Zinc Transporter 8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes

Abstract

OBJECTIVEZinc transporter 8 (ZnT8) is an islet β-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine the prevalence and role of antibodies to ZnT8 (ZnT8As) in adult-onset diabetes.RESEARCH DESIGN AND METHODSZnT8As were measured by a radioimmunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH2-terminal proteins in 193 patients with adult-onset autoimmune diabetes having antibodies to either GAD (GADAs) or IA-2 (IA-2As) and in 1,056 antibody-negative patients with type 2 diabetes from the Non Insulin Requiring Autoimmune Diabetes (NIRAD) study.RESULTSZnT8As-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8As-NH2 were rare. ZnT8As were associated with younger age and a high GADA titer. The use of GADAs, IA-2As, and ZnT8As in combination allowed a stratification of clinical phenotype, with younger age of onset of diabetes and characteristics of more severe insulin deficiency (higher fasting glucose and A1C, lower BMI, total cholesterol, and triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one, and no antibodies (all Ptrend < 0.001). Autoantibody titers, association with high-risk HLA genotypes, and prevalence of thyroid peroxidase antibodies followed the same trend (all P < 0.001).CONCLUSIONSZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes.

LADA and CARDS: A Prospective Study of Clinical Outcome in Established Adult-Onset Autoimmune Diabetes

“…Second, since GADA is not specific for autoimmune diabetes, a positive result could reflect an autoimmune tendency, independent of diabetes. Yet, in all the major studies of autoimmune diabetes, now amounting to many thousands of patients, those GADA-positive cases have a clinical phenotype different from that of the type 2 diabetic patients without GADA (15,22,24). Specifically, GADA-positive patients with adult-onset diabetes tend to have less metabolic syndrome and higher HbA 1c and are more likely to be on insulin therapy than GADA-negative patients with type 2 diabetesddifferences even apparent in patients with low-titer GADA.…”

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

“…Rapamycin was measured in whole blood using IMx sirolimus MEIA (Abbott Laboratories, Abbott Park, IL, USA). IA and GADA were determined by immunoprecipitation of recombinant antigens as previously described [20] and validated in the Diabetes Autoantibody Standardization Program (Laboratory 153) [21].…”

The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes

“…However, as many as 10% of new T1D patients may be negative for any of ICA, IAA, GADA or IA-2A. It has been suggested that the addition of ZnT8RA, ZnT8WA and ZnT8QA may improve the diagnostic sensitivity particularly in adults [20][21][22][23][24][25] The first aim of this study is to determine the diagnostic sensitivity of all three autoantibodies ZnT8RA, ZnT8WA and ZnT8QA and their relation to the other islet autoantibodies and HLA. Our second aim is to test if HLA DQ A1-B1 alleles, haplotypes or genotypes were associated with any of the ZnT8 autoantibodies.…”