Available online 25 May 2024

Author links open overlay panelAbstract

The blood–brain barrier (BBB) is a unique system of the brain microvasculature that limits the exchange between the blood and the brain. Brain microvascular endothelial cells form the BBB as part of the neurovascular unit and express insulin receptors. The insulin receptor at the BBB has been studied in two different functional aspects. These functions include (1) the supplying of blood insulin to the brain and (2) the modulation of BBB function via insulin signaling. The first function involves drug delivery to the brain, while the second function is related to the association between central nervous system diseases and type 2 diabetes through insulin resistance. This chapter summarizes recent progress in research on the function of insulin receptors at the BBB.

Section snippetsInsulin and the blood–brain barrier

The blood–brain barrier (BBB) is the physiological barrier between circulating blood and the central nervous system (CNS). As a result, vitamins and hormones cannot freely enter the brain from the blood. The BBB is composed of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, neurons, and the extracellular basal membrane (Fig. 1). This multi-cellular unit is called the “neurovascular unit” (Solar, Zamani, Lakatosova, & Joukal, 2022). BMECs express various transporters and

Insulin receptor and BBB transport

The insulin receptor is expressed in BMECs. Our proteomic analysis revealed similar expression levels of insulin receptors in brain microvessels isolated from humans, monkeys, and mice (Ohtsuki et al., 2014). This result raises the possibility that the insulin receptors in BMECs mediate insulin transport across the BBB. According to Pardridge et al., insulin binds to isolated bovine and human brain microvessels with high affinity (1–2 nM). In addition, a protein with a molecular weight of

Insulin receptor as a brain drug delivery target

Macromolecules, such as genes, proteins, and nanoparticles, are new and essential modalities for drug development. However, the BBB interferes with the distribution of these compounds throughout the brain. Therefore, drug delivery to the brain is critical in the development of CNS-active macromolecular drugs (Ohtsuki & Terasaki, 2007). Although the contribution of insulin receptors to the transport of insulin via the BBB might be limited, insulin receptors have been utilized for drug delivery

BBB signaling via the insulin receptor

The insulin receptor is involved in intracellular signaling for the regulation of BBB function. The insulin receptor mediates two mechanisms related to the regulation of BBB function. The first mechanism involves regulation by basal insulin. BMECs perform specific functions in the BBB by interacting with the surrounding cells, such as astrocytes and pericytes. As BMECs are exposed to circulating blood, blood factors, including insulin, are expected to play a role in the function of BBB in

Conclusions and future directions

Insulin receptors at the BBB were mainly analyzed in terms of transport, including the transport of insulin across the BBB, and drug delivery targets. As noted above, the contribution of the insulin receptor might be limited in the transport of insulin across the BBB. The transferrin receptor is currently a major target receptor for drug delivery to the brain across the BBB (Wu et al., 2023). Pabinafusp alfa is an antibody against the human transferrin receptor fused with iduronate-2-sulfatase

Acknowledgments

The authors acknowledge the support of the JPSP KAKENHI, JST CREST, and AMED BINDS.

References (45)D.B. Agus et al.Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters

The Journal of Clinical Investigation

(1997)

W.A. Banks et al.Evidence for an alternative insulin transporter at the blood-brain barrier

Aging Pathobiology and Therapeutics

(2022)

R.J. Boado et al.Drug targeting of erythropoietin across the primate blood-brain barrier with an IgG molecular Trojan horse

The Journal of Pharmacology and Experimental Therapeutics

(2010)

R.J. Boado et al.Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier

Biotechnology and Bioengineering

(2007)

R.J. Boado et al.GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier

Biotechnology and Bioengineering

(2008)

Y. Chen et al.Insulin receptor trafficking: Consequences for insulin sensitivity and diabetes

International Journal of Molecular Sciences

(2019)

H.J. Frank et al.A direct in vitro demonstration of insulin binding to isolated brain microvessels

Diabetes

(1981)

R. Giugliani et al.Neurocognitive and somatic stabilization in pediatric patients with severe mucopolysaccharidosis type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): An open label phase 1-2 trial

Orphanet Journal of Rare Diseases

(2018)

S.A. HamedBrain injury with diabetes mellitus: Evidence, mechanisms and treatment implications

Expert Review of Clinical Pharmacology

(2017)

M.J. Iraburu et al.Revising endosomal trafficking under insulin receptor activation

International Journal of Molecular Sciences

(2021)

S. Ito et al.Identification of cell-surface proteins endocytosed by human brain microvascular endothelial cells in vitro

Pharmaceutics

(2020)

T. Matsuzaki et al.Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama study

Neurology

(2010)

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