Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study

Abstract

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

Figure 1

Age effect on the longitudinal metabolome of TEDDY subjects in the nested case-control cohort for islet autoimmunity.

Figure 2

Metabolites with preseroconversion trajectories identified as top differentiated in the two-step time course analysis. Mean abundance of metabolites per age point is plotted for matched pairs who had preseroconversion measurement available and experienced seroconversion before 2 years of age (A) or after 2 years of age (B). P values <0.01 in the second step of time course analysis are presented on the plots.

Figure 3

Metabolic pathways involving trajectory signals and independent time point biomarkers for IA in TEDDY. TCA, tricarboxylic acid.

Figure 4

Mean abundance of preseroconversion GABA, glutamic acid, glutamine, α-ketoglutarate, leucine, and plasmenyl-PC (ether PC) per age point for case and control subjects in GADA-first and IAA-first groups.