ABSTRACT
Background and Aims: Type 2 diabetes (T2D) is a major risk factor for developing severe infectious disease, such as COVID-19. The endocrine and immune system closely interact following viral infection, which is deregulated in T2D. Previously, we showed in humans and mice that viral infection causes transient insulin resistance, which can lead to permanent loss of glycemic control in subjects with pre-diabetes. How changes in systemic glycemia benefit the antiviral response, and how this derails in T2D is mostly unknown. Methods: Mice were infected with virulent strains of cytomegalovirus or lymphocytic choriomeningitis virus. Glucose-, insulin- and pyruvate-tolerance tests and hyperinsulinemic euglycemic clamping were used to determine the metabolic state of animals. Conditional knock-out models were used to measure the impact of cytokines on metabolism of specific organs. Dietinduced obesity models were used to determine the impact of hyperglycemia on the antiviral response. Results: Severe viral infection causes pancreatic β-cell hyperfunctionality following their stimulation with the cytokine IFNγ by local T cells. Virus-induced hyperinsulinemia impaired glucose release by the liver and promoted induction of fasting metabolism, because of reduced hepatic glycogenolysis, causing relative, transient hypoglycemia (RHG). RHG was beneficial to the antiviral response by promoting the release of antiviral cytokines by endothelial cells, which impaired viral replication. Obese mice failed to induce fastng metabolsim, resulting in lower antiviral cytokines, higher viral titers and increased pathology. Conclusions: Metabolic adaptations following infection are of major importance for optimal control of viral replication. In context of T2D, these changes cannot be accomplished, thus leading to more frequent and severe infections.