Phospholipid Levels at Seroconversion Are Associated With Resolution of Persistent Islet Autoimmunity: The Diabetes Autoimmunity Study in the Young.

Abstract

Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA. Cox proportional hazards models were used to test whether the metabolites (2,487) predicted IA reversion: two or more consecutive visits negative for all autoantibodies. We conducted a principal components analysis (PCA) of the top metabolites; |hazard ratio (HR) >1.25| and nominal <i>P</i> < 0.01. Phosphatidylcholine (16:0_18:1(9Z)) was the strongest individual metabolite (HR per 1 SD 2.16, false discovery rate (FDR)-adjusted <i>P</i> = 0.0037). Enrichment analysis identified four clusters (FDR <i>P</i> < 0.10) characterized by an overabundance of sphingomyelin (d40:0), phosphatidylcholine (16:0_18:1(9Z)), phosphatidylcholine (30:0), and l-decanoylcarnitine. Overall, 63 metabolites met the criteria for inclusion in the PCA. PC1 (HR 1.4, <i>P</i> < 0.0001), PC2 (HR 0.85, <i>P</i> = 0.0185), and PC4 (HR 1.28, <i>P</i> = 0.0103) were associated with IA reversion. Given the potential influence of diet on the metabolome, we investigated whether nutrients were correlated with PCs. We identified 20 nutrients that were correlated with the PCs (<i>P</i> < 0.05). Total sugar intake was the top nutrient. Overall, we identified an association between phosphatidylcholine, sphingomyelin, and carnitine levels and reversion of IA.