Zinc Transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes.

doi:10.2337/dc08-2305

Zinc Transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes.

NIRAD 4

Vito Lampasona, B.Sc.¹,²,
Antonio Petrone, PhD³,
Claudio Tiberti, MD³,
Marco Capizzi, MD³,
Marialuisa Spoletini, MD³,
Sergio di Pietro, MD⁵,
Marco Sondini, MD⁶,
Sara Bonicchio, BSc¹,
Francesco Giorgino, MD⁷,
Ezio Bonifacio, PhD⁸,
Emanuele Bosi, MD (bosi.emanuele{at}hsr.it)¹,⁹,
Raffaella Buzzetti, MD³ and
for the NIRAD Study Group

¹Diabetes Research Institute, and
²Center for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milan, Italy
³Dept. of Clinical Sciences, “Sapienza” University, Polo Pontino, Rome, Italy
⁴ Diagnostica e Ricerca San Raffaele, Milan, Italy
⁵Diabetes Unit, IRCCS INRCA, Rome, Italy
⁶Diabetes, San Michele Hospital, Cagliari, Italy
⁷Endocrinology & Metabolism, Bari University, Bari, Italy
⁸Center for Regenerative Therapies, Dresden University of Technology, Dresden, Germany
⁹San Raffaele Vita Salute University, Milan, Italy

Abstract

Objective: Zinc Transporter 8 (ZnT8) is an islet beta-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine prevalence and role of antibodies to ZnT8 (ZnT8A) in adult-onset diabetes.

Research design and methods: ZnT8A were measured by a radio immunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH₂-terminal proteins in 193 patients with adult onset autoimmune diabetes as having antibodies to either GAD (GADA) or IA-2 (IA-2A) and in 1056 antibody-negative patients with type 2 diabetes from the NIRAD study.

Results: ZnT8A-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8A-NH₂ were rare. ZnT8A were associated with younger age and high GADA titre. The use of GADA, IA-2A and ZnT8A in combination allowed a stratification of clinical phenotype, with younger age of onset and characteristics of more severe insulin deficiency (higher fasting glucose and HbA1c, lower Body Mass Index, total cholesterol, triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one and no antibodies (all P for trend <0.001). Autoantibody titres, association with high risk HLA genotypes and prevalence of thyroid peroxidase antibodies followed the same trend (all P<0.001).

Conclusions: ZnT8A are detectable in a proportion of adult-onset autoimmune diabetes and appear as a valuable marker to differentiate clinical phenotypes.