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Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
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
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2018 (English)In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 10, no 2, p. 69-79Article in journal (Refereed) Published
Abstract [en]

It is currently unknown how the islet transcriptional pattern changes as glucose metabolism deteriorates and progresses to fulminant type 2 diabetes (T2D). In this study, we hypothesized that islets from donors with elevated HbA1c levels, but not yet diagnosed with T2D, would show signs of cell stress on a transcriptional level. Laser capture microdissection and qPCR arrays including 330 genes related to mitochondria, oxidative stress, or the unfolded protein response were used to extract and analyze islets from organ donors with HbA1c <5.5% (37 mmol/mol), elevated HbA1c (6.0-6.5% (42-48 mmol/mol)), high HbA1c (>6.5% (48 mmol/mol)) or established T2D. Principal component analysis and hierarchical clustering based on the expression of all 330 genes displayed no obvious separation of the four different donor groups, indicating that the inter-donor variations were larger than the differences between groups. However, 44 genes were differentially expressed (P < 0.05, false discovery rate <30%) between islets from donors with HbA1c <5.5% (37 mmol/mol) compared with islets from T2D subjects. Twelve genes were differentially expressed compared to control islets in both donors with established T2D and donors with elevated HbA1c (6.0-6.5% (42-48 mmol/mol)). Overexpressed genes were related mainly to the unfolded protein response, whereas underexpressed genes were related to mitochondria. Our data on transcriptional changes in human islets retrieved by LCM from high-quality biopsies, as pre-diabetes progresses to established T2D, increase our understanding on how islet stress contributes to the disease development.

Place, publisher, year, edition, pages
2018. Vol. 10, no 2, p. 69-79
Keywords [en]
HbA1c, laser capture, transcriptome, type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-342882DOI: 10.1080/19382014.2018.1433980ISI: 000428814700003PubMedID: 29446696OAI: oai:DiVA.org:uu-342882DiVA, id: diva2:1185325
Funder
Swedish Research Council, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wiberg FoundationTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvall FoundationErnfors FoundationSwedish Child Diabetes FoundationSwedish Diabetes AssociationAvailable from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-04Bibliographically 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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Lundberg, MarcusStenwall, Per-AntonTegehall, AngelicaKorsgren, OlleSkog, Oskar

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