Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis
dc.contributor.author | Leete, P | |
dc.contributor.author | Oram, RA | |
dc.contributor.author | McDonald, TJ | |
dc.contributor.author | Shields, BM | |
dc.contributor.author | Ziller, C | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Richardson, SJ | |
dc.contributor.author | Morgan, NG | |
dc.date.accessioned | 2020-03-11T15:50:35Z | |
dc.date.issued | 2020-03-15 | |
dc.description.abstract | Aims/hypothesis: It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue. Methods: Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7-12 years and >13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges. Results: Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at >13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group >13 years(p<0.0001). Among all individuals (including children in the middle [7-12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at >13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3–151; p<0.0001) while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged >13 years (0.18, IQR 0.10–0.31) vs 0.01, IQR 0.009, 0.10 pmol/l; p<0.0001). Conclusions/interpretation: Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression. | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | JDRF | en_GB |
dc.description.sponsorship | National Institute for Health Research (NIHR) | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.identifier.citation | Vol. 63, pp. 1258–1267 | en_GB |
dc.identifier.doi | 10.1007/s00125-020-05115-6 | |
dc.identifier.grantnumber | 16/0005480 | en_GB |
dc.identifier.grantnumber | 5-CDA-2014-221-A-N | en_GB |
dc.identifier.grantnumber | WT098395/Z/12/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/120220 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer Verlag | en_GB |
dc.rights | © The Author(s) 2020. 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/. | |
dc.subject | CD8+ cells | en_GB |
dc.subject | CD20+ cells | en_GB |
dc.subject | C-peptide | en_GB |
dc.subject | immunophenotype | en_GB |
dc.subject | insulitis | en_GB |
dc.subject | islets of Langerhans | en_GB |
dc.title | Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2020-03-11T15:50:35Z | |
dc.identifier.issn | 0012-186X | |
dc.description | This is the final version. Available on open access from Springer via the DOI in this record. | en_GB |
dc.description | Data Availability: The datasets generated during and/or analysed during the current study are available from the corresponding authors on reasonable request. | en_GB |
dc.identifier.journal | Diabetologia | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2020-02-03 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2020-02-03 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2020-03-11T13:40:46Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2020-03-17T16:25:40Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © The Author(s) 2020. 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/.