The risk determinants of type 1 diabetes, initiators of autoimmune
response, mechanisms regulating progress toward beta cell failure, and
factors determining time of presentation of clinical diabetes are poorly
understood. We investigated changes in the serum metabolome
prospectively in children who later progressed to type 1 diabetes. Serum
metabolite profiles were compared between sample series drawn from 56
children who progressed to type 1 diabetes and 73 controls who remained
nondiabetic and permanently autoantibody negative. Individuals who
developed diabetes had reduced serum levels of succinic acid and
phosphatidylcholine (PC) at birth, reduced levels of triglycerides and
antioxidant ether phospholipids throughout the follow up, and increased
levels of proinflammatory lysoPCs several months before seroconversion
to autoantibody positivity. The lipid changes were not attributable to
HLA-associated genetic risk. The appearance of insulin and glutamic acid
decarboxylase autoantibodies was preceded by diminished ketoleucine and
elevated glutamic acid. The metabolic profile was partially normalized
after the seroconversion. Autoimmunity may thus be a relatively late
response to the early metabolic disturbances. Recognition of these
preautoimmune alterations may aid in studies of disease pathogenesis and
may open a time window for novel type 1 diabetes prevention strategies.