Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2881-2886. doi: 10.1210/jc.2017-00569.


Context: Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease.

Objective: To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes.

Research design and methods: We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated antigen 2, and zinc transporter 8 and islet cell antibodies were tested every 6 to 12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8 years, 8 to 11 years, 12 to 17 years, and ≥18 years, and optimal age breakpoints were identified by recursive partitioning analysis.

Results: After median follow-up of 2 years, 141 relatives had developed at least one additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: Relatives with GADA showed a gradual decrease in risk over the four age groups, whereas relatives with IAA showed a sharp decrease above age 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA.

Conclusions: In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, whereas immune responses initially directed at glutamic acid decarboxylase can mature over a longer period. These differences have important implications for monitoring these patients and for designing prevention trials.

Trial registration: NCT00097292.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Autoantibodies / immunology*
  • Cation Transport Proteins / immunology*
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Progression
  • Family*
  • Female
  • Follow-Up Studies
  • Glucose Tolerance Test
  • Glutamate Decarboxylase / immunology*
  • Humans
  • Insulin / immunology*
  • Male
  • Radioimmunoassay
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology*
  • Young Adult
  • Zinc Transporter 8


  • Autoantibodies
  • Cation Transport Proteins
  • Insulin
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • islet cell antibody
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Glutamate Decarboxylase

Associated data