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Review
. 2018 Aug 1;315(2):C125-C136.
doi: 10.1152/ajpcell.00240.2017. Epub 2018 May 30.

Insulin transport into the brain

Sarah M Gray  1 , Eugene J Barrett  1   2
Affiliations
Review

Insulin transport into the brain

Sarah M Gray et al. Am J Physiol Cell Physiol. .

Abstract

While there is a growing consensus that insulin has diverse and important regulatory actions on the brain, seemingly important aspects of brain insulin physiology are poorly understood. Examples include: what is the insulin concentration within brain interstitial fluid under normal physiologic conditions; whether insulin is made in the brain and acts locally; does insulin from the circulation cross the blood-brain barrier or the blood-CSF barrier in a fashion that facilitates its signaling in brain; is insulin degraded within the brain; do privileged areas with a "leaky" blood-brain barrier serve as signaling nodes for transmitting peripheral insulin signaling; does insulin action in the brain include regulation of amyloid peptides; whether insulin resistance is a cause or consequence of processes involved in cognitive decline. Heretofore, nearly all of the studies examining brain insulin physiology have employed techniques and methodologies that do not appreciate the complex fluid compartmentation and flow throughout the brain. This review attempts to provide a status report on historical and recent work that begins to address some of these issues. It is undertaken in an effort to suggest a framework for studies going forward. Such studies are inevitably influenced by recent physiologic and genetic studies of insulin accessing and acting in brain, discoveries relating to brain fluid dynamics and the interplay of cerebrospinal fluid, brain interstitial fluid, and brain lymphatics, and advances in clinical neuroimaging that underscore the dynamic role of neurovascular coupling.

Keywords: blood CSF barrier; blood-brain barrier; endothelium; insulin; insulin resistance.

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Figures

Fig. 1.
Fig. 1.
Barriers of the brain and insulin movement across the blood-brain barrier. A: the blood-cerebrospinal fluid (CSF) barrier has fenestrated capillaries in the choroid plexus that lack tight junctions and allow para- and transcellular transport across the endothelium. Substances secreted into ventricular cerebrospinal fluid are actively transported across the epithelial cells (joined by tight junctions). B: architecture of the blood-brain barrier at the capillary level. Tight junctions (ovals) and adherens junctions (rectangles) between brain endothelial cells (BECs) where the tight junctions prevent paracellular movement. Pericytes and basement membrane material largely fill the Virchow-Robin space (VRS) between the BEC and the astrocyte boundary. BISF, brain interstitial fluid. C: magnified image of box in B demonstrating how insulin transits the BEC. Circulating insulin (hexagons) interacts with insulin receptor (IR) on the luminal membrane of the microvascular BEC. Subsequently, it is internalized by a lipid raft-mediated endocytotic process and shuttled to the antiluminal membrane. It is released there and can permeate the VRS, which at the capillary level is filled with basement membrane material. Once across the endothelium it may interact with pericytes, astrocytes, or enter the BISF and act directly on neurons. The proximity of astrocyte endfeet to the pericyte and endothelial cell (EC) may facilitate neurovascular coupling.
Fig. 2.
Fig. 2.
A simplified schematic of the circulation of blood through the brain originating in pial arteries which are bathed by subarachnoid cerebrospinal fluid (CSF). As pial vessels penetrate into brain parenchyma as arterioles, then capillaries, then venules, they are accompanied by a paravascular sheath (Virchow-Robin space, VRS) whose medial boundary (green) is the blood vessel basement membrane and whose lateral wall is the astrocyte foot processes (light blue). BEC, brain endothelial cell; BISF, brain interstitial fluid.
See this image and copyright information in PMC

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