A new study published in the International Journal of Molecular Sciences discusses the impact of herpes, influenza, hepatitis, human immunodeficiency virus (HIV), the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and respiratory syncytial virus (RSV) viruses on blood-brain barrier (BBB) function and insulin sensitivity, as well as their underlying mechanisms.
Study: The Effects of Viruses on Insulin Sensitivity and Blood–Brain Barrier Function. Image Credit: Billion Photos / Shutterstock.com
Viruses and DM
Previously, a diagnosis of acquired immunodeficiency syndrome (AIDS) was accompanied by a shortened life expectancy; however, medical advances have led to the development of effective treatments that have improved the quality of life and life expectancy of patients with AIDS. Nevertheless, as AIDS patients began to live longer, they became more likely to be diagnosed with lipodystrophy, metabolic syndrome, insulin resistance, hyperglycemia, and DM.
Various mechanisms have been proposed to contribute to the increased likelihood of DM among AIDS patients. For example, the redistribution of fat in AIDS patients can increase the release of tumor-necrosis factor α (TNF-α), a phenomenon that is further exacerbated in AIDS patients also diagnosed with hepatitis C.
Nevertheless, the most common link between DM and AIDS has been the treatment of protease inhibitors, which can lead to lipodystrophy, dyslipidemia, insulin resistance, as well as altered insulin release from the pancreas.
Herpes viruses are the most prevalent viruses in humans and include herpes simplex virus (HSV) 1, human herpesviruses (HHV) 6, cytomegalovirus (CMV), HHV 7, Epstein-Barr virus (EBV), HSV 2, HHV 8, and varicella‐zoster virus (VZV). All herpes viruses are capable of impairing glucose metabolism and increasing the risk of developing DM type II.
Viral hepatitis is a common condition that can be caused by infection with hepatitis A, B, C, D, and E. Of these, hepatitis C has been historically associated with DM and insulin resistance. Importantly, the degree of insulin resistance observed in hepatitis C patients is often dependent upon the genotype, with higher insulin resistance reported in those with genotypes 1 and 4 as compared to 2 and 3.
Various mechanisms may be responsible for the altered insulin function observed in hepatitis patients. These include the downregulation and ubiquitination of insulin receptor substrate proteins 1 and 2, as well as insulin resistance that arises due to altered phosphorylation of insulin receptor substrate proteins 1 and 2. Furthermore, hepatitis may lead to insulin resistance by increasing the production of TNF‐α and/or downregulating glucose transporter 2 (GLUT-2) and GLUT‐4.
Previous research suggests influenza viruses contribute to the etiopathogenesis of DM type I. In fact, following the 2009 H1N1 epidemic, numerous cases of both pancreatitis and DM type I were reported.
In vivo studies have demonstrated that although infection with influenza viruses in healthy mice did not lead to diabetes, its impact on the development of this condition may vary by strain, repeated infections, and existing pancreatic damage. Nevertheless, dysregulated glucose and fatty acid metabolism, as well as altered tricarboxylic acid (TCA) cycle activity, has been reported in influenza-infected mice.
RSV is a contagious respiratory virus that typically can cause mild to severe cold‐like symptoms in both infants and adults.
Infection of human adipocytes with RSV has been reported to cause over six-fold increased interleukin 6 (IL-6) production which, in turn, can modify insulin sensitivity. MicroRNA analysis of blood from infected infants also indicated that RSV infection can impact the insulin signaling pathway. Despite these observations, there remains limited data on how RSV leads to insulin resistance and whether this virus causes immediate or delayed changes in insulin sensitivity.
Few epidemiological studies have reported RSV infection to increase the risk of developing DM type I. Conversely, the presence of DM type I increases the risk of RSV‐positive acute respiratory illness infection in older adults, as well as children less than five years of age.
Metabolic syndrome, obesity, and DM are known risk factors for infection with SARS-CoV-2 and severe disease outcomes, with COVID-19 also reported to increase the risk of developing DM. In fact, patients who were newly diagnosed with DM after recovering from COVID-19 were at a significantly greater risk of death by 17%.
Most cases of COVID‐19‐related new‐onset DM has developed as a result of insulin resistance, rather than insufficiency. Some of the different mechanisms that appear to contribute to this increased insulin resistance include the COVID-19-induced cytokine storm, which leads to impaired glucose homeostasis and hyperglycemia. Furthermore, SARS-CoV-2 has been shown to interfere with various insulin/insulin growth factor signaling pathway genes, some of which include mTOR and MAPK.
Viruses and altered BBB function
HIV-1 can cross the BBB through both the passage of infected immune cells as a result of increased expression of vascular cell adhesion molecule 1 (VCAM‐1) and e‐selectin, as well as a free virus using the mannose‐6 phosphate receptor. Furthermore, HIV-1 has been shown to induce the circulation of amyloid β peptide, a protein that is the precursor to amyloid plaques that are overexpressed in the brains of Alzheimer’s disease (AD) patients, from the blood into the brain.
Like DM, infection with HIV has also been implicated with a loss of pericytes. Thus, patients with both AIDS and DM may be at an even greater risk of altered BBB function.
Herpes viruses are capable of increasing AD pathology, as well as the extracellular and intracellular production of amyloid β peptide. Furthermore, these viruses have been associated with insoluble amyloid plaque pathology, increased neuroinflammation, and tau hyperphosphorylation.
Hepatitis C can cross the BBB by attaching to receptors on its endothelial cells. Comparatively, hepatitis E appears to directly infect brain endothelial cells of the BBB, subsequently causing TNF‐α and IL-18 levels to rise and both gliosis and perivascular inflammation to ensue. The extent to which other hepatitis virus genotypes can cross or affect the BBB remains unknown.
In 2009, H1N1 was primarily implicated in pediatric infections. Soon after, a significant number of neurological complications, including encephalopathy, were reported in children under the age of 16. Further in vivo studies reported that infection with the influenza virus in mice led to neuronal spine loss in the hippocampus 30 days following infection, as well as altered learning function.
Severe RSV infection, particularly that which requires admission to the intensive care unit (ICU), increases the risk of neurological complications, including seizures, encephalopathy, and abnormal neurological examination. In one study, the analysis of cerebrospinal fluid (CSF) samples obtained from severely infected children with seizures confirmed the presence of both RSV and high IL-6 levels.
Several in vivo studies have also confirmed the neurological impact of RSV infection, with infected mice and rats exhibiting altered learning patterns one month after infection. Furthermore, human RSV infection in mice has been shown to alter the permeability of the BBB, as well as increase the filtration of immune cells into the central nervous system (CNS).
SARS-CoV-2 is capable of infecting brain endothelial cells and directly crossing the BBB to reach the brain. In addition to contributing to insulin resistance, the cytokine storm that arises in severe COVID-19 cases also leads to altered BBB function.
- Raber, J., Rhea, E. M., & Banks, W. A. (2023). The Effects of Viruses on Insulin Sensitivity and Blood–Brain Barrier Function. International Journal of Molecular Sciences. doi:10.3390/ijms24032377.