Long-term sustained autoimmune response to beta cell specific zinc transporter (ZnT8, W, R, Q) in young adult patients with preserved beta cell function at diagnosis of diabetes

Abstract

The aim of this study was to examine whether autoantibodies to: ZnT8-Tryptophan (ZnT8WA), ZnT8-Arginine (ZnT8RA) or ZnT8-Glutamine (ZnT8QA) correlated with C-peptide or other autoantibodies and to assess diagnostic sensitivity of ZnT8WRQA. Specimens from 270 newly diagnosed diabetic subjects (age 15–34 years) and after 5 years duration of disease were examined. Four linear regression models were used to dissect the importance of different factors from diagnosis for the respective difference of (logZnT8WA), (logZnT8RA) and (logZnT8QA); A) unadjusted model for: initial C-peptide, age, BMI, gender, clinical classification, ICA, GADA, IA-2A, (ZnT8WA/ZnT8RA/ZnT8QA); B) C-peptide corrected for clinical factors; C) C-peptide corrected for autoantibodies; D) C-peptide corrected for all factors. The least decrease of ZnT8WA was observed in patients with high initial C-peptide in all models A) p = 0.054; B) p = 0.021; C) p = 0.047 and D) p = 0.017. A less statistically significant decrease of ZnT8RA was observed in patients with high initial C-peptide in A) p = 0.038 and C) p = 0.047, but this finding was not confirmed in B or D. The decrease of ZnT8QA levels was not related to C-peptide in any model but correlated to age D) p = 0.049. Furthermore, patients with unclassifiable diabetes showed the least decrease in D) p = 0.035. ZnT8WA, ZnT8RA or ZnT8QA were identified as a single autoantibody in 3.8% (10/266) of patients, thereby increasing diagnostic sensitivity from 79.3% (211/266) to 83.1% (221/266). In conclusion, high initial C-peptide was the most important factor even after adjusting for other factors in patients positive for ZnT8WA or ZnT8RA to remain autoantibody positive 5 years after diagnosis.

Keywords::

• C-peptide
• Generalized Linear Regression Model
• glutamic acid decarboxylase autoantibodies
• islet antigen-2 autoantibodies
• islet cell antibodies

Acknowledgements

The Knut and Alice Wallenberg Foundation is acknowledged for a research grant contributing to this study. The baseline study from onset of diabetes and the first six years of disease with yearly blood sampling as well as the matched control study was funded by NIH grant DK 42 654 toÅke Lernmark, Malmö, Sweden. The authors wish to acknowledge the expert technical assistance of Birgitta Persson, Berit Persson and Ingrid Wigheden. Dr. Kristian Lynch, University of South Florida, Tampa, Florida, USA is thanked for advice on statistical calculations and evaluations. The present members of the DISS-study group are Hans Arnquist, Linköping, Jan Bolinder, Stockholm, Mona Landin-Olsson, Lund, Stina Lindmark, Umeå, Soffia Gudbjörnsdottir (President), Gothenburg and Lennarth Nyström, Umeå.

Declaration of interest: The authors declare no conflicts of interest. The authors are responsible for the content and the writing of this paper. This study was funded by The Crafoord Foundation, Lund, Sweden by a research grant (20080671) to CT.