Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

Matej Oresic, Satu Simell, Marko Sysi-Aho, Kirsti Näntö-Salonen, Tuulikki Seppänen-Laakso, Vilhelmiina Parikka, Mikko Katajamaa, Anne Hekkala, Ismo Mattila, Päivi Keskinen, Laxman Yetukuri, Arja Reinikainen, Jyrki Lähde, Tapani Suortti, Jari Hakalax, Tuula Simell, Heikki Hyöty, Riitta Veijola, Jorma Ilonen, Riitta LahesmaaMikael Knip, Olli Simell

    Research output: Contribution to journalArticleScientificpeer-review

    315 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)2975-2984
    Number of pages10
    JournalJournal of Experimental Medicine
    Volume205
    Issue number13
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

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