Characteristics of the pre‐diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish population—The ABIS study

Åkerman, Linda; Ludvigsson, Johnny; Swartling, Ulrica; Casas, Rosaura

doi:10.1002/dmrr.2900

Cited by 11 publications

(20 citation statements)

References 49 publications

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“…In SNAIL participants, GADA were common in all cohorts but more frequent in older individuals. Antibodies that recognise IA-2 and ZnT8 develop later in disease pathogenesis and are associated with progression [11]; however, ZnT8A were the second most frequent antibodies found in slow progressors. In contrast, IA-2A were less common and BABYDIAB participants had a particularly low prevalence of IA-2A (14%).…”

Section: Discussionmentioning

confidence: 99%

“…Islet autoantibodies (GADA, IA-2A, IAA and ZnT8A) were tested in each parent study by radiobinding assays as previously described [2,3,11,16,[19][20][21] and an overview of the testing strategy for each study is summarised in ESM Methods. Positivity was defined using a threshold determined by each laboratory and where multiple samples were available, persistent autoimmunity was confirmed.…”

Section: Autoantibody Assaysmentioning

confidence: 99%

“…These stages appear to be controlled by different genetic mechanisms, with different HLA alleles affecting seroconversion and/or progression to disease [7,8]. Positivity for and/or higher levels of IAA, IA-2A, IA-2βA and ZnT8A have also been associated with more rapid development of hyperglycaemia [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

et al. 2018

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Aims/hypothesis Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Methods Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the χ 2 test. Results In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. Conclusion No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.Keywords HLA class II . Islet autoantibodies . Slow progression . Type 1 diabetes Diabetologia (2018Diabetologia ( ) 61:1484Diabetologia ( -1490 https://doi.org/10.1007/s00125-018-4591-5Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4591-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 99%

Section: Autoantibody Assaysmentioning

confidence: 99%

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Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

et al. 2018

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“…Of note, emerging evidence suggests that beta cell mass may in fact be maintained until near the time of stage 2 to stage 3 transition [60] . There is also evidence that insulin resistance is present in at least a subset of stage 2 individuals [92][93][94][95] .…”

Section: Progression From Stage 2 T1dmentioning

confidence: 99%

Type 1 Diabetes: Disease Stratification

Insel¹,

Dutta²,

Hedrick³

2017

Biomed Hub

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Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.

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“…Number of AAB may incrementally increase the risk of progression . When used in combination, islet AAB can identify up to 80% or more of patients at disease onset or at risk of developing disease, but except for IA‐2A, their predictive potential is extremely reduced when assessed in single test . Based on this, staging of preclinical T1D has been recently updated to include multiple AAB, also termed islet autoimmunity, as the earliest stage of T1D .…”

Section: Introductionmentioning

confidence: 99%

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies

Strollo

Vinci

Napoli

et al. 2019

Diabetes Metabolism Res

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Background: Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB). Methods: We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AABpositive (AAB + ) children from the general population (median follow-up 8.8 years). Results: oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA + children. Risk for diabetes was higher (P = 0.03) among multiple AAB + who were also oxPTM-INS-Ab + compared with those who were oxPTM-INS-Ab -. Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab + in combination with GADA + and IA-2A + , compared with 84.37% in those with IAA + , GADA + , and IA-2A + (P = 0.04).Conclusions: Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB + children.

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Characteristics of the pre‐diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish population—The ABIS study

Cited by 11 publications

References 49 publications

Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

Type 1 Diabetes: Disease Stratification

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies

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