Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Insulitis in human diabetes: a histological evaluation of donor pancreases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.ORCID iD: 0000-0002-8524-9547
Show others and affiliations
2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 2, p. 346-353Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis According to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when >= 15 CD45(+) cells are found within the parenchyma or in the islet-exocrine interface in >= 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals. Methods Insulitis was determined by examining CD45(+) cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3(+) cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA(1c) or autoantibody positivity were examined. Results Overall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had >= 15 CD3(+) cells in >= 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45(+) cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45(+) cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA(1c). Conclusions/interpretation The current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when >= 15 CD3(+) cells, not CD45(+) cells, are found in >= 3 islets.

Place, publisher, year, edition, pages
2017. Vol. 60, no 2, p. 346-353
Keywords [en]
HLA, Inflammation, Insulin secretion, Insulitis, Islets, Macrophages, Tcells, Type 1 diabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-315054DOI: 10.1007/s00125-016-4140-zISI: 000391359800016PubMedID: 27796420OAI: oai:DiVA.org:uu-315054DiVA, id: diva2:1079531
Funder
EU, FP7, Seventh Framework Programme, 261441 PEVNETNovo NordiskÅke Wiberg FoundationSwedish Diabetes AssociationAvailable from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-05-02Bibliographically approved
In thesis
1. Characterization of the Pancreas in Type 1 and Type 2 Diabetes
Open this publication in new window or tab >>Characterization of the Pancreas in Type 1 and Type 2 Diabetes
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is recognized by hyperglycaemia and polyuria. Complications, reduced quality of life and staggering health-care costs are all derived from the disease. Two subclasses of diabetes are Type 1 diabetes (T1D) and Type 2 diabetes (T2D). The beta cell mass is reduced in T1D, which is generally considered to be caused by an immune-mediated beta-cell destruction, but definitive evidence for this hypothesis remains absent. Development of insulin resistance and dysfunctional beta cells are commonly recognized as important factors that contribute to fulminant T2D. The literature that describes human T1D and T2D pancreata is sparse due to the limited number of specimens available for study. If more features of the respective pancreata are described, we might be able to elucidate the mechanisms involved in the pathoaetiology of the diseases.

Accordingly, in this thesis pancreatic biopsies obtained from subjects with T1D or T2D have been examined with the aim to provide a more comprehensive picture of the respective pancreata. Paper I reports that aggregates of leucocytes substantiated mostly by macrophages are present in several T2D pancreata. Furthermore, as 28% of the T2D pancreata met the consensus definition of insulitis developed for T1D, a redefinition of insulitis is proposed. In Paper II, the density of parasympathetic axons was found to be reduced in the exocrine compartment in recent-onset T1D subjects compared to non-diabetic and long-standing T1D subjects. However, no alteration was discovered in islet-associated parasympathetic axons. In Paper III, interferon-stimulated genes were found to be over-expressed in recent-onset T1D islets, but no inducer explaining this expression has been discovered. Paper IV shows that T2D islets exhibit a stress response on a transcriptional level, and expression of these genes were investigated in islets from subjects with elevated HbA1c levels but without a clinical T2D diagnosis.

In conclusion, this thesis explores several new areas of the pancreas in both T1D and T2D, and demonstrate several important findings that increase our knowledge on how diabetes develops.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1470
Keywords
Type 1 diabetes, Type 2 diabetes, HbA1c, interferon-stimulated genes, parasympathetic, axon, cellular stress, islets, exocrine, immunology, leucocytes, inflammation, human, pancreas
National Category
Medical and Health Sciences Endocrinology and Diabetes Immunology in the medical area Neurosciences Cell and Molecular Biology
Research subject
Endocrinology and Diabetology; Immunology; Pathology
Identifiers
urn:nbn:se:uu:diva-349795 (URN)978-91-513-0356-7 (ISBN)
Public defence
2018-08-24, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Child Diabetes FoundationSwedish Research Council, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wiberg FoundationMagnus Bergvall FoundationErnfors FoundationSwedish Diabetes Association
Available from: 2018-05-30 Created: 2018-05-02 Last updated: 2018-09-27

Open Access in DiVA

fulltext(1829 kB)126 downloads
File information
File name FULLTEXT01.pdfFile size 1829 kBChecksum SHA-512
7977b6544b7f606164894092232817bb4eec0e10bb9533352ad842bfe993f9a47d0fa97b32631718e7ace535133d749fc13c6bd94ac2dd1b5b21c197f97916a4
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Lundberg, MarcusSeiron, PeterIngvast, SofieKorsgren, OlleSkog, Oskar
By organisation
Clinical Immunology
In the same journal
Diabetologia
Endocrinology and Diabetes

Search outside of DiVA

GoogleGoogle Scholar
Total: 126 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 452 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf