The Blood-Brain Barrier, Oxidative Stress, and Insulin Resistance

Abstract

The blood-brain barrier (BBB) is a network of specialized endothelial cells that regulates substrate entry into the central nervous system (CNS). Acting as the interface between the periphery and the CNS, the BBB must be equipped to defend against oxidative stress and other free radicals generated in the periphery to protect the CNS. There are unique features of brain endothelial cells that increase the susceptibility of these cells to oxidative stress. Insulin signaling can be impacted by varying levels of oxidative stress, with low levels of oxidative stress being necessary for signaling and higher levels being detrimental. Insulin must cross the BBB in order to access the CNS, levels of which are important in peripheral metabolism as well as cognition. Any alterations in BBB transport due to oxidative stress at the BBB could have downstream disease implications. In this review, we cover the interactions of oxidative stress at the BBB, how insulin signaling is related to oxidative stress, and the impact of the BBB in two diseases greatly affected by oxidative stress and insulin resistance: diabetes mellitus and Alzheimer's disease.

Keywords: Alzheimer’s disease; blood–brain barrier; diabetes mellitus; insulin resistance; oxidative stress.

Figure 1

The blood–brain barrier (BBB) and oxidative stress. There are 4 distinct ways brain endothelial cells (BECs) are at a greater exposure to oxidative factors. First, these cells must transport high levels of glucose into the brain for energy. Glucose must be metabolized to energy-utilizing substrates within mitochondria, generating free oxygen radicals. Second, BECs generate high levels of nitric oxide (NO) through endothelial nitric oxide synthase (eNOS), required for intracellular signaling and regulation of vascular tone. Third, BECs must transport dietary lipids and fatty acids into the brain as an alternative source of energy and signaling. This creates an increased opportunity for the generation of lipid peroxidation. Lastly, BECs contain a greater number of mitochondria compared to peripheral endothelial cells. Mitochondria are the primary source of reactive species, including superoxide. In all, BECs require a critical counter-regulatory process to combat the oxidative factors in order to maintain a functioning BBB with preserved tight junction (TJ) proteins and basement membrane (BM). Figure generated using BioRender.

Figure 2

Interaction between insulin and oxidative stress. Insulin receptor signaling is tightly linked with oxidative stress. Dysregulated or impaired insulin receptor signaling is also defined as insulin resistance. Not only does oxidative stress, including free fatty acid (FFA) oxidation, impair insulin receptor signaling, but insulin receptor signaling can also activate mTOR to inhibit autophagy and oxidative stress. It is also known that insulin receptor signaling can regulate mitochondria number, which can be blocked by oxidative stress. Additionally, low doses of oxidative stress can have a positive impact on insulin receptor signaling, mediated by the NADPH oxidase, Nox4. Nitric oxide (NO) can regulate insulin BBB transport. Diseases implicated in insulin receptor signaling, such as diabetes mellitus (DM) and Alzheimer’s disease (AD), are heavily linked to oxidative stress. Figure generated using BioRender.