Objective Cardiovascular autonomic neuropathy (CAN) in diabetes is associated with increased mortality and morbidity and is a non-treatable complication. We investigated associations between circulating metabolites and presence of CAN in persons with type 1 diabetes (T1D). Methods CAN was assessed by cardiovascular reflex tests (CARTs) in 302 persons with T1D as heart rate response to: deep breathing; lying-to-standing test; and the Valsalva manoeuvre. More than 1 pathological CART defined the CAN diagnosis. Serum metabolomics and lipidomics profiles were analysed with two complementary non-targeted massspectrometry methods. Cross-sectional associations between single metabolites and CAN were assessed by linear regression. Models were fitted with and without adjustments for relevant confounders and multiple testing. Results Participants were mean (IQR) aged 55(49, 63) years, 50% males, with diabetes duration 39(32, 47) years, HbA1c 63(55,69) mmol/mol and 34% had the CAN diagnosis. A total of 75 metabolites and 106 lipids were examined. In crude models, CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4–deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and amino acid methionine (p&lt;0.05). Upon adjustment, positive associations with CAN were retained with hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, and citric acid and phenols (P adjusted &lt;0.05). Conclusions Metabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives, were associated with CAN in T1D. These novel metabolic pathways associated with CAN could prove to be future modifiable risk factors.

Cardiovascular Autonomic Neuropathy in Type 1 Diabetes is Associated with Several Metabolic Pathways – New Risk Markers on the Horizon