Type 2 Diabetes Reduces IFN-α2 and Compromises Antiviral Defense: Evidence From Mendelian Randomization and H1N1-Infected Diabetic Mice

Type 2 diabetes (T2D) impairs antiviral immunity; however, the causal link between T2D and interferon-α2 (IFN-α2) deficiency remains unclear. This study used genome-wide association study-based Mendelian randomization (MR) to investigate this relationship and validated the findings in an H1N1-infected diabetic mouse model. MR analysis of 26 single nucleotide polymorphisms showed a significant negative association between T2D and IFN-α2 levels (inverse variance weighted odds ratio 0.667; P = 0.000116) without heterogeneity or pleiotropy. In vivo experiments confirmed that db/db mice exhibited more severe H1N1-induced lung injury, higher viral loads, and lower survival rates compared with nondiabetic controls. However, exogenous IFN-α2 treatment significantly reversed these pathologic outcomes. Inflammatory cytokine profiling showed that IFN-α2 downregulated 21 elevated cytokines and restored Fas ligand levels in lung tissue. Mechanistically, Western blotting demonstrated that IFN-α2 inhibited the phosphorylation of JAK1/2 and STAT3, thereby suppressing excessive inflammation. In conclusion, our findings indicate that T2D leads to IFN-α2 deficiency, contributing to susceptibility to viral infection. Supplementation with IFN-α2 effectively attenuated virus-induced lung injury by inhibiting JAK/STAT3 signaling and cytokine storms, positioning IFN-α2 supplementation as a promising therapeutic strategy for managing influenza complications in patients with diabetes. ARTICLE HIGHLIGHTS: Type 2 diabetes (T2D) is linked to impaired antiviral immunity, but whether it drives interferon-α2 (IFN-α2) deficiency remains unknown. We asked whether T2D causally suppresses IFN-α2 levels and whether exogenous supplementation could rescue host defense mechanisms against influenza infection. By integrating genetic analysis with an H1N1-infected diabetic mouse model, we show that T2D genetically lowers IFN-α2 and that treatment reverses lung injury by inhibiting JAK/STAT3-mediated hyperinflammation. Our study positions IFN-α2 supplementation as a promising therapeutic strategy to prevent severe viral pneumonia in patients with T2D.