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Shannon L. Kelleher - One of the best experts on this subject based on the ideXlab platform.
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essential role for Zinc Transporter 2 znt2 mediated Zinc transport in mammary gland development and function during lactation
Journal of Biological Chemistry, 2015Co-Authors: Sooyeon Lee, Samina Alam, Stephen R Hennigar, Keigo Nishida, Shannon L. KelleherAbstract:The Zinc Transporter ZnT2 (SLC30A2) imports Zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for Zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports Zinc into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation, and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat, and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated Zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk Zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women.
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essential role for Zinc Transporter 2 znt2 mediated Zinc transport in mammary gland development and function during lactation
Journal of Biological Chemistry, 2015Co-Authors: Sooyeon Lee, Samina Alam, Stephen R Hennigar, Keigo Nishida, Shannon L. KelleherAbstract:The Zinc Transporter ZnT2 (SLC30A2) imports Zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for Zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports Zinc into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation, and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat, and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated Zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk Zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women. Background: ZnT2 is expressed in non-secreting and secreting mammary epithelium; however, the physiological role is not understood. Results: ZnT2-null mice have impaired mammary expansion and compromised mammary differentiation and milk secretion during lactation. Conclusion: ZnT2-mediated Zinc transport is critical for mammary development and function during lactation. Significance: This study identifies novel consequences of ZnT2 function in the mammary gland.
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Zinc Transporter 2 znt2 variants are localized to distinct subcellular compartments and functionally transport Zinc
Biochemical Journal, 2009Co-Authors: Veronica Lopez, Shannon L. KelleherAbstract:ZnT2 (Zinc Transporter-2) expression is restricted to tissues with unique Zinc requirements such as mammary and prostate glands. We previously determined that ZnT2 plays a major role in Zinc export from mammary glands, as women with a mutation in the gene encoding ZnT2 (SLC30A2) had an approximately 75% reduction in milk Zinc concentration. Two distinct human ZnT2 isoforms (approximately 42 and 35 kDa) are predicted to result from alternative splicing of SLC30A2. We examined the localization and function of each ZnT2 isoform, in cells generated to express ZnT2-HA (haemagglutinin) fusion proteins. The 42 kDa isoform was localized primarily to the endosomal/secretory compartment and overexpression resulted in increased Zinc vesicularization. In contrast, the 35 kDa isoform is associated with the plasma membrane. Importantly, Zinc transport was higher in cells over-expressing each isoform, indicating that both proteins are functional. Endogenous expression of the secretory vesicle-associated ZnT2 isoform predominates in mammary cells and expression is higher in secreting cells, whereas the smaller isoform plays a minor role in Zinc export, directly reflecting the secretory function of the mammary gland. Together our data shed further light on the complex integration of cellular Zinc transport mechanisms, which may be facilitated by multiple isoforms of specific Zinc Transporters with unique cellular functions.
John C Hutton - One of the best experts on this subject based on the ideXlab platform.
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Genetic association of Zinc Transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases
Diabetologia, 2012Co-Authors: Joanna M. M. Howson, Janet M Wenzlau, John C Hutton, Ezio Bonifacio, S Krause, Helen E. Stevens, Deborah J. Smyth, Ag Ziegler, John A. Todd, Peter AchenbachAbstract:Aims/hypothesis Autoantibodies to Zinc Transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.
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Zinc Transporter-8 autoantibodies improve prediction of type 1 diabetes in relatives positive for the standard biochemical autoantibodies.
Diabetes care, 2012Co-Authors: David Boulware, Janet M Wenzlau, John C Hutton, Polly J. Bingley, Craig A. Beam, Carla J. Greenbaum, Jeffrey P. Krischer, Jay M. Sosenko, Jay S. SkylerAbstract:OBJECTIVE We assessed diabetes risk associated with Zinc Transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A). RESEARCH DESIGN AND METHODS For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives. RESULTS ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA + vs. 8 of 911 [0.8%] BAA − , P P + relatives with ZnT8A than ZnT8A − relatives (31 vs. 7%, P P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not ( P = 0.81 and 0.86, respectively). CONCLUSIONS In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.
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Diabetes Antibody Standardization Program: First Proficiency Evaluation of Assays for Autoantibodies to Zinc Transporter 8
Clinical chemistry, 2011Co-Authors: Vito Lampasona, Janet M Wenzlau, John C Hutton, Peter Achenbach, Alistair J K Williams, Michael Schlosser, Patricia W. Mueller, Participating LaboratoriesAbstract:BACKGROUND: Zinc Transporter 8 (ZnT8) is a recently identified major autoantigen in type 1 diabetes, and autoantibodies to ZnT8 (ZnT8A) are new markers for disease prediction and diagnosis. Here we report the results of the first international proficiency evaluation of ZnT8A assays by the Diabetes Antibody Standardization Program (DASP). METHODS: After a pilot workshop in 2007, an expanded ZnT8A workshop was held in 2009, with 26 participating laboratories from 13 countries submitting results of 63 different assays. ZnT8A levels were measured in coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls. Results were analyzed comparing area under the ROC curve (ROC-AUC), sensitivity adjusted to 95% specificity (AS95), concordance of sample ZnT8A positive or negative designation, and autoantibody levels. RESULTS: ZnT8A radio binding assays (RBAs) based on combined immunoprecipitation of the 2 most frequent ZnT8 COOH-terminal domain polymorphic variants showed a median ROC-AUC of 0.848 [interquartile range (IQR) 0.796–0.878] and a median AS95 of 70% (IQR 60%–72%). These RBAs were more sensitive than assays using as antigen either 1 ZnT8 variant only or chimeric constructs joining NH2- and COOH-terminal domains, assays based on immunoprecipitation and bioluminescent detection, or assays based on immunofluorescent staining of cells transfected with full-length antigen. CONCLUSIONS: The DASP workshop identified immunoprecipitation-based ZnT8A assays and antigen constructs that achieved both a high degree of sensitivity and specificity and were suitable for more widespread clinical application.
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Contribution of Antibodies Against IA-2β and Zinc Transporter 8 to Classification of Diabetes Diagnosed Under 40 Years of Age
Diabetes care, 2011Co-Authors: Ilse Vermeulen, Janet M Wenzlau, Vito Lampasona, Ilse Weets, M. Asanghanwa, Johannes B Ruige, Luc F. Van Gaal, Chantal Mathieu, Bart Keymeulen, John C HuttonAbstract:OBJECTIVE We investigated whether measuring autoantibodies against Zinc Transporter 8 (ZnT8A) and IA-2β (IA-2βA) may improve classification of new-onset type 1 diabetic patients based on detection of autoantibodies against insulin (IAA), GAD (GADA), and IA-2 (IA-2A). In addition, we studied the correlation of IA-2βA and ZnT8A with other biological and demographic variables. RESEARCH DESIGN AND METHODS Circulating autoantibodies were determined by liquid phase radiobinding assays from 761 healthy control subjects and 655 new-onset ( RESULTS At diagnosis, IA-2βA and ZnT8A prevalences were 41 and 58%, respectively. In IAA-negative, GADA-negative, and IA-2A–negative patients, one IA-2βA–positive and eleven ZnT8A-positive individuals were identified at the expense of eight and seven additional positive control subjects (1%), respectively, for each test. ZnT8A or IA-2βA screening increased ( P HLA-DQ8 and negatively with HLA-DQ2. ZnT8A could replace IAA for classification of patients above age 10 without loss of sensitivity or specificity. CONCLUSIONS ZnT8A, and to a lesser degree IA-2βA, may usefully complement GADA, IA-2A, and IAA for classifying insulin-treated diabetes under age 40 years.
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human type 1 diabetes is associated with t cell autoimmunity to Zinc Transporter 8
Journal of Immunology, 2011Co-Authors: Mylinh Dang, Janet M Wenzlau, John C Hutton, Jennifer Rockell, Rebecca Wagner, Peter A. Gottlieb, Howard W DavidsonAbstract:Recently we demonstrated that Zinc Transporter 8 (ZnT8) is a major target of autoantibodies in human type 1 diabetes (T1D). Because the molecules recognized by T1D autoantibodies are typically also targets of autoreactive T cells, we reasoned that this would likely be the case for ZnT8. To test this hypothesis, IFN-γ-producing T cells specific for ZnT8 in the peripheral blood of 35 patients with T1D (<6 mo after onset at blood draw) and 41 age-matched controls were assayed by ELISPOT using a library of 23 overlapping dipeptide pools covering the entire 369 aa primary sequence. Consistent with our hypothesis, patients showed significantly higher T cell reactivity than the matched controls, manifest in terms of the breadth of the overall response and the magnitude of responses to individual pools. Therefore, the median number of pools giving positive responses (stimulation index ≥ 3) in the control group was 1.0 (range, 0-7) compared with 6.0 (range, 1-20; p < 0.0001) for the patients. Similarly, the median stimulation index of positive responses in controls was 3.1 versus 5.0 in the patients (p < 0.0001). Individually, 7 of 23 pools showed significant disease association (p < 0.001), with several of the component peptides binding the disease associated HLA-DR3 (0301) and -DR4 (0401) molecules in vitro. We conclude that ZnT8 is also a major target of disease-associated autoreactive T cells in human T1D, and we suggest that reagents that target ZnT8-specific T cells could have therapeutic potential in preventing or arresting the progression of this disease.
Janet M Wenzlau - One of the best experts on this subject based on the ideXlab platform.
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Zinc Transporter 8 (ZnT8) and β cell function.
Trends in endocrinology and metabolism: TEM, 2014Co-Authors: Howard W Davidson, Janet M Wenzlau, Richard M. O'brienAbstract:Human pancreatic β cells have exceptionally high Zinc content. In β cells the highest Zinc concentration is in insulin secretory granules, from which it is cosecreted with the hormone. Uptake of Zinc into secretory granules is mainly mediated by Zinc Transporter 8 (ZnT8), the product of the SLC30A8 [solute carrier family 30 (Zinc Transporter), member 8] gene. The minor alleles of several single-nucleotide polymorphisms (SNPs) in SLC30A8 are associated with decreased risk of type 2 diabetes (T2D), but the precise mechanisms underlying the protective effects remain uncertain. In this article we review current knowledge of the role of ZnT8 in maintaining Zinc homeostasis in β cells, its role in glucose metabolism based on knockout mouse studies, and current theories regarding the link between ZnT8 function and T2D.
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Genetic association of Zinc Transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases
Diabetologia, 2012Co-Authors: Joanna M. M. Howson, Janet M Wenzlau, John C Hutton, Ezio Bonifacio, S Krause, Helen E. Stevens, Deborah J. Smyth, Ag Ziegler, John A. Todd, Peter AchenbachAbstract:Aims/hypothesis Autoantibodies to Zinc Transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.
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Zinc Transporter-8 autoantibodies improve prediction of type 1 diabetes in relatives positive for the standard biochemical autoantibodies.
Diabetes care, 2012Co-Authors: David Boulware, Janet M Wenzlau, John C Hutton, Polly J. Bingley, Craig A. Beam, Carla J. Greenbaum, Jeffrey P. Krischer, Jay M. Sosenko, Jay S. SkylerAbstract:OBJECTIVE We assessed diabetes risk associated with Zinc Transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A). RESEARCH DESIGN AND METHODS For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives. RESULTS ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA + vs. 8 of 911 [0.8%] BAA − , P P + relatives with ZnT8A than ZnT8A − relatives (31 vs. 7%, P P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not ( P = 0.81 and 0.86, respectively). CONCLUSIONS In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.
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Diabetes Antibody Standardization Program: First Proficiency Evaluation of Assays for Autoantibodies to Zinc Transporter 8
Clinical chemistry, 2011Co-Authors: Vito Lampasona, Janet M Wenzlau, John C Hutton, Peter Achenbach, Alistair J K Williams, Michael Schlosser, Patricia W. Mueller, Participating LaboratoriesAbstract:BACKGROUND: Zinc Transporter 8 (ZnT8) is a recently identified major autoantigen in type 1 diabetes, and autoantibodies to ZnT8 (ZnT8A) are new markers for disease prediction and diagnosis. Here we report the results of the first international proficiency evaluation of ZnT8A assays by the Diabetes Antibody Standardization Program (DASP). METHODS: After a pilot workshop in 2007, an expanded ZnT8A workshop was held in 2009, with 26 participating laboratories from 13 countries submitting results of 63 different assays. ZnT8A levels were measured in coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls. Results were analyzed comparing area under the ROC curve (ROC-AUC), sensitivity adjusted to 95% specificity (AS95), concordance of sample ZnT8A positive or negative designation, and autoantibody levels. RESULTS: ZnT8A radio binding assays (RBAs) based on combined immunoprecipitation of the 2 most frequent ZnT8 COOH-terminal domain polymorphic variants showed a median ROC-AUC of 0.848 [interquartile range (IQR) 0.796–0.878] and a median AS95 of 70% (IQR 60%–72%). These RBAs were more sensitive than assays using as antigen either 1 ZnT8 variant only or chimeric constructs joining NH2- and COOH-terminal domains, assays based on immunoprecipitation and bioluminescent detection, or assays based on immunofluorescent staining of cells transfected with full-length antigen. CONCLUSIONS: The DASP workshop identified immunoprecipitation-based ZnT8A assays and antigen constructs that achieved both a high degree of sensitivity and specificity and were suitable for more widespread clinical application.
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Contribution of Antibodies Against IA-2β and Zinc Transporter 8 to Classification of Diabetes Diagnosed Under 40 Years of Age
Diabetes care, 2011Co-Authors: Ilse Vermeulen, Janet M Wenzlau, Vito Lampasona, Ilse Weets, M. Asanghanwa, Johannes B Ruige, Luc F. Van Gaal, Chantal Mathieu, Bart Keymeulen, John C HuttonAbstract:OBJECTIVE We investigated whether measuring autoantibodies against Zinc Transporter 8 (ZnT8A) and IA-2β (IA-2βA) may improve classification of new-onset type 1 diabetic patients based on detection of autoantibodies against insulin (IAA), GAD (GADA), and IA-2 (IA-2A). In addition, we studied the correlation of IA-2βA and ZnT8A with other biological and demographic variables. RESEARCH DESIGN AND METHODS Circulating autoantibodies were determined by liquid phase radiobinding assays from 761 healthy control subjects and 655 new-onset ( RESULTS At diagnosis, IA-2βA and ZnT8A prevalences were 41 and 58%, respectively. In IAA-negative, GADA-negative, and IA-2A–negative patients, one IA-2βA–positive and eleven ZnT8A-positive individuals were identified at the expense of eight and seven additional positive control subjects (1%), respectively, for each test. ZnT8A or IA-2βA screening increased ( P HLA-DQ8 and negatively with HLA-DQ2. ZnT8A could replace IAA for classification of patients above age 10 without loss of sensitivity or specificity. CONCLUSIONS ZnT8A, and to a lesser degree IA-2βA, may usefully complement GADA, IA-2A, and IAA for classifying insulin-treated diabetes under age 40 years.
Howard W Davidson - One of the best experts on this subject based on the ideXlab platform.
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Zinc Transporter 8 (ZnT8) and β cell function.
Trends in endocrinology and metabolism: TEM, 2014Co-Authors: Howard W Davidson, Janet M Wenzlau, Richard M. O'brienAbstract:Human pancreatic β cells have exceptionally high Zinc content. In β cells the highest Zinc concentration is in insulin secretory granules, from which it is cosecreted with the hormone. Uptake of Zinc into secretory granules is mainly mediated by Zinc Transporter 8 (ZnT8), the product of the SLC30A8 [solute carrier family 30 (Zinc Transporter), member 8] gene. The minor alleles of several single-nucleotide polymorphisms (SNPs) in SLC30A8 are associated with decreased risk of type 2 diabetes (T2D), but the precise mechanisms underlying the protective effects remain uncertain. In this article we review current knowledge of the role of ZnT8 in maintaining Zinc homeostasis in β cells, its role in glucose metabolism based on knockout mouse studies, and current theories regarding the link between ZnT8 function and T2D.
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human type 1 diabetes is associated with t cell autoimmunity to Zinc Transporter 8
Journal of Immunology, 2011Co-Authors: Mylinh Dang, Janet M Wenzlau, John C Hutton, Jennifer Rockell, Rebecca Wagner, Peter A. Gottlieb, Howard W DavidsonAbstract:Recently we demonstrated that Zinc Transporter 8 (ZnT8) is a major target of autoantibodies in human type 1 diabetes (T1D). Because the molecules recognized by T1D autoantibodies are typically also targets of autoreactive T cells, we reasoned that this would likely be the case for ZnT8. To test this hypothesis, IFN-γ-producing T cells specific for ZnT8 in the peripheral blood of 35 patients with T1D (<6 mo after onset at blood draw) and 41 age-matched controls were assayed by ELISPOT using a library of 23 overlapping dipeptide pools covering the entire 369 aa primary sequence. Consistent with our hypothesis, patients showed significantly higher T cell reactivity than the matched controls, manifest in terms of the breadth of the overall response and the magnitude of responses to individual pools. Therefore, the median number of pools giving positive responses (stimulation index ≥ 3) in the control group was 1.0 (range, 0-7) compared with 6.0 (range, 1-20; p < 0.0001) for the patients. Similarly, the median stimulation index of positive responses in controls was 3.1 versus 5.0 in the patients (p < 0.0001). Individually, 7 of 23 pools showed significant disease association (p < 0.001), with several of the component peptides binding the disease associated HLA-DR3 (0301) and -DR4 (0401) molecules in vitro. We conclude that ZnT8 is also a major target of disease-associated autoreactive T cells in human T1D, and we suggest that reagents that target ZnT8-specific T cells could have therapeutic potential in preventing or arresting the progression of this disease.
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The diagnostic value of Zinc Transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese.
Diabetes metabolism research and reviews, 2010Co-Authors: Lin Yang, Howard W Davidson, Janet M Wenzlau, Gan Huang, Shuoming Luo, Jian Peng, Xiang Yan, Jian Lin, John C HuttonAbstract:Background Zinc Transporter-8 (ZnT8) was recently identified as a novel autoantigen in human type 1 diabetes (T1D). Autoantibody to ZnT8 (ZnT8A) were detected in up to 80% of new-onset T1D and 26% of T1D patients otherwise classified as negative on the basis of existing markers. Since no data of ZnT8A in Chinese has been reported, we aim to evaluate the utility of ZnT8A for diagnosis of autoimmune T1D in Chinese relative to other autoantibody markers.
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Kinetics of the post-onset decline in Zinc Transporter 8 autoantibodies in type 1 diabetic human subjects.
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Janet M Wenzlau, Thomas J. Gardner, Lisa M. Frisch, Howard W Davidson, Anette-g. Ziegler, George S Eisenbarth, Liping Yu, M. Walter, John C HuttonAbstract:Context: Zinc Transporter 8 (ZnT8) is a newly discovered islet autoantigen in human type 1A diabetes (T1D). Objective: The objective was to document changes in ZnT8 autoantibody (ZnT8A) titer and prevalence after onset of disease in relationship to 65 kDa glutamate decarboxylase antibody (GADA) and islet cell antigen antibody (IA2A). Design/Patients: Autoantibody radioimmunoprecipitation assays were performed on sera from three groups: 21 individuals monitored every 3 months from diagnosis for 2.5 yr; 61 individuals monitored at six monthly intervals for 5–12 yr; and a cross-sectional study of 424 patients with T1D of 20–57 yr duration. Circulating C-peptide was determined as an index of residual β-cell function. Results: ZnT8A titers declined exponentially from clinical onset of T1D with a t1/2 ranging from 26 to 530 wk, similar to C-peptide (23–300 wk). Life-table analysis of antibody prevalence to 12 yr indicated that ZnT8A measured with either Arg325 or Trp325 probes persisted for a shorter interval t...
Sooyeon Lee - One of the best experts on this subject based on the ideXlab platform.
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essential role for Zinc Transporter 2 znt2 mediated Zinc transport in mammary gland development and function during lactation
Journal of Biological Chemistry, 2015Co-Authors: Sooyeon Lee, Samina Alam, Stephen R Hennigar, Keigo Nishida, Shannon L. KelleherAbstract:The Zinc Transporter ZnT2 (SLC30A2) imports Zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for Zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports Zinc into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation, and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat, and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated Zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk Zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women.
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essential role for Zinc Transporter 2 znt2 mediated Zinc transport in mammary gland development and function during lactation
Journal of Biological Chemistry, 2015Co-Authors: Sooyeon Lee, Samina Alam, Stephen R Hennigar, Keigo Nishida, Shannon L. KelleherAbstract:The Zinc Transporter ZnT2 (SLC30A2) imports Zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for Zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports Zinc into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation, and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat, and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated Zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk Zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women. Background: ZnT2 is expressed in non-secreting and secreting mammary epithelium; however, the physiological role is not understood. Results: ZnT2-null mice have impaired mammary expansion and compromised mammary differentiation and milk secretion during lactation. Conclusion: ZnT2-mediated Zinc transport is critical for mammary development and function during lactation. Significance: This study identifies novel consequences of ZnT2 function in the mammary gland.
