympathetic Nerve Activity
Muntzel, M. S., Anderson, E. A., Johnson, A. K., & Mark, A. L. (1995) · Clinical and Experimental Hypertension · doi:10.3109/10641969509087053 · Cited by 135 · see citing works
The evaluation of insulin as a metabolic signal influencing behavior via the brain
Woods, S. C., Chavez, M., Park, C. R., Riedy, C. A., Kaiyala, K. J., Richardson, R. D., Figlewicz, D. P., Schwartz, M. W., Porte, D., & Seeley, R. J. (1996) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(95)00044-f · Cited by 135 · see citing works
Self-citationGold, P. W., Licinio, J., & Pavlatou, M. G. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.167 · Cited by 132 · see citing works
Diabetes, lipids, and adipocyte secretagogues
Faraj, M., Lu, H. L., & Cianflone, K. (2004) · Biochemistry and Cell Biology · doi:10.1139/o03-078 · Cited by 127 · see citing works
Regulation of Food Intake Through Hypothalamic Signaling Networks Involving mTOR
Woods, S. C., Seeley, R. J., & Cota, D. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155505 · Cited by 125 · see citing works
Self-citationPeripheral insulin and brain structure in early Alzheimer disease
Burns, J. M., Donnelly, J. E., Anderson, H. S., Mayo, M. S., Spencer-Gardner, L. S., Thomas, G., Cronk, B. B., Haddad, Z., Klima, D., Hansen, D., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000276952.91704.af · Cited by 121 · see citing works
Nonsaturable entry of neuropeptide Y into brain
Kastin, A. J., & Akerstrom, V. L. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.276.3.e479 · Cited by 119 · see citing works
Brown, J. A., Woodworth, H. L., & Leinninger, G. M. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00009 · Cited by 100 · see citing works
Young, C. N., Deo, S. H., Chaudhary, K. R., Thyfault, J. P., & Fadel, P. J. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.191866 · Cited by 102 · see citing works
Diggs‐Andrews, K. A., Zhang, X., Song, Z., Daphna-Iken, D., Routh, V. H., & Fisher, S. J. (2010) · Diabetes · doi:10.2337/db10-0401 · Cited by 99 · see citing works
Neuroendocrine mechanisms regulating food intake and body weight
McMinn, J. E., Baskin, D. G., & Schwartz, M. W. (2000) · Obesity Reviews · doi:10.1046/j.1467-789x.2000.00007.x · Cited by 97 · see citing works
Self-citationNew model for the regulation of energy balance and adiposity by the central nervous system
Kaiyala, K., Woods, S. C., & Schwartz, M. (1995) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/62.5.1123s · Cited by 98 · see citing works
Self-citationPotential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier
Strazielle, N., & Ghersi‐Egea, J. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160726112115 · Cited by 98 · see citing works
Sahu, A., Dube, M. G., Phelps, C. P., Sninsky, C. A., Kalra, P. S., & Kalra, S. P. (1995) · Endocrinology · doi:10.1210/endo.136.12.7588328 · Cited by 92 · see citing works
Hallschmid, M., & Schultes, B. (2009) · Diabetologia · doi:10.1007/s00125-009-1501-x · Cited by 90 · see citing works
Gailliot, M. T. (2008) · Perspectives on Psychological Science · doi:10.1111/j.1745-6924.2008.00077.x · Cited by 88 · see citing works
Tanaka, T., Nagatani, S., Bucholtz, D. C., Ohkura, S., Tsukamura, H., Maeda, K.-I., & Foster, D. L. (2000) · Biology of Reproduction · doi:10.1095/biolreprod62.5.1256 · Cited by 87 · see citing works
Diabetes and brain aging: Epidemiologic evidence
Launer, L. J. (2005) · Current Diabetes Reports · doi:10.1007/s11892-005-0069-1 · Cited by 85 · see citing works
Developmental Programming of Energy Balance and Its Hypothalamic Regulation
Remmers, F., & de Waal, H. A. D. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0028 · Cited by 82 · see citing works
Gut Hormones and Energy Balance, The Future for Obesity Therapy?
Meiliana, A., & Wijaya, A. (2009) · The Indonesian Biomedical Journal · doi:10.18585/inabj.v1i3.99 · Cited by 78 · see citing works
Insulin transport into the brain
Gray, S. M., & Barrett, E. J. (2018) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00240.2017 · Cited by 74 · see citing works
Glucose tolerance predicts performance on tests of memory and cognition
Fothergill, R. T., & Benton, D. (2000) · Physiology & Behavior · doi:10.1016/s0031-9384(00)00359-0 · Cited by 76 · see citing works
Uptake and degradation of blood-borne insulin by the olfactory bulb
Banks, W. A., Kastin, A. J., & Pan, W. (1999) · Peptides · doi:10.1016/s0196-9781(99)00045-5 · Cited by 75 · see citing works
State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease
Rhea, E. M., Leclerc, M., Yassine, H. N., Capuano, A. W., Tong, H., Petyuk, V. A., Macauley, S. L., Fioramonti, X., Carmichael, O., Calon, F., et al. (2023) · Aging and disease · doi:10.14336/ad.2023.0814 · Cited by 70 · see citing works
López‐Fernández, J., Sánchez‐Franco, F., Velasco, B., Tolón, R. M., Pazos, F., & Cacicedo, L. (1996) · Endocrinology · doi:10.1210/endo.137.10.8828499 · Cited by 69 · see citing works
Sasaki, T. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00109 · Cited by 66 · see citing works
Miller, D. W., Keller, B. T., & Borchardt, R. T. (1994) · Journal of Cellular Physiology · doi:10.1002/jcp.1041610218 · Cited by 65 · see citing works
Subba, R., Sandhir, R., Singh, S. P., Mallick, B. N., & Mondal, A. C. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15136 · Cited by 64 · see citing works
Veldhuis, J. D., Bidlingmaier, M., Anderson, S. M., Evans, W. S., Wu, Z., & Strasburger, C. J. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2001-011885 · Cited by 61 · see citing works
Insulin, Neuropeptide Y, and Food Intake
Schwartz, M. W., Figlewicz, D. P., Woods, S. C., Porte, D., & Baskin, D. G. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb26206.x · Cited by 59 · see citing works
Self-citationRegulation of energy homeostasis by peripheral signals
Woods, S. C., Benoit, S. C., Clegg, D. J., & Seeley, R. J. (2004) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2004.08.004 · Cited by 55 · see citing works
Self-citationIsrael, P. A., Park, C. R., Schwartz, M. W., Green, P. K., Sipols, A. J., Woods, S. C., Porte, D., & Figlewicz, D. P. (1993) · Brain Research Bulletin · doi:10.1016/0361-9230(93)90084-o · Cited by 54 · see citing works
Self-citationCerebrocortical Beta Activity in Overweight Humans Responds to Insulin Detemir
Tschritter, O., Hennige, A. M., Preissl, H. T., Porubská, K., Schäfer, S., Lutzenberger, W., Machicao, F. E., Birbaumer, N., Fritsche, A., & Häring, H. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001196 · Cited by 53 · see citing works
Madadi, A. K., & Sohn, M. (2024) · Pharmaceuticals · doi:10.3390/ph17081070 · Cited by 52 · see citing works
Hallschmid, M., Schultes, B., Marshall, L., Mölle, M., Kern, W., Bredthauer, J., Fehm, H. L., & Jan Born, A. (2004) · Diabetes · doi:10.2337/diabetes.53.9.2202 · Cited by 50 · see citing works
Hersom, M., Helms, H. C. C., Schmalz, C., Pedersen, T. Å., Buckley, S. T., & Brodin, B. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00350.2016 · Cited by 47 · see citing works
Feeding-related immunoreactive insulin changes in the PVN-VMH revealed by microdialysis
Orosco, M., Gerozissis, K., Rouch, C., & Nicolaı̈dis, S. (1995) · Brain Research · doi:10.1016/0006-8993(94)01347-k · Cited by 48 · see citing works
Mode of Transcapillary Transport of Insulin and Insulin Analog NN304 in Dog Hindlimb
Hamilton-Wessler, M., Ader, M., Dea, M. K., Moore, D. M., Loftager, M., Markussen, J., & Bergman, R. N. (2002) · Diabetes · doi:10.2337/diabetes.51.3.574 · Cited by 48 · see citing works
Self-citationPathways for insulin access to the brain: the role of the microvascular endothelial cell
Meijer, R. I., Gray, S. M., Aylor, K. W., & Barrett, E. J. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00081.2016 · Cited by 47 · see citing works
Insulin Responses to a Fat Meal in Hypothalamic Microdialysates and Plasma
Gerozissis, K., Orosco, M., Rouch, C., & Nicolaı̈dis, S. (1997) · Physiology & Behavior · doi:10.1016/s0031-9384(97)00195-9 · Cited by 45 · see citing works
Doyle, P., Cusin, I., Rohner‐Jeanrenaud, F., & Jeanrenaud, B. (1995) · Brain Research · doi:10.1016/0006-8993(95)00402-c · Cited by 45 · see citing works
Evidence for cephalic phase insulin release in humans: A systematic review and meta-analysis
Wiedemann, S. J., Rachid, L., Illigens, B. M. W., Böni‐Schnetzler, M., & Donath, M. Y. (2020) · Appetite · doi:10.1016/j.appet.2020.104792 · Cited by 44 · see citing works
Routes for the delivery of insulin to the central nervous system: A comparative review
Rhea, E. M., Salameh, T. S., & Banks, W. A. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2018.11.007 · Cited by 43 · see citing works
Gerozissis, K., Orosco, M., Rouch, C., & Nicolaı̈dis, S. (1993) · Brain Research · doi:10.1016/0006-8993(93)90511-k · Cited by 40 · see citing works
Faijerson, J. (2007) · Gothenburg University Publications Electronic Archive (Gothenburg University) · doi:10.1002/jnr.21044 · Cited by 40 · see citing works
Cytokines and food intake: The relevance of the immune system to the student of ingestive behavior
Weingarten, H. P. (1996) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(95)00035-d · Cited by 39 · see citing works
Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses
Alves, S. S., da Silva-Júnior, R. M. P., Servilha‐Menezes, G., Homolak, J., Šalković‐Petrišić, M., & Garcia‐Cairasco, N. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210234 · Cited by 38 · see citing works
Declining Blood Glucose Levels after a Cognitively Demanding Task Predict Subsequent Memory
Fothergill, R. T., & Benton, D. (1999) · Nutritional Neuroscience · doi:10.1080/1028415x.1999.11747295 · Cited by 38 · see citing works
Lenz, A., & Diamond, F. (2008) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e3282f43a5b · Cited by 38 · see citing works
Stimulation of luteinizing hormone secretion by food intake: evidence against a role for insulin
Williams, N. I., Lancas, M. J., & Cameron, J. L. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641210 · Cited by 37 · see citing works
Jensen, V. F. H., Bøgh, I. B., & Lykkesfeldt, J. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12133 · Cited by 37 · see citing works
McCarty, M. F. (1994) · Medical Hypotheses · doi:10.1016/0306-9877(94)90075-2 · Cited by 35 · see citing works
A historical perspective on the interactions of insulin at the blood‐brain barrier
Rhea, E. M., & Banks, W. A. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12929 · Cited by 34 · see citing works
Why study transport of peptides and proteins at the neurovascular interface
Pan, W., & Kastin, A. J. (2004) · Brain Research Reviews · doi:10.1016/j.brainresrev.2004.04.006 · Cited by 34 · see citing works
Brain Insulin Response to Feeding in the Rat Is Both Macronutrient and Area Specific
Gerozissis, K., Rouch, C., Nicolaı̈dis, S., & Orosco, M. (1999) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00061-x · Cited by 33 · see citing works
Kim, H., Hotta, N., Ishizawa, R., Iwamoto, G. A., Vongpatanasin, W., Mitchell, J. H., Smith, S. A., & Mizuno, M. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00061.2019 · Cited by 32 · see citing works
Wei, L., Ji, L., Miao, Y., Han, X., Li, Y., Wang, Z., Fu, J., Guo, L., Su, Y., & Zhang, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115202 · Cited by 33 · see citing works
Byun, M. S., Kim, H. J., Yi, D., Choi, H. J., Baek, H., Lee, J. H., Choe, Y. M., Sohn, B. K., Lee, J., Lee, Y., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.07.004 · Cited by 31 · see citing works
CCK increases the transport of insulin into the brain
May-Zhang, A. A., Liu, M., Woods, S. C., & Begg, D. P. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.08.025 · Cited by 31 · see citing works
Self-citationThe Brain-Gut-Islet Connection
Woods, S. C., Benoit, S. C., & Clegg, D. J. (2006) · Diabetes · doi:10.2337/db06-s015 · Cited by 30 · see citing works
Self-citationOrosco, M., & Gerozissis, K. (2001) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(01)00004-5 · Cited by 30 · see citing works
A mathematical model of brain glucose homeostasis
Gaohua, L., & Kimura, H. (2009) · Theoretical Biology and Medical Modelling · doi:10.1186/1742-4682-6-26 · Cited by 29 · see citing works
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
