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.

BACKGROUND: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. METHODS: We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive sample and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. RESULTS: Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. CONCLUSIONS: These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.

Autoantibodies against zinc transporter 8 are related to age, metabolic state and HLA DR genotype in children with newly diagnosed type 1 diabetes.

BACKGROUND: We set out to define the characteristics of humoral autoimmunity against ZnT8 in children and adolescents with newly diagnosed T1D in relation to age and metabolic status at diagnosis, human leucocyte antigen (HLA) genotype and family history of T1D. METHODS: A total of 2115 subjects <15 years of age were analysed for antibodies against zinc transporter 8, ICA, GADA, IAA, IA-2A, HLA DR-DQ genotype, blood pH, plasma glucose and ß-hydroxybutyrate concentrations. Their family history of T1D was also recorded. RESULTS: Zinc transporter 8 antibodies (ZnT8A) were detected in 63% of the cases. ZnT8A positivity was associated with older age at diagnosis (mean 8.2 years versus 7.5 years, p < 0.001). Seven subjects (0.3%) had ZnT8A as their single autoantibody. Diabetic ketoacidosis at diagnosis was less common among subjects with ZnT8A than among those without (16% versus 20%, p = 0.012). The prevalence of ZnT8A was decreased in DR3/DR4 heterozygotes when compared with those with other DR combinations (p < 0.001). Subjects with the neutral DR13-DQB1*0604 haplotype tested more frequently positive for ZnT8A than the rest of the population (p < 0.001). A positive family history of T1D showed no association with ZnT8A prevalence or levels. CONCLUSIONS: Antibodies for ZnT8 is related to age and metabolic status at diagnosis as well as HLA genotype but does not significantly improve the detection rate of ß-cell autoimmunity in Finnish children and adolescents affected by T1D.