Kirsi M Salonen1, Samppa J Ryhänen1, Josephine M Forbes2, Danielle J Borg2, Taina Härkönen1, Jorma Ilonen3, Olli Simell4, Riitta Veijola5, Per-Henrik Groop6, Mikael Knip7. 1. Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland. 2. Glycation and Diabetes Group, Mater Research Institute, University of Queensland Translational Research Institute, Brisbane, Australia. 3. Immunogenetics Laboratory, University of Turku, Turku, Finland Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland. 4. Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland. 5. Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland. 6. 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. 7. 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.
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. RESEARCH DESIGN AND 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.
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. RESEARCH DESIGN AND 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 prediabeticchildren 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). Prediabeticchildren had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc < 0.001). CONCLUSIONS:Prediabeticchildren 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 prediabeticchildren may reflect a higher AGE scavenger capacity.
Authors: William H. Hoffman; Takaki Ishikawa; James Blum; Naoto Tani; Tomoya Ikeda; Carol M. Artlett Journal: J Clin Res Pediatr Endocrinol Date: 2019-09-13