Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 311, Issue 5, Pages H1132-H1138Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00081.2016
Keywords
blood-brain barrier; brain interstitial fluid; high-fat diet; insulin receptor; Virchow-Robin space
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-057878, DK-073059]
- American Diabetes Association [11-BS6]
- National Heart, Lung, and Blood Institute [5-T32-HL-007284]
- American Heart Association [14PRE20100048]
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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 injected I-125-TyrA14insulin 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 brain I-125-TyrA14- insulin clearance. We further confirmed that 125I-TyrA14insulin was internalized by brain microvascular endothelial cells, indicating that the in vivo tissue association reflected cellular transport, not simply microvascular tracer binding.
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