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Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes
AIMS/HYPOTHESIS: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects ca...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174109/ https://www.ncbi.nlm.nih.gov/pubmed/35501400 http://dx.doi.org/10.1007/s00125-022-05697-3 |
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author | Wyatt, Rebecca C. Hagopian, William A. Roep, Bart O. Patel, Kashyap A. Resnick, Brittany Dobbs, Rebecca Hudson, Michelle De Franco, Elisa Ellard, Sian Flanagan, Sarah E. Hattersley, Andrew T. Oram, Richard A. Johnson, Matthew B. |
author_facet | Wyatt, Rebecca C. Hagopian, William A. Roep, Bart O. Patel, Kashyap A. Resnick, Brittany Dobbs, Rebecca Hudson, Michelle De Franco, Elisa Ellard, Sian Flanagan, Sarah E. Hattersley, Andrew T. Oram, Richard A. Johnson, Matthew B. |
author_sort | Wyatt, Rebecca C. |
collection | PubMed |
description | AIMS/HYPOTHESIS: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM). METHODS: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39–2.9 months]; median age collected 4.6 months [IQR 1.8–27.6 months]; median diabetes duration 2 months [IQR 0.6–23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0–48.6 months]) for autoantibodies. RESULTS: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all). CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-022-05697-3. |
format | Online Article Text |
id | pubmed-9174109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-91741092022-06-09 Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes Wyatt, Rebecca C. Hagopian, William A. Roep, Bart O. Patel, Kashyap A. Resnick, Brittany Dobbs, Rebecca Hudson, Michelle De Franco, Elisa Ellard, Sian Flanagan, Sarah E. Hattersley, Andrew T. Oram, Richard A. Johnson, Matthew B. Diabetologia Short Communication AIMS/HYPOTHESIS: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM). METHODS: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39–2.9 months]; median age collected 4.6 months [IQR 1.8–27.6 months]; median diabetes duration 2 months [IQR 0.6–23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0–48.6 months]) for autoantibodies. RESULTS: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all). CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-022-05697-3. Springer Berlin Heidelberg 2022-04-30 2022 /pmc/articles/PMC9174109/ /pubmed/35501400 http://dx.doi.org/10.1007/s00125-022-05697-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Short Communication Wyatt, Rebecca C. Hagopian, William A. Roep, Bart O. Patel, Kashyap A. Resnick, Brittany Dobbs, Rebecca Hudson, Michelle De Franco, Elisa Ellard, Sian Flanagan, Sarah E. Hattersley, Andrew T. Oram, Richard A. Johnson, Matthew B. Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title | Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title_full | Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title_fullStr | Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title_full_unstemmed | Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title_short | Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
title_sort | congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes |
topic | Short Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174109/ https://www.ncbi.nlm.nih.gov/pubmed/35501400 http://dx.doi.org/10.1007/s00125-022-05697-3 |
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