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Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
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2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 10, p. 3104-3110Article in journal (Refereed) Published
Abstract [en]

A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-gamma/interleukin-1 beta or IFN-alpha.

Place, publisher, year, edition, pages
2016. Vol. 65, no 10, p. 3104-3110
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-311223DOI: 10.2337/db16-0616ISI: 000388372900029PubMedID: 27422384OAI: oai:DiVA.org:uu-311223DiVA, id: diva2:1059592
Funder
Novo NordiskSwedish Research Council, K2011-65X-12219-15-6, K2015-54X-12219-19-4Åke Wiberg FoundationSwedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2016-12-22 Created: 2016-12-22 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: 2018-05-30

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