Detection and characterization of ZnT8 autoantibodies could help to screen latent autoimmune diabetes in adult-onset patients with type 2 phenotype

Abstract

Autoantibodies to zinc transporter 8 (ZnT8A) constitute an additional marker of autoimmune diabetes, complementing those already used in diagnosis support. ZnT8A could also be found in latent autoimmune diabetes of adults (LADA). The aim of this study was to evaluate the prevalence of ZnT8A in adult-onset diabetic patients in Argentinian population. A total of 271 patients diagnosed for diabetes at mean age 53.4 ± 10.9, body mass index ≤ 30, without insulin treatment for the first year of disease, and initially classified as type 2 diabetic patients were tested for ZnT8A using cDNA plasmids encoding the C-terminal domains (aa 268–369) carrying 325Arg, 325Trp, and a dimeric cDNA construct carrying both 325Arg and 325Trp (ZnT8 Arg–Trp325). We also analyzed proinsulin autoantibodies (PAA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2 autoantibodies (IA-2A). A subset of 101 patients was followed during 6 years in order to analyze insulin requirement. Out of the 271 patients, 22.1% presented at least one humoral marker, 2.6% were PAA+, 12.5% were GADA+, 3.3% were IA-2A+, and 10.7% were ZnT8A+. Among the latter, 7.0% were ZnT8A–Arg325, 51.7% were ZnT8A–Trp325, and 62.1% were ZnT8A–Arg–Trp325. Furthermore, the prevalence of autoantibodies in the group of patients treated with insulin (n = 18) was 55.6%. These results demonstrated that a significant proportion of autoimmune adult-onset diabetic patients presented ZnT8A as the only humoral marker. Between them, the higher prevalence was for ZnT8A–Trp325. We suggest that screening for LADA patients, best performed with a minimal set of marker determination, must include at least the screening of GADA and ZnT8A–Arg–Trp325.

Keywords::

• Zinc transporter 8
• humoral immune response
• adult-onset diabetes mellitus
• diagnostic support
• ZnT8A prevalence

Acknowledgments

We are grateful to J. Hutton from the Barbara Davis Center of Childhood Diabetes, University of Colorado, Aurora, CO, USA, for the gift of cDNA plasmids encoding the COOH-terminal fragment (aa 268–369) of the ZnT8 aa 325-Arg allele, the ZnT8 aa 325-Trp allele, and a chimeric construct encoding both alleles in combination.

Declaration of interest: This work was supported in part by grants from FONCYT Programme of the Agency for Science and Technology Promotion (ANPCyT), National Research Council (CONICET), and the University of Buenos Aires, Buenos Aires, Argentina. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.