The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes

Abstract

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic ␤ cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using newonset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60 -80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.autoantibody ͉ zinc transport ͉ prediabetes

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…In our study, ZnT8A were only detected with the high‐risk conversion pattern. Similar to prospective studies of relatives and patients 43, 44, ZnT8A were the last autoantibodies to become positive on follow‐up, positivity was short lived, and their appearance was much closer to the development of diabetes symptoms (0.66 years vs. 2.27 and 3.63 years for GADA and IA‐2A, respectively). Thus, ZnT8A positivity raises the concern that diabetes recurrence may occur in the near future.…”

Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients

“…of four constructs used in this study. Numbers correspond to the amino acid residues of the ZnT8 published sequence [4,6]. A hinge sequence of CW-CR construct is derived from the human IgG heavy chain.…”

“…Recently, the cation efflux transporter zinc transporter 8 (ZnT8) has been identified as a novel target autoantigen in patients with type 1 diabetes [4]. Zinc transporters are multipass transmembrane proteins that function in the transport of zinc out of the cytoplasm or into vesicles [5].…”

“…Zinc transporters are multipass transmembrane proteins that function in the transport of zinc out of the cytoplasm or into vesicles [5]. ZnT8 is specifically expressed in the pancreatic β-cells and plays a major role in insulin maturation [4,6]. Previous studies have reported that autoantibodies to ZnT8 (ZnT8A) were identified in more than 60% of young patients with type 1 diabetes and the combined measurement of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), and protein tyrosine phosphatase IA-2 (IA-2A), and ZnT8A raised autoimmunity detection rates to 98% at disease onset in Caucasoid populations [4].…”

“…ZnT8 is specifically expressed in the pancreatic β-cells and plays a major role in insulin maturation [4,6]. Previous studies have reported that autoantibodies to ZnT8 (ZnT8A) were identified in more than 60% of young patients with type 1 diabetes and the combined measurement of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), and protein tyrosine phosphatase IA-2 (IA-2A), and ZnT8A raised autoimmunity detection rates to 98% at disease onset in Caucasoid populations [4]. However, the relevance of ZnT8A in patients with adult-onset type 1 diabetes, especially in cases of slow-onset and fulminant type 1 diabetes, has not been clarified.…”