title: Pathways for insulin access to the brain: the role of the microvascular endothelial cell.
abstract: Insulin affects multiple important central nervous system (CNS) functions including memory and appetite, yet the pathway(s) by which insulin reaches brain interstitial fluid (bISF) has not been clarified. Recent studies demonstrate that to reach bISF, subarachnoid cerebrospinal fluid (CSF) courses through the Virchow-Robin space (VRS) which sheaths penetrating pial vessels down to the capillary level. Whether insulin predominantly enters the VRS and bISF by local transport through the blood-brain barrier, or by being secreted into the CSF by the choroid plexus, is unknown. We injected125I-TyrA14-insulin or regular insulin intravenously and compared the rates of insulin reaching subarachnoid CSF with its plasma clearance by brain tissue samples (an index of microvascular endothelial cell binding/uptake/transport). The latter process was more than 40-fold more rapid. We then showed that selective insulin receptor blockade or 4 wk of high-fat feeding each inhibited microvascular brain125I-TyrA14-insulin clearance. We further confirmed that125I-TyrA14-insulin was internalized by brain microvascular endothelial cells, indicating that the in vivo tissue association reflected cellular transport, not simply microvascular tracer binding.
authors: Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia; and.
authors: Rick I
authors: RI
authors: Meijer
authors: Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, Virginia.
authors: Sarah M
authors: SM
authors: Gray
authors: Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia; and.
authors: Kevin W
authors: KW
authors: Aylor
authors: Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia; and ejb8x@Virginia.edu.|Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, Virginia.
authors: Eugene J
authors: EJ
authors: Barrett
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007328:Insulin / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D055806:Microvessels / Q000378:metabolism*; D010841:Pia Mater / Q000098:blood supply; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013346:Subarachnoid Space / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D007457:Iodine Radioisotopes; D011972:Receptor, Insulin
keywords: Virchow-Robin space; blood-brain barrier; brain interstitial fluid; high-fat diet; insulin receptor