title: Decrease in circulating concentrations of soluble receptors for advanced glycation end products at the time of seroconversion to autoantibody positivity in children with prediabetes.
abstract: OBJECTIVE
  Dietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association of circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes.
  
  
  METHODS
  Serum concentrations of sRAGE, N-ε(carboxymethyl)lysine (CML) adducts, and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The samples were taken at four time points: before seroconversion, at the time of the first autoantibody-positive sample, at the time of the first sample positive for multiple (>2) autoantibodies, and close to the disease diagnosis. Samples of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points.
  
  
  RESULTS
  The prediabetic children had higher sRAGE concentrations before seroconversion (Pc = 0.03), at the appearance of multiple autoantibodies (Pc = 0.008), and close to diagnosis (Pc = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (Pc = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc < 0.001).
  
  
  CONCLUSIONS
  Prediabetic children have higher concentrations of sRAGE and a higher sRAGE/CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Kirsi M
authors.initials: KM
authors.lastname: Salonen
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Samppa J
authors.initials: SJ
authors.lastname: Ryhänen
authors.affiliation: Glycation and Diabetes Group, Mater Research Institute, University of Queensland Translational Research Institute, Brisbane, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: Glycation and Diabetes Group, Mater Research Institute, University of Queensland Translational Research Institute, Brisbane, Australia.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Borg
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Härkönen
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Pediatrics, Tampere University Hospital, Tampere, Finland mikael.knip@helsinki.fi.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000453:epidemiology; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D011236:Prediabetic State / Q000097:blood* / Q000453:epidemiology / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*
chemical_list: D001323:Autoantibodies; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C048496:N(6)-carboxymethyllysine; D008239:Lysine