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dc.contributor.authorJohnson, M. B.
dc.contributor.authorPatel, Kashyap
dc.contributor.authorDe Franco, Elisa
dc.contributor.authorMcDonald, Timothy J.
dc.contributor.authorHudson, Michelle
dc.contributor.authorHammersley, S.
dc.contributor.authorDobbs, Rebecca
dc.contributor.authorEllard, Sian
dc.contributor.authorFlanagan, Sarah
dc.contributor.authorHattersley, Andrew T.
dc.contributor.authorOram, Richard A.
dc.date.accessioned2021-05-18T08:37:14Z
dc.date.available2021-05-18T08:37:14Z
dc.date.issued2020-12
dc.identifier.citationJohnson MB et al. Type 1 diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta cells. Diabetologia. 2020 Dec;63(12):2605-2615. doi: 10.1007/s00125-020-05276-4. Epub 2020 Oct 8.en_US
dc.identifier.pmid33029656
dc.identifier.doi10.1007/s00125-020-05276-4
dc.identifier.urihttps://rde.dspace-express.com/handle/11287/621717
dc.description.abstractAims/hypothesis: Diabetes diagnosed at <6 months of age is usually monogenic. However, 10-15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages. Methods: We studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6-24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features. Results: We found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6-24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score -0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score -1.98). Conclusions/interpretation: We provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age. Graphical abstract.en_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.urlhttps://doi.org/10.1007/s00125-020-05276-4en_US
dc.rights# The Author(s) 2020 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/.en_US
dc.rightsCC0 1.0 Universal*
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/*
dc.subjectAutoimmunityen_US
dc.subjectGenetic risk scoreen_US
dc.subjectNeonatal diabetesen_US
dc.subjectType 1 diabetesen_US
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen_US
dc.titleType 1 diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta cellsen_US
dc.typeJournal Articleen_US
dc.identifier.journalDiabetologiaen_US
dc.identifier.pmcidPMC7641942
dc.description.noteThis article is available to RD&E staff via NHS OpenAthens (subject to any publisher embargo). Click on the Publisher URL, and log in with NHS OpenAthens if prompted.en_US
dc.description.fundingRAO is a Diabetes UK Harry Keen Fellow (16/0005529). This work was supported by a Wellcome Trust Senior Investigator Award to SE and ATH (grant no. 098395/Z/12/Z). ATH is a National Institute for Health Research (NIHR) senior investigator. MBJ is the recipient of an Exeter Diabetes Centre of Excellence Independent Fellowship funded by Research England’s Expanding Excellence in England (E3) fund. EDF is a Diabetes UK R.D. Lawrence Fellow (19/005971). SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). TJM is funded by an NIHR HEE Senior Lecturer Fellowship. TIMT is supported by Diabetes UK (DUK-15/0005232) and the Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D049G-2018PG-T1D049). Additional support came from the Leona M. and Harry B. Helmsley Charitable Trust's Breakthrough Initiative, the Diabetes Research and Wellness Foundation, University of Exeter and the NIHR Exeter Clinical Research Facility. The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School, College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Careen_US
dc.type.versionPublisheden_US
dc.description.admin-notepublished version, accepted version (12 month embargo)en_US


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# The Author(s) 2020
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/.
Except where otherwise noted, this item's license is described as # The Author(s) 2020 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/.