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Characterization of the Pancreas in Type 1 and Type 2 Diabetes
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.ORCID-id: 0000-0001-7916-2237
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 50
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1470
Nyckelord [en]
Type 1 diabetes, Type 2 diabetes, HbA1c, interferon-stimulated genes, parasympathetic, axon, cellular stress, islets, exocrine, immunology, leucocytes, inflammation, human, pancreas
Nationell ämneskategori
Medicin och hälsovetenskap Endokrinologi och diabetes Immunologi inom det medicinska området Neurovetenskaper Cell- och molekylärbiologi
Forskningsämne
Endokrinologi och Diabetologi; Immunologi; Patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-349795ISBN: 978-91-513-0356-7 (tryckt)OAI: oai:DiVA.org:uu-349795DiVA, id: diva2:1203232
Disputation
2018-08-24, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
BarndiabetesfondenVetenskapsrådet, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wibergs StiftelseMagnus Bergvalls StiftelseStiftelsen familjen Ernfors fondDiabetesförbundetTillgänglig från: 2018-05-30 Skapad: 2018-05-02 Senast uppdaterad: 2018-09-27
Delarbeten
1. Insulitis in human diabetes: a histological evaluation of donor pancreases
Öppna denna publikation i ny flik eller fönster >>Insulitis in human diabetes: a histological evaluation of donor pancreases
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2017 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr 2, s. 346-353Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
HLA, Inflammation, Insulin secretion, Insulitis, Islets, Macrophages, Tcells, Type 1 diabetes, Type 2 diabetes
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-315054 (URN)10.1007/s00125-016-4140-z (DOI)000391359800016 ()27796420 (PubMedID)
Forskningsfinansiär
EU, FP7, Sjunde ramprogrammet, 261441 PEVNETNovo NordiskÅke Wibergs StiftelseDiabetesförbundet
Tillgänglig från: 2017-03-08 Skapad: 2017-03-08 Senast uppdaterad: 2018-05-02Bibliografiskt granskad
2. The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes
Öppna denna publikation i ny flik eller fönster >>The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes
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2017 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 6, artikel-id e0179911Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes.

Ort, förlag, år, upplaga, sidor
PUBLIC LIBRARY SCIENCE, 2017
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-330731 (URN)10.1371/journal.pone.0179911 (DOI)000404043100049 ()28628651 (PubMedID)
Forskningsfinansiär
Novo NordiskEU, FP7, Sjunde ramprogrammet, 261441 PEVNETBarndiabetesfondenVetenskapsrådet, 65X-12219-15-6, K2015-54X-12219-19-4, 2008-4216, 521-2012-2119DiabetesförbundetMagnus Bergvalls Stiftelse
Tillgänglig från: 2017-10-10 Skapad: 2017-10-10 Senast uppdaterad: 2018-05-02Bibliografiskt granskad
3. Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes
Öppna denna publikation i ny flik eller fönster >>Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes
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2016 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 10, s. 3104-3110Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-311223 (URN)10.2337/db16-0616 (DOI)000388372900029 ()27422384 (PubMedID)
Forskningsfinansiär
Novo NordiskVetenskapsrådet, K2011-65X-12219-15-6, K2015-54X-12219-19-4Åke Wibergs StiftelseDiabetesförbundetBarndiabetesfondenEXODIAB - Excellence of Diabetes Research in Sweden
Tillgänglig från: 2016-12-22 Skapad: 2016-12-22 Senast uppdaterad: 2018-05-02Bibliografiskt granskad
4. Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
Öppna denna publikation i ny flik eller fönster >>Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
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2018 (Engelska)Ingår i: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 10, nr 2, s. 69-79Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
HbA1c, laser capture, transcriptome, type 2 diabetes
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-342882 (URN)10.1080/19382014.2018.1433980 (DOI)000428814700003 ()29446696 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wibergs StiftelseTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvalls StiftelseStiftelsen familjen Ernfors fondBarndiabetesfondenDiabetesförbundet
Tillgänglig från: 2018-02-23 Skapad: 2018-02-23 Senast uppdaterad: 2018-08-30Bibliografiskt granskad

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