Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: implications for early screening

Chmiel, Ruth; Giannopoulou, Eleni Z.; Winkler, Christiane; Achenbach, Peter; Ziegler, Anette‐Gabriele; Bonifacio, Ezio

doi:10.1007/s00125-014-3443-1

Cited by 35 publications

(27 citation statements)

References 5 publications

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“…Several factors reported to predict overall progression to clinical diabetes also, in fact, explain the progression rate, e.g. development of multipositivity at a young age, high ICA and IAA titres at seroconversion, and persistent vs fluctuating IAA [24,[26][27][28][29][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

et al. 2017

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Aims/hypothesis In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. Methods We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Results Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (>7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. Conclusions/interpretation At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.Heli Siljander and Mikael Knip are joint senior authors.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

et al. 2017

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“…These autoantibodies may develop throughout childhood, but seroconversion is most frequent from 6 months to 2 years of age [3]. Seroconversion typically involves IAA and/or GADA, and is often followed quickly by expansion to multiple islet autoantibodies [4], an event that defines an asymptomatic stage of type 1 diabetes. Over 80% of children with multiple islet autoantibodies progress to symptomatic, insulin-requiring diabetes within 15 years [2].…”

Section: Introductionmentioning

confidence: 99%

Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes

et al. 2015

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Aims/hypothesis Autoantibodies that precede type 1 diabetes frequently develop in early childhood and target distinct beta cell proteins. The aim of this study was to determine the heterogeneity of islet autoantibody development and fate. Methods The ages of development of insulin autoantibodies (IAA) and GAD autoantibodies (GADA), followed by multiple islet autoantibodies and progression to diabetes were examined in 2,441 children participating in two German birth cohorts. Results In 218 children who developed islet autoantibodies, the first islet autoantibody-positive sample was characterised by single IAA in 80 (37%), multiple islet autoantibodies in 68 (31%) and single GADA in 63 (29%) children. Of the children who were single antibody positive at seroconversion, 35 (44%) IAA-positive and 15 (24%) GADA-positive children developed multiple islet autoantibodies. Single persistent antibodies had heterogeneous affinities; GADA were also heterogeneous in their binding to N-terminally truncated GAD65 and in an ELISA. Progression to diabetes occurred in >50% of children within 10 years in all groups that developed multiple islet autoantibodies and in 44% of children with persistent single high-affinity IAA or persistent single GADA that were positive in both a radiobinding assay and ELISA. The earliest autoantibody development was seen in children with single IAA that progressed to multiple islet autoantibodies or in those with persistent high-affinity single IAA, with a sharp peak in incidence observed at age 9 months. The peak incidence occurred at age 2 years for children who underwent seroconversion directly to multiple islet autoantibodies and at 5 years for children who first seroconverted to GADA and subsequently developed other autoantibodies. Seroconversion to low-affinity IAA or persistent single GADA occurred at a low incidence after the age of 9 months. Conclusions/interpretation Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.

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“…Factors involved in rate of progression are poorly understood, although some determinants have been observed to be associated with rate of progression including younger age at seroconversion, number of autoantibodies, higher levels of IAA [21] and more recently higher levels of IA-2A [22*], but not GADA. In children with confirmed positive IAbs, the time of progression from single to multiple IAbs is influenced by family history of T1D and the presence of the high-risk HLA-DR3-DQ2/DR4-DQ8 genotype, while family history and HLA genotypes did not influence the time of progression to T1D in children with multiple IAbs [23**]. The rate of conversion from single to multiple IAbs was significantly higher in children with younger age less than 5 years in a recent study of the BABYDIAB/BABYDIET and the rate of conversion from single to multiple IAbs was highest in the first 2 years after seroconversion and declined rapidly after 4 years of follow-up (p = 0.003) [23**].…”

Section: Text Of Reviewmentioning

confidence: 99%

T1D Autoantibodies: room for improvement?

Zhao

Steck

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin (IAA) and other pancreatic β-cells proteins including GAD65 (GADA), islet antigen 2 (IA-2A) and zinc transporter 8 (ZnT8A). The assay technology for IAbs has made great progress; however, several important aspects still need to be addressed and improved. Recent findings Currently a radio-binding assay (RBA) has been well established as the ‘gold’ standard assay for all 4 IAbs. New generation of non-radioactive IAb assay with electrochemiluminescence technology has been shown to further improve sensitivity and disease specificity. Recently, multiplexed assays have opened the possibility of more efficient screening in large populations. Identification of potential new autoantibodies to neo-antigens or neo-epitopes post-translational modification is a new important field to be explored. Summary Individuals having a single positive autoantibody are at low risk for progression to T1D, while individuals expressing two or more positive autoantibodies, especially on multiple tests over time, have nearly 100% risk of developing clinical T1D when followed for over 2 decades. More efficient and cost effective IAb assays will hopefully lead to point-of-care screening in the general population.

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Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: implications for early screening

Cited by 35 publications

References 5 publications

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes

T1D Autoantibodies: room for improvement?

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