| 1. |
- Granlund, Louise, et al.
(författare)
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Altered microvasculature in pancreatic islets from subjects with type 1 diabetes
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The transcriptome of different dissociated pancreatic islet cells has been described in enzymatically isolated islets in both health and disease. However, the isolation, culturing, and dissociation procedures likely affect the transcriptome profiles, distorting the biological conclusions. The aim of the current study was to characterize the cells of the islets of Langerhans from subjects with and without type 1 diabetes in a way that reflects the in vivo situation to the highest possible extent.Methods: Islets were excised using laser capture microdissection directly from frozen pancreatic tissue sections obtained from organ donors with (n = 7) and without (n = 8) type 1 diabetes. Transcriptome analysis of excised samples was performed using AmpliSeq. Consecutive pancreatic sections were used to estimate the proportion of beta-, alpha-, and delta cells using immunofluorescence and to examine the presence of CD31 positive endothelial regions using immunohistochemistry.Results: The proportion of beta cells in islets from subjects with type 1 diabetes was reduced to 0% according to both the histological and transcriptome data, and several alterations in the transcriptome were derived from the loss of beta cells. In total, 473 differentially expressed genes were found in the islets from subjects with type 1 diabetes. Functional enrichment analysis showed that several of the most upregulated gene sets were related to vasculature and angiogenesis, and histologically, vascular density was increased in subjects with type 1 diabetes. Downregulated in type 1 diabetes islets was the gene set epithelial mesenchymal transition.Conclusion: A number of transcriptional alterations are present in islets from subjects with type 1 diabetes. In particular, several gene sets related to vasculature and angiogenesis are upregulated and there is an increased vascular density, suggesting an altered microvasculature in islets from subjects with type 1 diabetes. By studying pancreatic islets extracted directly from snap-frozen pancreatic tissue, this study reflects the in vivo situation to a high degree and gives important insights into islet pathophysiology in type 1 diabetes.
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| 2. |
- Granlund, Louise, et al.
(författare)
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Histological and transcriptional characterization of the pancreatic acinar tissue in type 1 diabetes
- 2021
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Ingår i: BMJ Open Diabetes Research and Care. - : BMJ. - 2052-4897. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Despite a reduced function and volume of the exocrine pancreas in type 1 diabetes, the acinar cells remain understudied in type 1 diabetes research. The hypothesis of this study is that the acinar tissue is altered in subjects with type 1 diabetes compared with subjects without diabetes. Research design and methods The cell density, expression of digestive enzymes, and transcriptome of acinar tissue at varying distances from islets were analyzed using histology, immunostaining, and AmpliSeq RNA sequencing of laser capture microdissected tissue. Pancreases examined were from organ donors with or without type 1 diabetes. Results We demonstrate preserved acinar nuclei density and find no support of acinar atrophy in type 1 diabetes. Staining for digestive enzymes (amylase, lipase, and trypsin) demonstrated an evenly distributed expression in the exocrine parenchyma; although occasional amylase-negative regions appeared in tissue that had been formalin-fixed and paraffin-embedded, this phenomenon was not evident in frozen tissue. Gene set enrichment analysis of whole transcriptome data identified transcriptional alterations in type 1 diabetes that were present in the acinar tissue independent of the distance from islets. Among these, the two most enriched gene sets were Myc Targets V2 and Estrogen Response Early. Conclusion Taken together, these new data emphasize the involvement of the entire pancreas in type 1 diabetes pathology. The alteration of the gene sets Myc Targets V2 and Estrogen Response Early is a possible link to the increased incidence of pancreatic cancer in type 1 diabetes. © 2021 Authors.
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| 3. |
- Helker, Christian S M, et al.
(författare)
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A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.
- 2019
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 146:14
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Tidskriftsartikel (refereegranskat)abstract
- An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage, where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFβ signaling led to α-cell to β-cell transdifferentiation. HC toxin, another HDAC inhibitor, enhances β-cell function in primary mouse and human islets. Thus, using a whole organism screening strategy, this study identified new pdx1 expression modulators that can be used to influence different steps in pancreas and β-cell development.
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| 4. |
- Jonsson, Alexander, et al.
(författare)
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Protein Kinase R Is Constitutively Expressed in the Human Pancreas
- 2019
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Ingår i: Journal of Histochemistry & Cytochemistry. - : SAGE Publications. - 0022-1554 .- 1551-5044. ; 67:2, s. 99-105
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Tidskriftsartikel (refereegranskat)abstract
- Viral infection of the insulin-producing cells in the pancreas has been proposed in the etiology of type 1 diabetes. Protein kinase R (PKR) is a cytoplasmic protein activated through phosphorylation in response to cellular stress and particularly viral infection. As PKR expression in pancreatic beta-cells has been interpreted as a viral footprint, this cross-sectional study aimed at characterizing the PKR expression in non-diabetic human pancreases. PKR expression was evaluated in pancreas tissue from 16 non-diabetic organ donors, using immunohistochemistry, qPCR, and western blot. Immunohistochemistry and western blot showed readily detectable PKR expression in the pancreatic parenchyma. The qPCR detected PKR mRNA in both endocrine and exocrine samples, with a slightly higher expression in the islets. In conclusion, PKR is constitutively expressed in both endocrine and exocrine parts of the pancreas and its expression should not be interpreted as a viral footprint in pancreatic beta cells.
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| 5. |
- Jonsson, Alexander, et al.
(författare)
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Transcriptional profiles of human islet and exocrine endothelial cells in subjects with or without impaired glucose metabolism
- 2020
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Ingår i: Scientific Reports. - BERLIN GERMANY : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- In experimental studies, pancreatic islet microvasculature is essential for islet endocrine function and mass, and islet vascular morphology is altered in diabetic subjects. Even so, almost no information is available concerning human islet microvascular endothelial cell (MVEC) physiology and gene expression. In this study, islets and exocrine pancreatic tissue were acquired from organ donors with normoglycemia or impaired glucose metabolism (IGM) immediately after islet isolation. Following single-cell dissociation, primary islet- and exocrine MVECs were obtained through fluorescence-activated cell sorting (FACS) and transcriptional profiles were generated using AmpliSeq. Multiple gene sets involved in general vascular development and extracellular matrix remodeling were enriched in islet MVEC. In exocrine MVEC samples, multiple enriched gene sets that relate to biosynthesis and biomolecule catabolism were found. No statistically significant enrichment was found in gene sets related to autophagy or endoplasmic reticulum (ER) stress. Although ample differences were found between islet- and exocrine tissue endothelial cells, no differences could be observed between normoglycemic donors and donors with IGM at gene or gene set level. Our data is consistent with active angiogenesis and vascular remodeling in human islets and support the notion of ongoing endocrine pancreas tissue repair and regeneration even in the adult human.
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| 6. |
- Korsgren, Olle, et al.
(författare)
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Imagining a better future for all people with type 1 diabetes mellitus
- 2019
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Ingår i: Nature Reviews Endocrinology. - : Springer Science and Business Media LLC. - 1759-5029 .- 1759-5037. ; 15:11, s. 623-624
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- For a person with type 1 diabetes mellitus, lifelong insulin treatment is the only therapeutic option. However, increased blood levels of glucose are just a symptom of impaired beta-cell function. Approaching the centenary of the first insulin injection, broadening of international therapeutic guidelines to improve diagnostics, as well as monitor and preserve beta-cell function, is warranted.
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| 7. |
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| 8. |
- Kuric, Enida, et al.
(författare)
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No Evidence for Presence of Mucosal-Associated Invariant T Cells in the Insulitic Lesions in Patients Recently Diagnosed with Type 1 Diabetes
- 2018
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 188:8, s. 1744-1748
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize bacteria-infected cells and are thought to play a role in autoimmune diseases. Translocation of duodenal bacteria and viruses to the pancreas through the pancreatic duct has been hypothesized to initiate an innate inflammatory response that could contribute to the development of type 1 diabetes, a process that could involve MAIT cells. In this study, we used immunohistochemistry and quantitative PCR to search for evidence of MAIT cells in the insulitic lesions in the pancreas of human patients recently diagnosed with type 1 diabetes. Only a few scattered MAIT cells were found within the exocrine parenchyma in all pancreatic samples, but no MAIT cells were found in association to the islets. Also, only low gene expression levels of the MAIT T-cell receptor V alpha 7.2-3 alpha 33 were found in the pancreas of patients with type 1 diabetes, in similar Levels as that in nondiabetic organ donors used as control. The absence of MAIT cells shown in insulitic lesions in humans questions the direct cytotoxic role of these cells in beta-cell destruction.
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| 9. |
- Neiman, Daniel, et al.
(författare)
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Multiplexing DNA methylation markers to detect circulating cell-free DNA derived from human pancreatic β cells
- 2020
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:14
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that unmethylated insulin promoter fragments in plasma derive exclusively from β cells, reflect their recent demise, and can be used to assess β cell damage in type 1 diabetes. Herein we describe an ultrasensitive assay for detection of a β cell–specific DNA methylation signature, by simultaneous assessment of 6 DNA methylation markers, that identifies β cell DNA in mixtures containing as little as 0.03% β cell DNA (less than 1 β cell genome equivalent). Based on this assay, plasma from nondiabetic individuals (N = 218, aged 4–78 years) contained on average only 1 β cell genome equivalent/mL. As expected, cell-free DNA (cfDNA) from β cells was significantly elevated in islet transplant recipients shortly after transplantation. We also detected β cell cfDNA in a patient with KATP congenital hyperinsulinism, in which substantial β cell turnover is thought to occur. Strikingly, in contrast to previous reports, we observed no elevation of β cell–derived cfDNA in autoantibody-positive subjects at risk for type 1 diabetes (N = 32), individuals with recent-onset type 1 diabetes (<4 months, N = 92), or those with long-standing disease (>4 months, N = 38). We discuss the utility of sensitive β cell cfDNA analysis and potential explanations for the lack of a β cell cfDNA signal in type 1 diabetes.
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| 10. |
- Oikarinen, Sami, et al.
(författare)
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Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study
- 2021
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 64:11, s. 2491-2501
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24-35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported. Methods In the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals. Results All six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EVnegative in all individuals. Sequencing the 5' untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines. Conclusions/interpretation EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.
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| 11. |
- Seiron, Peter, et al.
(författare)
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Characterisation of the endocrine pancreas in type 1 diabetes : islet size is maintained but islet number is markedly reduced
- 2019
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Ingår i: The journal of pathology. Clinical research. - : Wiley. - 2056-4538. ; 5:4, s. 248-255
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Tidskriftsartikel (refereegranskat)abstract
- Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of similar to 65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.
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| 12. |
- Seiron, Peter, 1990-
(författare)
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Studies of the Pancreas: Implications for Type 1 Diabetes Aetiology
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is a disease of severe insulin deficiency through loss of β cells in the endocrine pancreas. The T1D dogma maintains that a precipitating event unleashes autoimmunity in at-risk individuals, often measured through autoantibodies against β cell antigens. This is followed by the death of β cells at the hands of autoreactive cytotoxic T cells. However, several findings have not found their place within this dogma; first, the immune cell infiltrate in islets is usually located outside the islets, and second, there is a pronounced impact on the exocrine pancreas with lower pancreatic weight and fibrosis surrounding the ducts. In this thesis, pancreata from human subjects without diabetes (ND) as well as with T1D or type 2 diabetes (T2D) have been examined in an attempt to clarify the aetiology of T1D.The consensus definition of insulitis (≥15 CD45+ cells per islet in ≥3 islets) was validated against ND pancreata. In paper I we show that this definition cannot sufficiently discriminate between the findings in T1D and T2D pancreata, due to an increase in exocrine infiltration in T2D, predominantly made up by macrophages. As exocrine infiltration is also a common finding in T1D, we propose a new definition. In paper II we found tissue resident memory T (TRM) cells in association to islets in both ND and T1D pancreata, and they made up a significant proportion of the insulitic lesion in T1D. Islets contain on average 60% β cells. In paper III we found that despite the seeming loss of this predominant cell type in the T1D islets, islet size remained the same. Instead, islet density was markedly reduced. The islets contained mainly α cells, some of which expressed PDX1, a transcription factor marker of β cells. In paper IV we examined pancreata from ND organ donors aged 1-81 years. For the first time, the islet transcriptome was analysed without prior enzymatic digestion of the tissue. We corroborate earlier findings of reduced cell cycle activity and increased senescence with increasing age, as well as present a hypothesis of how islet age might affect T1D.The findings in this thesis sprout an alternative hypothesis that disturbed establishment of β cells in early life, due to lower islet density and lower pancreatic weight, would lead to β cell stress as insulin demand increases with physical growth. However, as islets do not decrease in size, we suggest that the disappearance of β cells could be explained by transdifferentiation into glucagon-producing cells.
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| 13. |
- Seiron, Peter, et al.
(författare)
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Transcriptional analysis of islets of Langerhans from organ donors of different ages
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is impaired with increasing age. In this study, we aimed to determine whether aging induces specific transcriptional changes in human islets. Laser capture microdissection was used to extract pancreatic islet tissue from 37 deceased organ donors aged 1-81 years. The transcriptomes of the extracted islets were analysed using Ion AmpliSeq sequencing. 346 genes that co-vary significantly with age were found. There was an increased transcription of genes linked to senescence, and several aspects of the cell cycle machinery were downregulated with increasing age. We detected numerous genes not linked to aging in previous studies likely because earlier studies analysed islet cells isolated by enzymatic digestion which might affect the islet transcriptome. Among the novel genes demonstrated to correlate with age, we found an upregulation of SPP1 encoding osteopontin. In beta cells, osteopontin has been seen to be protective against both cytotoxicity and hyperglycaemia. In summary, we present a transcriptional profile of aging in human islets and identify genes that could affect disease course in diabetes.
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| 14. |
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| 15. |
- Skog, Oskar, Docent, PhD, 1981-, et al.
(författare)
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On the dynamics of the human endocrine pancreas and potential consequences for the development of type 1 diabetes
- 2020
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 57:503-511
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the human islet life span, and beta-cell neogenesis is generally considered rare in adults. However, based on available data on beta-cell proliferation, calculations can be made suggesting that the dynamics of the endocrine pancreas is considerable even during adulthood, with islet neogenesis and a sustained increase in size of already formed islets. Islet-associated hemorrhages, frequently observed in most mammals including humans, could account for a considerable loss of islet parenchyma balancing the constant beta-cell proliferation. Notably, in subjects with type 1 diabetes, periductal accumulation of leukocytes and fibrosis is frequently observed, findings that are likely to negatively affect islet neogenesis from endocrine progenitor cells present in the periductal area. Impaired neogenesis would disrupt the balance, result in loss of islet mass, and eventually lead to beta-cell deficiency and compromised glucose metabolism, with increased islet workload and blood perfusion of remaining islets. These changes would impose initiation of a vicious circle further increasing the frequency of vascular events and hemorrhages within remaining islets until the patient eventually loses all beta-cells and becomes c-peptide negative. © 2019, The Author(s).
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| 16. |
- Stenwall, Anton, et al.
(författare)
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Characterization of host defense molecules in the human pancreas
- 2019
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Ingår i: Islets. - : Informa UK Limited. - 1938-2014 .- 1938-2022. ; 11:4, s. 89-101
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota can play a role in pancreatitis and, likely, in the development of type 1 diabetes (T1D). Anti-microbial peptides and secretory proteins are important mediators of the innate immune response against bacteria but their expression in the human pancreas is not fully known. In this study, immunohistochemistry was used to analyze the expression of seven anti-microbial peptides (Defensin alpha 1, alpha 4, beta 1-4 and Cathelicidin) and two secretory proteins with known antimicrobial properties (REG3A and GP2) in pancreatic and duodenal biopsies from 10 non-diabetic organ donors and one organ donor that died at onset of T1D. Immunohistochemical data was compared with previously published whole-transcriptome data sets. Seven (Defensin alpha 1, beta 2, beta 3, alpha 4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (Defensin beta 1 and beta 4) were negative in all non-diabetic donors. Two molecules (Defensin alpha 1 and GP2) were restricted to the exocrine pancreas whereas two (Defensin beta 3, alpha 4) were only expressed in islet tissue. Cathelicidin, beta 2, and REG3A were expressed in both islets and exocrine tissue. The donor that died at onset of T1D had generally less positivity for the host defense molecules, but, notably, this pancreas was the only one where defensin beta 1 was found. Neither donor age, immune-cell infiltration, nor duodenal expression correlated to the pancreatic expression of host defense molecules. In conclusion, these findings could have important implications for the inflammatory processes in diabetes and pancreatitis as we find several host defense molecules expressed by the pancreatic tissue.
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| 17. |
- Stenwall, Anton
(författare)
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Transcriptional and morphological analysis of organ donor pancreata
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The diabetes disease panorama affects more than 400 million people world wide – a number projected to rise above 640 million in the next 20 years. Type 1 and type 2 diabetes are associated with adverse complications, resulting in severe morbidity and high healthcare costs exerting substantial strain on society. Type 1 diabetes results from the destruction of the insulin producing beta-cells, while type 2 diabetes is a multifactorial combination of a decreased ability of the beta cells to secrete sufficient insulin and a peripheral resistance to insulin-mediated glucose uptake. The cause of diabetes is unknown, as are the possibly sequential cellular events resulting in overt disease. In this thesis, organ-donor pancreata from donors with or without diabetes are analysed in order to deepen our understanding of the Islets of Langerhans, the beta cells and the pancreas. In Paper I, islets from a donor that died at onset of type 1 diabetes, showing morphological signs of hydropic degeneration are analyzed on a gene-expression level, and the results are compared to islets from a donor without diabetes. We find no signs of ongoing inflammation, apoptosis or ER stress. In Paper IIwe compare the expression levels of genes related to cellular stress, in islets from donors with type 2 diabetes and from donors with high pre-mortal HbA1c levels but without a diabetes diagnosis, to the expression levels in islets from donors with normal HbA1c levels. We report that islets from donors with type 2 diabetes show signs of cellular stress on a transcriptional level compared with islets from donors without diabetes. In Paper III we performed a transcriptional analysis of the islets from organ donors aged between 1 and 81 years in order to elucidate whether age induces specific changes in the islet transcriptome. We found 20 genes that co-varied with increasing age. In Paper IV,the pancreatic expression of host-defense molecules is characterized, and we report the expression of several host-defense molecules not previously described in the human pancreas. Together, these results deepen our understanding of the effects of ageing and prolonged exposure to high blood sugar levels on the islets, as well as our knowledge about the innate immunity of the human pancreas.
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| 18. |
- Tegehall, Angelica, et al.
(författare)
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A decisive bridge between innate immunity and the pathognomonic morphological characteristics of type 1 diabetes demonstrated by instillation of heat-inactivated bacteria in the pancreatic duct of rats
- 2022
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Ingår i: Acta Diabetologica. - : Springer Nature. - 0940-5429 .- 1432-5233. ; 59:8, s. 1011-1018
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Tidskriftsartikel (refereegranskat)abstract
- Aims Periductal inflammation and accumulation of granulocytes and monocytes in the periislet area and in the exocrine pancreas is observed within hours after instillation of heat-inactivated bacteria in the ductal compartment of the pancreas in healthy rats. The present investigation was undertaken to study how the acute inflammation developed over time. Methods Immunohistochemical evaluation of the immune response triggered by instillation of heat-inactivated bacteria in the ductal compartment in rats. Results After three weeks, the triggered inflammation had vanished and pancreases showed normal morphology. However, a distinct accumulation of both CD4+ and CD8+ T cells within and adjacent to affected islets was found in one-third of the rats instilled with heat-inactivated E. faecalis, mimicking the insulitis seen at onset of human T1D. As in T1D, this insulitis affected a minority of islets and only certain lobes of the pancreases. Notably, a fraction of the T cells expressed the CD103 antigen, mirroring the recently reported presence of tissue resident memory T cells in the insulitis in humans with recent onset T1D. Conclusions The results presented unravel a previously unknown interplay between innate and acquired immunity in the formation of immunopathological events indistinguishable from those described in humans with recent onset T1D.
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