Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 205, Issue 13, Pages 2975-2984Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20081800
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Funding
- Juvenile Diabetes Research Foundation International [4-1999-731, 4-2001-435]
- European Community [HEALTH-F2-2008-202013]
- Academy of Finland
- Sigrid Juselius Foundation
- Paivikki and Sakari Sohlberg Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation, Finland
- Special Federal Funds to the Turku, Oulu
- Tampere University Hospitals
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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.
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