Dengue virus is involved in insulin resistance via the downregulation of IRS-1 by inducing TNF-α secretion

During the epidemic, the individuals with underlying diseases usually have a higher rate of mortality. Diabetes is highly prevalent worldwide, making it a frequent comorbidity in dengue fever patients. Therefore, understanding the relationship between dengue virus (DENV) infection and diabetes is important. We first demonstrated that DENV-3 infection down-regulated the expression of IRS-1. In vitro, treatment of HepG2 cells with TNF-α inhibitors and siRNA proved that after DENV-3 infection in HepG2 cells, cellular TNF-α secretion was increased, which negatively regulated IRS-1, thereby leading to an insulin-resistant state. In vivo, DENV-3 induced insulin resistance (IR) in hepatocytes by promoting the secretion of TNF-α and inhibiting the expression of IRS-1 was proved. In vivo approaches also showed that after DENV-3 infection, TNF-α levels in the serum of C57BL/6 mice with insulin resistance increased, and upon TNF-α antagonist III treatment, IRS-1 expression in the liver, reduced by infection, was upregulated. In addition, transcriptomic analysis revealed more negative regulatory events in the insulin receptor signaling pathway after DENV-3 infection. This is the first report of a link between DENV-3 infection and insulin resistance, and it lays a foundation for further research.