title: Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes.
abstract: 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.
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland. matej.oresic@vtt.fi
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Satu
authors.initials: S
authors.lastname: Simell
authors.forename: Marko
authors.initials: M
authors.lastname: Sysi-Aho
authors.forename: Kirsti
authors.initials: K
authors.lastname: Näntö-Salonen
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Seppänen-Laakso
authors.forename: Vilhelmiina
authors.initials: V
authors.lastname: Parikka
authors.forename: Mikko
authors.initials: M
authors.lastname: Katajamaa
authors.forename: Anne
authors.initials: A
authors.lastname: Hekkala
authors.forename: Ismo
authors.initials: I
authors.lastname: Mattila
authors.forename: Päivi
authors.initials: P
authors.lastname: Keskinen
authors.forename: Laxman
authors.initials: L
authors.lastname: Yetukuri
authors.forename: Arja
authors.initials: A
authors.lastname: Reinikainen
authors.forename: Jyrki
authors.initials: J
authors.lastname: Lähde
authors.forename: Tapani
authors.initials: T
authors.lastname: Suortti
authors.forename: Jari
authors.initials: J
authors.lastname: Hakalax
authors.forename: Tuula
authors.initials: T
authors.lastname: Simell
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
mesh_terms: D000293:Adolescent; D000596:Amino Acids / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D050356:Lipid Metabolism; D008297:Male; D008659:Metabolic Diseases / Q000276:immunology / Q000503:physiopathology; D055432:Metabolomics
chemical_list: D000596:Amino Acids; D001323:Autoantibodies