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Matej Orei¹, Satu Simell², Marko Sysi-Aho¹, Kirsti Näntö-Salonen², Tuulikki Seppänen-Laakso¹, Vilhelmiina Parikka², Mikko Katajamaa¹, Anne Hekkala⁴, Ismo Mattila¹, Päivi Keskinen⁵, Laxman Yetukuri¹, Arja Reinikainen⁶, Jyrki Lähde⁵, Tapani Suortti¹, Jari Hakalax², Tuula Simell², Heikki Hyöty^7,8, Riitta Veijola⁴, Jorma Ilonen^3,9, Riitta Lahesmaa⁶, Mikael Knip^5,10, and Olli Simell²

¹ VTT Technical Research Centre of Finland, Espoo FI-02044, Finland
² Department of Pediatrics and ³ Immunogenetics Laboratory, University of Turku, Turku FI-20520, Finland
⁴ Department of Pediatrics, University of Oulu, Oulu FI-90014, Finland
⁵ Department of Pediatrics, Tampere University Hospital, Tampere FI-33521, Finland
⁶ Turku Centre for Biotechnology, Turku FI-20521, Finland
⁷ Department of Virology, University of Tampere, Tampere FI-33520, Finland
⁸ Centre for Laboratory Medicine, University Hospital of Tampere, Tampere FI-33520, Finland
⁹ Department of Clinical Microbiology, University of Kuopio, FI-70211 Kuopio, Finland
¹⁰ Hospital for Children and Adolescents, University of Helsinki, Helsinki FI-00014, Finland

CORRESPONDENCE Matej Orei: matej.oresic{at}vtt.fi OR Olli Simell: olli.simell{at}utu.fi

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β 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.

Abbreviations used: BCAA, branched chain amino acids; DIPP, Type 1 Diabetes prediction and prevention study; GABA, -aminobutyric acid; GADA, glutamic acid decarboxylase antibody; GCxGC-TOF/MS, two-dimensional gas chromatography coupled to time-of-flight mass spectrometry; IAA, insulin autoantibody; ICA, islet cell autoantibody; PC, phosphatidylcholine; STRIP, Special Turku Coronary Risk Factor Intervention Project for Children.

S. Simell, M. Sysi-Aho, K. Näntö-Salonen, T. Seppänen-Laakso, V. Parikka, and M. Katajamaa contributed equally to this paper.

© 2008 Orei et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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