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Diabetologia. 2018 Jul;61(7):1644-1649. doi: 10.1007/s00125-018-4605-3. Epub 2018 Apr 4.

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

Author information

1
Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Munich-Neuherberg, Germany. peter.achenbach@helmholtz-muenchen.de.
2
Forschergruppe Diabetes, Technische Universität München, at Klinikum rechts der Isar, Munich, Germany. peter.achenbach@helmholtz-muenchen.de.
3
German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany. peter.achenbach@helmholtz-muenchen.de.
4
Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. peter.achenbach@helmholtz-muenchen.de.
5
Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
6
Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Munich-Neuherberg, Germany.
7
Forschergruppe Diabetes, Technische Universität München, at Klinikum rechts der Isar, Munich, Germany.
8
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
9
Diabetes and Metabolism, School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, UK.
10
Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
11
DFG Research Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
12
Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Technische Universität Dresden, Dresden, Germany.
13
German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.
14
Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK. r.d.g.leslie@qmul.ac.uk.

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.

KEYWORDS:

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

PMID:
29619531
PMCID:
PMC6445455
DOI:
10.1007/s00125-018-4605-3
[Indexed for MEDLINE]
Free PMC Article

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