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

  • Biochim Biophys Acta Mol Basis Dis. 2022 Oct 1;1868(10):166472. doi: 10.1016/j.bbadis.2022.166472.
Xuling Liu  1 ,  Zuxin Liang  1 ,  Hongwei Duan  1 ,  Jianhai Yu  1 ,  Zhiran Qin  1 ,  Jingshu Li  1 ,  Li Zhu  1 ,  Qinghua Wu  1 ,  Weiwei Xiao  1 ,  Chenguang Shen  1 ,  Chengsong Wan  1 ,  Kefeng Wu  2 ,  Hua Ye  3 ,  Bao Zhang  4 ,  Wei Zhao  5
Affiliations
  • 1. BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
  • 2. Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China.
  • 3. Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China. Electronic address: [email protected].
  • 4. BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 5. BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 35752384 DOI: 10.1016/j.bbadis.2022.166472
Abstract

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.

Keywords
Dengue virus; IRS-1; Insulin resistance; TNF-α.
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