Wenzlau, J. M. et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc. Natl Acad. Sci. USA 104, 17040-17045

Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, 1775 North Ursula Street, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(43):17040-5. DOI: 10.1073/pnas.0705894104
Source: PubMed


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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Available from: Jan Jensen, Oct 04, 2015
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    • "autoantigens. So far, five T1DM-specific autoantibodies have been identified: islet-cell antibodies; insulin autoantibodies; autoantibodies to glutamic acid decarboxylase; the tyrosine phosphatase-related insulinoma-associated 2 molecule; and zinc transporter 8 (Andersen et al., 2012; Knip et al., 2011; Lernmark and Larsson, 2013; Wenzlau et al., 2007; Ziegler et al., 2012). Human insulin differs only in three residues from bovine insulin (A8, A10 and B30; Yip et al., 1998). "
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    ABSTRACT: The objective of this study was to examine the possible binding of bovine insulin (BI) with bovine serum albumin (BSA) to form a new potential diabetogenic irreversible complex protein. Several preparations of BSA and BI were prepared. Both capillary electrophoresis and spectrophotometric analysis were undertaken to test the possibility of complexation between BI and BSA. HPLC was used to test whether the potential complex of BI and BSA is reversible or irreversible. The optimum deviation between the real and calculated absorbances was observed at a BI/BSA ratio of 2. Moreover, the migration time of BI decreased substantially with increasing ratio of BI to BSA until it became almost constant at equal molar ratio of BI/BSA. While the majority of the 2:1 BI-BSA sample detached during the HPLC analysis, which confirms the reversible character of BI-BSA binding, the HPLC chromatogram also emphasizes the formation of an irreversible complexation between the two proteins. This study provides evidence of the formation of reversible and irreversible new BI-BSA complexes under physiological conditions. This highlights the importance of examining the possible diabetogenicity of BI-BSA complex in genetically susceptible people. Copyright © 2013 John Wiley & Sons, Ltd.
    Biomedical Chromatography 03/2014; 28(3). DOI:10.1002/bmc.3050 · 1.72 Impact Factor
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    • "Zinc (Zn), which is essential for many cellular processes, has also been reported to play a potential role for second messenger in signal pathway linked with various physiological actions [5], [6]. Moreover, the imbalances in Zn homeostasis cause disease states including Alzheimer's disease [7], diabetes [8], [9], [10], cancer [11] and others [5], [12]. In breast cancer patients, the level of Zn has been found to be lower in serum than healthy subjects and elevated in malignant tissues [13], [14], [15], [16], whereas in liver, prostate and gallbladder cancers, the level of Zn in the malignant tissues has been found to be decreased [13], [14], [17], [18], [19]. "
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    ABSTRACT: The diabetes patients have been associated with an increased risk of mortality by breast cancer and there are difference between the breast cancer patients with diabetes, and their nondiabetic counterparts in the regimen choice and effects of breast cancer treatment. However, the pathophysiological relationships of diabetes and breast cancer have not yet been elucidated in detail. In this study, we investigate the breast cancer cell line, MCF-7 motility, which linked to invasion and metastasis, in high glucose level corresponding to hyperglycemia and the role of Zn and its transporter. We demonstrated the significant motility of MCF-7 cultured in hyperglycemic level (25 mM glucose) in comparison to normal physiological glucose level (5.5 mM glucose). The other hand, the osmotic control medium, 5.5 mM glucose with 19.5 mM mannitol or fructose had no effect on migratory, suggesting that high glucose level promotes the migration of MCF-7. Moreover, the activity of intracellular Zn(2+) uptake significantly increased in high glucose-treated cells in comparison to 5.5 mM glucose, and the mRNA expression of zinc transporters, ZIP6 and ZIP10, was upregulated in 25 mM glucose-treated cells. The deficiency of ZIP6 or ZIP10 and intracellular Zn(2+) significantly inhibited the high migration activity in 25 mM glucose medium, indicating that Zn(2+) transported via ZIP6 and ZIP10 play an essential role in the promotion of cell motility by high glucose stimulation. Zinc and its transporters, ZIP6 and ZIP10, are required for the motility stimulated with high glucose level. These findings provide the first evidence proposing the novel strategies for the diagnosis and therapy of breast cancer with hyperglycemia.
    PLoS ONE 02/2014; 9(2):e90136. DOI:10.1371/journal.pone.0090136 · 3.23 Impact Factor
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    • "Once helper T cells are activated, they will induce B cells to secrete autoantibodies to autoantigens expressed in the pancreatic beta cells. Autoantibodies to insulin(IAA), the tyrosine- phosphatase-like protein IA-2, the 65-KD form of glutamate decarboxylase (GAD65) and zinc transporter 8 (ZnT8) autoantibodies are routinely used in the evaluation of the autoimmune response, risk assessment of individuals and progression to type 1 diabetes [8]. However, indirect evidence against a pathogenic role for autoantibodies came from the decreased incidence of type 1 diabetes in offspring of diabetic mothers compared with diabetic fathers, despite transmission of maternal anti-islet autoantibodies [9]. "
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    ABSTRACT: Follicular helper T (Tfh) cells exert an important role in autoimmune diseases. Whether it might be involved in type 1 diabetes (T1D) is unknown. Our aim was to investigate the role of Tfh cells in patients with T1D and the effect of anti-CD20 monoclonal antibody (rituximab) on Tfh cells from T1D patients. Fifty-four patients with T1D and 37 healthy controls were enrolled in the current study. 20 of those patients were treated with rituximab. The frequencies of circulating CD4(+)CXCR5(+)ICOS(+)T cells were analyzed by flow cytometry. The serum autoantibodies were detected by radioligand assay. The levels of IL-21, IL-6 and BCL-6 were assessed using ELISA and/or real-time PCR. Increased frequencies of circulating Tfh cells together with enhanced expression of IL-21 were detected in patients. The correlation between the frequencies of circulating Tfh cells and the serum autoantibodies or C-peptide level was comfirmed. After rituximab therapy, follow-up analysis demonstrated that the frequencies of circulating Tfh cell and serum IA2A were decreased. The levels of IL-21, IL-6 and Bcl-6 mRNA were decreased after treatment. Furthermore, beta cell function in 10 of 20 patients was improved. These data indicate Tfh cells may participate in the T1D-relatede immune responses and B cells might play a role in the development of Tfh responses in the disease progression.
    PLoS ONE 11/2013; 8(11):e79858. DOI:10.1371/journal.pone.0079858 · 3.23 Impact Factor
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