Severity of Cardiovascular Autonomic Neuropathy Is Linked to Increasing Levels of Circulating Proinflammatory Cytokines

AIMS: Cardiovascular autonomic neuropathy (CAN) is a severe form of diabetic neuropathy affecting approximately one in five people with diabetes and is a major predictor of cardiovascular mortality. Low-grade inflammation may contribute to CAN development, but the exact inflammatory factors associated with CAN remain unclear. Here, we examined the circulating levels of cytokines across different stages of CAN severity in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: From an initial T2D cohort with 899 participants undergoing cardiovascular autonomic reflex tests (CARTs) and measures of heart rate variability (HRV) indices, a final sub-cohort of 249 participants was selected and classified as: no CAN (n = 83), early CAN (n = 69) or manifest CAN (n = 97), according to CARTs. One abnormal test constituted early CAN; two or three abnormal CARTs constituted manifest CAN. Ten cytokines were measured in serum samples using Meso Scale Discovery multiplex technology. RESULTS: Individuals with manifest CAN exhibited subtle but significantly higher circulating levels of the proinflammatory cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-α and interferon (IFN)-γ compared to the no CAN group. Furthermore, TNF-α levels tended to be upregulated already in early CAN compared to no CAN. Higher levels of IL-6, IL-8, IL-10, IFN-γ and TNF-α were associated with worse autonomic function outcomes, including HRV indices and CARTs. CONCLUSION: CAN severity is associated with increased circulating levels of IL-6, IFN-γ and TNF-α in T2D. These cytokines may therefore hold promise as clinically useful biomarkers and/or therapeutic targets to mitigate CAN burden and possibly cardiovascular risk. TRIAL REGISTRATION: Number: NCT05043636; Diabetic Neuropathy Screening Study 1.1 + Substudy 1.2-1.3-1.4.