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. 2017 Aug;60(8):1467-1474.
doi: 10.1007/s00125-017-4296-1. Epub 2017 May 20.

Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children

Rocky Strollo  1 , Chiara Vinci  1   2 , Nicola Napoli  1   3 , Paolo Pozzilli  4   5 , Johnny Ludvigsson  6 , Ahuva Nissim  7
Affiliations

Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children

Rocky Strollo et al. Diabetologia. 2017 Aug.

Abstract

Aims/hypothesis: We have shown that autoimmunity to insulin in type 1 diabetes may result from neoepitopes induced by oxidative post-translational modifications (oxPTM). Antibodies specific to oxPTM-insulin (oxPTM-INS-Ab) are present in most newly diagnosed individuals with type 1 diabetes and are more common than autoantibodies to native insulin. In this study, we investigated whether oxPTM-INS-Ab are present before clinical onset of type 1 diabetes, and evaluated the ability of oxPTM-INS-Ab to identify children progressing to type 1 diabetes.

Methods: We used serum samples collected longitudinally from the 'All Babies in Southeast Sweden (ABIS)' cohort tested for the gold standard islet autoantibodies to insulin (IAA), GAD (GADA), tyrosine phosphatase 2 (IA-2A) and zinc transporter 8 (ZnT8A). We studied 23 children who progressed to type 1 diabetes (progr-T1D) and 63 children who did not progress to type 1 diabetes (NP) after a median follow-up of 10.8 years (interquartile range 7.7-12.8). Of the latter group, 32 were positive for one or more islet autoantibodies (NP-AAB+). oxPTM-INS-Ab to insulin modified by •OH or HOCl were measured by our developed ELISA platform.

Results: Antibodies to at least one oxPTM-INS were present in 91.3% of progr-T1D children. oxPTM-INS-Ab co-existed with GADA, IA-2A, IAA or ZnT8A in 65.2%, 56.5%, 38.9% and 33.3% progr-T1D children, respectively. In addition, oxPTM-INS-Ab were present in 17.4%, 26.1%, 38.9% and 41.6% of progr-T1D children who were negative for GADA, IA-2A, IAA and ZnT8A, respectively. •OH-INS-Ab were more common in progr-T1D children than in NP-AAB+ children (82.6% vs 19%; p < 0.001) and allowed discrimination between progr-T1D and NP-AAB+ children with 74% sensitivity and 91% specificity. None of the NP-AAB- children were positive for oxPTM-INS-Ab.

Conclusions/interpretation: oxPTM-INS-Ab are present before the clinical onset of type 1 diabetes and can identify children progressing to type 1 diabetes.

Keywords: Biomarker; Insulin; Insulin autoantibodies; Islet autoantibodies; Oxidative stress; Post-translational modifications; Type 1 diabetes.

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Conflict of interest statement

Data availability

The data are available on request from the authors.

Funding

This study was supported by the EFSD/JDRF/Lilly European Programme in Type 1 Diabetes Research (3-PAR-2016-277-A-N) and by the JDRF innovative grant (INO-2015-78-S-B). ABIS and the autoantibody determinations were supported by the Swedish Research Council (K2005-72X-11242-11A and K2008-69X-20826-01-4), the Swedish Child Diabetes Foundation (Barndiabetesfonden), JDRF Wallenberg Foundation (K 98-99D-12813-01A), Medical Research Council of Southeast Sweden (FORSS) and the Swedish Council for Working Life and Social Research (FAS2004–1775).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

RS, PP, JL and AN conceived the study. CV contributed to acquisition and analysis of data. NN contributed to data acquisition. RS analysed the data and wrote the first draft. All authors critically revised the manuscript for intellectual content. All authors have seen and approved the final draft. RS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Figures

Fig. 1
Fig. 1
Cross-sectional evaluation of antibody binding to oxPTM-INS in study population. (a) Reactivity to NT-INS and oxPTM-INS was significantly higher in samples from progr-T1D children compared with non-progressing children, regardless of whether they were NP-AAB+ or NP-AAB− to the standard islet autoantibody markers (p < 0.001). Binding to oxPTM-INS modified by HOCl and •OH was significantly higher than to NT-INS in progr-T1D children (p < 0.0001). Data on the earliest time point available are reported. Values above the dashed lines were defined as positive for antibodies to NT-INS and oxPTM-INS modified by glycation (GLY), HOCl or •OH, respectively (99th percentile of a group of 88 healthy control children). (b–d) Overlapping prevalence of antibodies to NT-INS and oxPTM-INS in all children positive for at least one islet autoantibody (b) and in progr-T1D (c) and NP-AAB+ children (d). Values outside the circles are children negative for the antibody evaluated in the diagram
Fig. 2
Fig. 2
Longitudinal changes of oxPTM-INS-Ab in prog-T1D children according to age (a) and time before diagnosis of type 1 diabetes (b). Values above the dashed lines were defined as positive for antibodies to oxPTM-INS; •OH-INS is shown as an example for oxPTM-INS-Ab
Fig. 3
Fig. 3
Overlapping prevalence of oxPTM-INS-Ab, GADA, IA-2A, IAA and ZnT8A. Data are shown for the whole study population of children positive to at least one islet autoantibody (a–d) and for progr-T1D (e–h) and NP-AAB+ children (i–l). Data for IAA and ZnT8A were available in 45 and 22 children, respectively. ZnT8A included positivity to one or more ZnT8RA, ZnT8AWA and ZnT8QA variants. •OH-INS is shown as example for oxPTM-INS-Ab. Values outside the circles are children negative to the antibody evaluated in the diagram
Fig. 4
Fig. 4
Overlapping prevalence of oxPTM-INS-Ab, GADA, IA-2A and IAA evaluated with three standard islet autoantibodies or with oxPTM-INS-Ab substituted for GADA, IA-2A or IAA. Data are shown for the whole study population of children positive to at least one islet autoantibody (a–d) and for progr-T1D (e–h) and NP-AAB+ children (i–l). IAA was not available in five progr-T1D and five NP-AAB+ children; therefore these children are not included in the diagrams assessing the overlapping prevalence of IAA. •OH-INS is shown as example for oxPTM-INS-Ab. Values outside the circles are children negative to the antibodies evaluated in the diagram
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