The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening

  • Laura M. JacobsenEmail author
  • Laura Bocchino
  • Carmella Evans-Molina
  • Linda DiMeglio
  • Robin Goland
  • Darrell M. Wilson
  • Mark A. Atkinson
  • Tandy Aye
  • William E. Russell
  • John M. Wentworth
  • David Boulware
  • Susan Geyer
  • Jay M. Sosenko



Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status.


Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1–49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study.


Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%.


Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.


Age Autoantibodies Index60 Metabolic Type 1 diabetes 



Glutamic acid decarboxylase autoantibodies


Insulin autoantibodies


Insulinoma-associated antigen-2 autoantibodies


Islet cell autoantibodies


Multiple autoantibody


Pathway to Prevention


The Environmental Determinants of Diabetes in the Young


Zinc transporter 8 autoantibodies



We acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. The authors also acknowledge M. Warnock (TrialNet statistician; Tampa, FL, USA) and the TrialNet Coordinating Center for their assistance and support. Parts of this study were presented in oral presentation at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, USA (9–13 June 2017).

Contribution statement

LMJ analysed the data and wrote the manuscript. LB, DB and SG analysed the data, contributed to discussion and provided statistical guidance. CEM, LD, RG, DMW, MAA, TA, WER, JMW, SG and DB were involved in the acquisition and interpretation of data, as well as revising the manuscript critically for important intellectual content. LB and JMS assisted in drafting and revising the manuscript. All authors have provided final approval of the version to be published. JMS conceptualised this study and 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.


The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, and the JDRF. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF.

Duality of interest

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

Supplementary material

125_2019_5047_MOESM1_ESM.pdf (505 kb)
ESM (PDF 504 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Laura M. Jacobsen
    • 1
    Email author
  • Laura Bocchino
    • 2
  • Carmella Evans-Molina
    • 3
  • Linda DiMeglio
    • 3
  • Robin Goland
    • 4
  • Darrell M. Wilson
    • 5
  • Mark A. Atkinson
    • 6
  • Tandy Aye
    • 5
  • William E. Russell
    • 7
  • John M. Wentworth
    • 8
    • 9
  • David Boulware
    • 2
  • Susan Geyer
    • 2
  • Jay M. Sosenko
    • 10
  1. 1.Division of Pediatric Endocrinology, Department of Pediatrics, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Health Informatics InstituteUniversity of South FloridaTampaUSA
  3. 3.Center for Diabetes and Metabolic DiseasesIndiana University School of MedicineIndianapolisUSA
  4. 4.Division of Pediatric Endocrinology, Diabetes, and MetabolismColumbia University Medical CenterNew YorkUSA
  5. 5.Department of PediatricsStanford University School of MedicineStanfordUSA
  6. 6.Department of Pathology, Immunology and Laboratory MedicineUniversity of Florida College of MedicineGainesvilleUSA
  7. 7.Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  8. 8.Walter and Eliza Hall InstituteParkvilleAustralia
  9. 9.Department of Diabetes and EndocrinologyRoyal Melbourne HospitalParkvilleAustralia
  10. 10.Division of EndocrinologyUniversity of MiamiMiamiUSA

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