The Effects of Viruses on Insulin Sensitivity and Blood-Brain Barrier Function

Abstract

In this review manuscript, we discuss the effects of select common viruses on insulin sensitivity and blood-brain barrier (BBB) function and the potential overlapping and distinct mechanisms involved in these effects. More specifically, we discuss the effects of human immunodeficiency virus (HIV), herpes, hepatitis, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 viruses on insulin sensitivity and BBB function and the proposed underlying mechanisms. These viruses differ in their ability to be transported across the BBB, disrupt the BBB, and/or alter the function of the BBB. For RSV and SARS-CoV-2, diabetes increases the risk of infection with the virus, in addition to viral infection increasing the risk for development of diabetes. For HIV and hepatitis C and E, enhanced TNF-a levels play a role in the detrimental effects. The winter of 2022-2023 has been labeled as a tridemic as influenza, RSV, and COVID-19 are all of concern during this flu season. There is an ongoing discussion about whether combined viral exposures of influenza, RSV, and COVID-19 have additive, synergistic, or interference effects. Therefore, increased efforts are warranted to determine how combined viral exposures affect insulin sensitivity and BBB function.

Keywords: blood–brain barrier; insulin resistance; viruses.

Figure 1

HIV, insulin resistance, and the BBB. The effects of HIV on insulin resistance might involve increases in TNF-a levels induced by redistribution of fat or enhanced growth hormone levels. HIV combined with the use of protease inhibitors as treatment can cause insulin resistance. Effects of HIV on the BBB might lead to an increase in brain Aβ levels and a decrease in pericytes. The arrows in bold indicate the direction of the effects. For more details, see text.

Figure 2

Herpes virus, insulin resistance, and the BBB. Herpes virus can induce AD-related neuropathology, including Aβ pathology, tau hyperphosphorylation, and neuroinflammation. Herpes virus might negatively affect glucose metabolism and cause insulin resistance because of increased inflammation. As there is more viral replication in E4 than E3 carriers, these effects are expected to be more pronounced in E4 than E3 carriers. In case of Herpes encephalitis, effects on the BBB might result in enhanced Aβ levels and enhanced Golgi stress and an increase in CD3-positive infiltrating cells and apoptosis of neurons and glia. The arrows in bold indicate the direction of the effects. For more details, see text.

Figure 3

Hepatitis, insulin resistance, and the BBB. Hepatitis C might cause insulin resistance via distinct pathways. Effects of Hepatitis C on the BBB might result in enhanced TNF-α levels. These effects might involve effects of PBMCs on the BBB. Hepatitis E might cause perivascular inflammation and gliosis by increasing brain levels of TNF-α and IL-18. The arrows in bold indicate the direction of the effects. For more details, see text.

Figure 4

Influenza virus, insulin resistance, and the BBB. Influenza virus might cause insulin resistance by affecting cholesterol homeostasis, dysregulating glucose and fatty acid metabolism, and increasing ApoE levels. Influenza virus might cause hippocampal neuronal spine loss by affecting ZO-1 on endothelial cells of the BBB. The arrows in bold indicate the direction of the effects. For more details, see text.

Figure 5

RSR, insulin resistance, and the BBB. RSV might induce insulin resistance via the IGF-1R and involve inflammation, especially enhanced IL-6 levels, and type I diabetes. The arrows in bold indicate the direction of the effects. For more details, see text.

Figure 6

COVID-19, insulin resistance, and the BBB. Type I and type II diabetes are risk factor for COVID-19. COVID-19 might cause insulin resistance via downregulating ACE II and upregulating angiotensin II levels, increased inflammation involving a cytokine storm, or via IRS, PI3K, AKT, mTOR, and MAPK. COVID-19 might induce neuroinflammation through effects on the BBB. The arrows in bold indicate the direction of the effects. For more details, see text.