Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12

Peter Achenbach*, Mohammed I. Hawa, Stephanie Krause, Vito Lampasona, Samuel T. Jerram, Alistair J.K. Williams, Ezio Bonifacio, Anette G. Ziegler, R. David Leslie, Action LADA consortium

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

17 Citations (Scopus)
272 Downloads (Pure)

Abstract

AIMS/HYPOTHESIS: Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy.

METHODS: Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96-585) GAD65 autoantibodies (t-GADA). Individuals' clinical phenotypes were analysed according to antibody binding patterns.

RESULTS: Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p < 0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p = 0.0005).

CONCLUSIONS/INTERPRETATION: In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.

Original languageEnglish
Pages (from-to)1644-1649
Number of pages6
JournalDiabetologia
Volume61
Issue number7
Early online date4 Apr 2018
DOIs
Publication statusPublished - 1 Jul 2018

Keywords

  • Adult-onset diabetes
  • Autoantibodies
  • Autoimmune
  • Clinical phenotype
  • GAD
  • LADA
  • N-terminally truncated GAD65
  • Patients
  • Type 1 diabetes

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