Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes.
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.
Oresic
Matej
M
VTT Technical Research Centre of Finland, Espoo, Finland. matej.oresic@vtt.fi
Simell
Satu
S
Sysi-Aho
Marko
M
Näntö-Salonen
Kirsti
K
Seppänen-Laakso
Tuulikki
T
Parikka
Vilhelmiina
V
Katajamaa
Mikko
M
Hekkala
Anne
A
Mattila
Ismo
I
Keskinen
Päivi
P
Yetukuri
Laxman
L
Reinikainen
Arja
A
Lähde
Jyrki
J
Suortti
Tapani
T
Hakalax
Jari
J
Simell
Tuula
T
Hyöty
Heikki
H
Veijola
Riitta
R
Ilonen
Jorma
J
Lahesmaa
Riitta
R
Knip
Mikael
M
Simell
Olli
O
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
D000596:Amino Acids; D001323:Autoantibodies