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

Diabetes. 2020 Mar;69(3):465-476. doi: 10.2337/db19-0756. Epub 2020 Feb 6.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine / metabolism
  • Amino Acids, Branched-Chain
  • Autoantibodies / immunology*
  • Child, Preschool
  • Dehydroascorbic Acid / metabolism
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Fatty Acids / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / immunology
  • Humans
  • Infant
  • Infant, Newborn
  • Insulin Antibodies / immunology
  • Longitudinal Studies
  • Male
  • Metabolome*
  • Methionine / metabolism
  • Phosphatidylethanolamines / metabolism
  • Prodromal Symptoms*
  • Proline / metabolism
  • Risk
  • Triglycerides / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Amino Acids, Branched-Chain
  • Autoantibodies
  • Fatty Acids
  • Insulin Antibodies
  • Phosphatidylethanolamines
  • Triglycerides
  • gamma-Aminobutyric Acid
  • Proline
  • Methionine
  • Glutamate Decarboxylase
  • Alanine
  • Dehydroascorbic Acid