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

OBJECTIVEDietary 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 METHODSSerum concentrations of sRAGE, N-«(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. RESULTSThe prediabetic children had higher sRAGE concentrations before seroconversion (P c = 0.03), at the appearance of multiple autoantibodies (P c = 0.008), and close to diagnosis (P c = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (P c = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (P c = 0.008) and at diagnosis (P c < 0.001). CONCLUSIONSPrediabetic 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.

A drop in the circulating concentrations of soluble receptor for advanced glycation end products is associated with seroconversion to autoantibody positivity but not with subsequent progression to clinical disease in children en route to type 1 diabetes

“…The current study suggests that the natural pattern of circulating sRAGE concentrations is different between children who seroconvert to positivity for disease‐associated autoantibodies early in life and progress to overt diabetes before puberty and those children whose autoimmune process begins somewhat later and is either slower or does not lead to clinical disease during childhood. This survey confirms the findings of our previous study, where a decrease in sRAGE concentrations coincided with seroconversion to autoantibody positivity in those children who progressed to clinical type 1 diabetes. This was expected because the study subjects were partly overlapping between the 2 studies.…”

“…Decreased sRAGE concentrations have been described for instance in acute Kawasaki disease and systemic onset juvenile idiopathic arthritis and in the cerebrospinal fluid of patients with multiple sclerosis . We reported recently that children who later progressed to type 1 diabetes experienced a reduction in their circulating sRAGE concentrations at seroconversion to positivity for diabetes‐predictive autoantibodies . The objective of the current study was to define the possible subsequent changes in sRAGE concentrations during the diabetic disease process from the initiation of beta‐cell autoimmunity to the diagnosis of clinical type 1 diabetes in progressors and in children who seroconverted to positivity for multiple (≥2) autoantibodies but remained nondiabetic until the end of the follow‐up period.…”

“…The series included 168 children (93 boys and 72 girls) who progressed to overt type 1 diabetes during prospective follow‐up and 43 children (29 boys and 14 girls) who turned positive for multiple diabetes‐associated autoantibodies but have not progressed to clinical disease during the follow‐up. Out of the progressors, 114 children were included in our previous study . We analyzed longitudinally samples by selecting a sample taken before seroconversion to autoantibody positivity, the first autoantibody‐positive sample, and thereafter annual samples until the diagnosis of type 1 diabetes or end of follow‐up.…”

Circulating Concentrations of Soluble Receptor for AGE Are Associated With Age and AGER Gene Polymorphisms in Children With Newly Diagnosed Type 1 Diabetes

“…Islet cell antibodies, insulin autoantibodies (IAAs), autoantibodies to GAD, islet antigen 2, and zinc transporter 8 (ZnT8A) are measured from the serum samples of the affected children and their family members. The autoantibody measurement protocol has been described previously (23). HLA-DR/DQ genotypes are analyzed as well.…”

Dietary gluten and type 1 diabetes

“…For example, cereal products that are baked at high temperatures contain advanced glycation end products that have been suggested as a risk factor for type 1 diabetes 1314. Grains also contain several other components generally considered harmful to health but that have not yet been studied in relation to type 1 diabetes, such as mycotoxins, heavy metals, and remnants of pesticides and fertilisers 1516…”