Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study

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OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in the Environmental Determinants of Diabetes in the Young study.

RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or IA2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

RESULTS: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282 or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] = 1.12, 95% CI = 0.88-1.42, P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR = 3.08; 95% CI = 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.

CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.


  • Kendra Vehik
  • Ezio Bonifacio
  • Ake Lernmark
  • Liping Yu
  • Alistair Williams
  • Desmond Schatz
  • Marian Rewers
  • Jin-Xiong She
  • Jorma Toppari
  • William Hagopian
  • Beena Akolkar
  • Anette G Ziegler
  • Jeffrey P Krischer
  • TEDDY Study Group
External organisations
  • University of South Florida
  • University of Colorado-Denver
  • Augusta University
  • Pacific Northwest Diabetes Research Institute
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Dresden University of Technology
  • Skåne University Hospital
  • University of Bristol
  • University of Florida
  • Turku University Hospital
  • Technical University of Munich
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)2066-2073
JournalDiabetes Care
Issue number9
Early online date2020 Jul 8
Publication statusPublished - 2020
Publication categoryResearch