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      Prevalence of diabetes and presence of autoantibodies against zinc transporter 8 and glutamic decarboxylase at diagnosis and at follow up of Graves’ disease

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          Abstract

          Purpose

          The aim of this work was to investigate, in patients with newly diagnosed Graves’ disease (GD), the frequency of islet autoantibodies including autoantibodies against Zink transporter 8 (ZnT8A), as well as to investigate the relation between thyroid autoantibodies, islet autoantibodies and diabetes both before GD diagnosis and at follow-up.

          Methods

          Blood samples from 278 patients with newly diagnosed GD were analyzed for autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA2-A), three variants of zinc transporter 8 (ZnT8A), thyroid peroxidase (TPOA) and the TSH receptor (TRAb). Information on other autoimmune diseases, as well as development of diabetes during follow up was gathered from patient’s medical journal.

          Results

          At GD diagnosis, 13.7% were positive for islet autoantibodies, with the majority being positive for GADA (8.7%) and ZnT8A (7.6%). TPOA were found positive in 71% and TRAb in 83%. No association was found between islet autoantibodies and thyroid autoantibodies or diabetes diagnosis during follow up. Positive association was found between islet autoantibodies and all forms of diabetes, diagnosed both before and after GD (OR: 2.5, CI: 1.1–6.8, p = 0.03) but not to other autoimmune diseases at GD diagnosis.

          Conclusions

          The incidence of GADA and ZnT8A in patients with GD is high and might indicate wide range endocrine autoimmunity, as well as risk for non-autoimmune diabetes rather than exclusively mark beta cell autoimmunity and type 1 diabetes.

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          Most cited references26

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

          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 beta 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 new-onset 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.
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            Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.

            The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.
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              Autoimmune polyendocrine syndromes.

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                Author and article information

                Contributors
                +46-40 33 19 85 , berglind.jonsdottir@gmail.com
                Journal
                Endocrine
                Endocrine
                Endocrine
                Springer US (New York )
                1355-008X
                1559-0100
                19 February 2019
                19 February 2019
                2019
                : 64
                : 1
                : 48-54
                Affiliations
                [1 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Endocrinology, , Lund University, ; SE-221 00 Lund, Sweden
                [2 ]ISNI 0000 0004 0623 9987, GRID grid.411843.b, Department of Clinical Sciences, , Skåne University Hospital, ; SE-205 02 Malmö, Sweden
                Author information
                http://orcid.org/0000-0003-4129-1767
                Article
                1852
                10.1007/s12020-019-01852-w
                6454080
                30783963
                e061a9ee-e01f-42f8-9044-181945d0fb8e
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 16 October 2018
                : 21 January 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100006738, Medicinska Fakulteten, Lunds Universitet;
                Award ID: 0
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100011077, Sk?nes universitetssjukhus;
                Award ID: .
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Endocrinology & Diabetes
                islet autoantibodies,graves’ disease,thyroid autoantibodies,diabetes

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