A Change in Paradigm: Diabetes Exacerbates Infection Severity by Hyperinflammation, Not Immunosuppression

Background: Diabetes mellitus has long been believed to be immunosuppressive due to defective phagocytic clearance of microbes.

Methods:We measured inflammatory biomarkers, blood bacterial density, and survival in diet-induced obesity (DIO) diabetic wild-type and congenic knockout mice infected with Gram-negative bacteria.

Results: We confirmed that diabetic mice were hyper-susceptible to bacteremia caused by Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli.However, despite excess mortality, bacterial burden was not significantly higher in diabetic mice, indicating that phagocytic clearance of bacteria was not impaired. Rather, diabetic mice exhibited dramatically increased pro-inflammatory cytokines compared to non-diabetic mice. Furthermore, immunosuppressing diabetic mice with dexamethasone reversed their hypersusceptibility to lethal infection. Disruption of Toll-like receptor 4 (TLR4), the receptor for advanced glycation end-products (RAGE), or their common pro-inflammatory signal transducer MyD88 also protected mice from lethal infection.

Conclusion: We thus define a molecular mechanism by which diabetic mice are more susceptible to bacterial infections. Rather than immunosuppression, the primary driver of diabetes-associated susceptibility to Gram-negative bacterial infections is increased inflammation, induced by MyD88 signaling through RAGE and TLR4.