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Immunopathology of the Pancreas in Type 1 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.ORCID iD: 0000-0002-4563-4432
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) results from a loss of functional insulin-producing pancreatic beta cells. The etiology of T1D is poorly understood, but the detection of infiltrating inflammatory cells in the pancreas and circulating autoantibodies has led to the common notion that an autoimmune process plays a central role in the pathogenesis of the disease.

The aim of this doctoral thesis was to assess various aspects of the immunopathology of type 1 diabetes. To this purpose, studies have been conducted on pancreatic material from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection, the Nordic Network for Islet Transplantation, and the Diabetes Virus Detection (DiViD) study.

Paper I is a study on pancreatic tissue from organ donors with varying duration of T1D as well as non-diabetic donors and subjects with other types of diabetes, in which persistent expression of glucose transporters was shown on the beta cell membrane despite several years of T1D. Glucose transporter 1 was also confirmed as the predominant glucose transporter on human pancreatic islets. In paper II, we report on signs of inflammation in the exocrine but not in the endocrine pancreas in non-diabetic organ donors with diabetes-related autoantibodies, suggesting that diabetes-associated autoantibodies can occur in response to unspecific pancreatic lesions.

Paper III aimed to characterize the T cell-infiltration of pancreatic islets in material from recent-onset T1D patients. Insulitis was shown in all subjects, but with distinct differences in expression analysis of T- and B cell activation to cell-mediated allorejected kidney transplant. Also Paper IV was conducted on material from recent-onset cases and showed increased islet glucagon content, in combination with a reduced number of islets but sustained mean islet size.

Together, these results provide expansion of our knowledge of the immunopathology in T1D, and will hopefully assist in bringing us towards a deeper understanding of T1D aetiology and eventually an effective cure.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1263
Keyword [en]
Type 1 diabetes, glucagon, T cells, autoantibodies, glucose transporters, islets of Langerhans, pancreas
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
URN: urn:nbn:se:uu:diva-304621ISBN: 978-91-554-9711-8OAI: oai:DiVA.org:uu-304621DiVA: diva2:1033235
Public defence
2016-11-24, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2016-11-01 Created: 2016-10-06 Last updated: 2016-11-02
List of papers
1. Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals
Open this publication in new window or tab >>Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals
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2011 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 8, 746-754 p.Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

BACKGROUND: Recent reports have established the notion that many patients with longstanding type 1 diabetes (T1D) possess a remnant population of insulin-producing beta cells. It remains questionable, however, whether these surviving cells can physiologically sense and respond to glucose stimuli.

METHODS: Frozen pancreatic sections from non-diabetic donors (n=8), type 2 diabetic patients (n=4), islet autoantibody-positive non-diabetic patients (n=3), type 1 diabetic patients (n=10) and one case of gestational diabetes were obtained via the network for Pancreatic Organ Donors. All longstanding T1D samples were selected based on the detection of insulin-producing beta cells in the pancreas by immunohistochemistry. RNA was isolated from all sections followed by cDNA preparation and quantitative real-time polymerase chain reaction for insulin, glucose transporter 1 (GLUT1), GLUT2 and GLUT3. Finally, immunofluorescent staining was performed on consecutive sections for all four of these markers and a comparison was made between the expression of GLUT2 in humans versus NOD mice.

RESULTS: In contrast to islets from the most widely used T1D model, the NOD mouse, human islets predominantly express GLUT1 and, to a much lesser extent, GLUT3 on their surface instead of GLUT2. Relative expression levels of these receptors do not significantly change in the context of the various (pre-)diabetic conditions studied. Moreover, in both species preservation of GLUT expression was observed even under conditions of substantial leucocyte infiltration or decades of T1D duration.

CONCLUSIONS: These data suggest that despite being subjected to multiple years of physiological stress, the remaining beta-cell population in longstanding T1D patients retains a capacity to sense glucose via its GLUTs.

Keyword
glucose transporters; type 1 diabetes; beta cells; pancreas; islets of Langerhans; insulin
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-304613 (URN)10.1002/dmrr.1246 (DOI)000300108000005 ()22069254 (PubMedID)
Available from: 2016-10-06 Created: 2016-10-06 Last updated: 2016-10-06Bibliographically approved
2. Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies
Open this publication in new window or tab >>Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies
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2015 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 182, no 3, 278-288 p.Article in journal (Refereed) Published
Abstract [en]

In this study we aim to describe the characteristics of non-diabetic organ donors with circulating diabetes-associated autoantibodies collected within the Nordic Network for Islet Transplantation. One thousand and thirty organ donors have been screened in Uppsala for antibodies against glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A). The 32 non-diabetic donors that tested positive for GADA (33% of all non-diabetic donors) were studied in more detail, together with 32 matched controls. Mean age among the autoantibody-positive donors was 526 (range 21-74), family history of type 1 diabetes (T1D) was unknown, and no donor was genetically predisposed for T1D regarding the human leucocyte antigen (HLA) locus. Subjects were analysed for islet cell antibodies (ICA), insulin autoantibodies (IAA) and zinc transporter 8 antibodies (ZnT8A), and pancreas morphology and clinical data were examined. Eight non-diabetic donors tested positive for two antibodies and one donor tested positive for four antibodies. No insulitis or other signs of a diabetic process were found in any of the donors. While inflammatory cells were present in all donors, subjects with high GADA titres had significantly higher CD45 cell numbers in exocrine tissue than controls. The extent of fibrosis was more pronounced in autoantibody-positive donors, even in subjects with lower GADA titres. Notably, it is possible that events not related directly to T1D (e.g. subclinical pancreatitis) may induce autoantibodies in some cases.

Keyword
autoantibodies, exocrine pancreas, fibrosis, inflammation, type 1 diabetes
National Category
Immunology in the medical area Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-268390 (URN)10.1111/cei.12698 (DOI)000364235000005 ()26313035 (PubMedID)
Funder
Swedish Research Council, 65X-12219-15-6Swedish Research Council, K2015-54X-12219-19-4EU, FP7, Seventh Framework Programme, PEVNET 261441Novo NordiskSwedish Diabetes AssociationSwedish Child Diabetes Foundation
Available from: 2015-12-09 Created: 2015-12-04 Last updated: 2016-10-06Bibliographically approved
3. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes
Open this publication in new window or tab >>Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 3, 492-501 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood.

Methods

In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3+ T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors.

Results

All six patients fulfilled the criteria for insulitis (5–58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61–83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro.

Conclusions/interpretation

Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

Keyword
Gene expression; Inflammation; Insulin; Insulitis; Pancreas; T cells; Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-274977 (URN)10.1007/s00125-015-3820-4 (DOI)000377302900012 ()26602422 (PubMedID)
Funder
Novo NordiskSwedish Child Diabetes FoundationSwedish Diabetes Association
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-27 Created: 2016-01-27 Last updated: 2016-10-06Bibliographically approved
4. Increased glucagon content in the endocrine pancreas in recent onset type 1 diabetes. Results from the DiViD study.
Open this publication in new window or tab >>Increased glucagon content in the endocrine pancreas in recent onset type 1 diabetes. Results from the DiViD study.
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(English)Article in journal (Refereed) Submitted
National Category
Clinical Laboratory Medicine
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-304618 (URN)
Available from: 2016-10-06 Created: 2016-10-06 Last updated: 2016-10-06

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