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Skog, O. & Korsgren, O. (2018). Aetiology of type 1 diabetes: Physiological growth in children affects disease progression. Diabetes, obesity and metabolism, 20(4), 775-785
Open this publication in new window or tab >>Aetiology of type 1 diabetes: Physiological growth in children affects disease progression
2018 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, no 4, p. 775-785Article in journal (Refereed) Published
Abstract [en]

The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β-cell mass resulting from T-cell-mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C-peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β-cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent-onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in β-cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β-cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.

Keywords
islet, type 1 diabetes, β-cell function
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342884 (URN)10.1111/dom.13144 (DOI)000427114800003 ()29083510 (PubMedID)
Funder
Ernfors FoundationSwedish Child Diabetes FoundationSwedish Diabetes AssociationTore Nilsons Stiftelse för medicinsk forskningÅke Wiberg FoundationNovo NordiskEU, FP7, Seventh Framework Programme, PEVNET 261441EU, FP7, Seventh Framework Programme, HumEn HEALTH-F4-2013-602889
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-08Bibliographically approved
Eich, T., Ståhle, M. U., Gustafsson, B., Horneland, R., Lempinen, M., Lundgren, T., . . . Korsgren, O. (2018). Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas. Cell Transplantation, 27(7), 1031-1038
Open this publication in new window or tab >>Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas
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2018 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 27, no 7, p. 1031-1038Article in journal (Refereed) Published
Abstract [en]

Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ ions at a concentration of 5–10 mM. The present study aimed to determine the Ca2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+ is required to maintain an optimal Ca2+ concentration during the various phases of the islet isolation process.

Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+ to reach a Ca2+ of 5 mM.

Results: Ca2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas.

Conclusions: Ca2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

Keywords
calcium, clinical islet transplantation, diabetes, islet isolation
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-364508 (URN)10.1177/0963689718779350 (DOI)000440338700003 ()29945463 (PubMedID)
Available from: 2018-11-05 Created: 2018-11-05 Last updated: 2018-11-05Bibliographically approved
Stenwall, A., Ingvast, S., Korsgren, O. & Skog, O. (2018). Characterization of host defense molecules in the human pancreas.
Open this publication in new window or tab >>Characterization of host defense molecules in the human pancreas
2018 (English)In: Article in journal (Refereed) Submitted
Abstract [en]

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 α1, α4, β1-4 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 (α1, β2, β3, α4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (β1 and β4) were negative in all non-diabetic donors. Two molecules (α1 and GP2) were restricted to the exocrine pancreas whereas two (β3, α4) were only expressed in islet tissue. Cathelicidin, β2, 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 β1 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.

Keywords
Pancreas, Islet of Langerhans, Diabetes, Defensin
National Category
Medical and Health Sciences
Research subject
Biology with specialization in Molecular Immunology
Identifiers
urn:nbn:se:uu:diva-358717 (URN)
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-08-30
Lundberg, M., Stenwall, P.-A., Tegehall, A., Korsgren, O. & Skog, O. (2018). Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.. Islets, 10(2), 69-79
Open this publication in new window or tab >>Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
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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.

Keywords
HbA1c, laser capture, transcriptome, type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342882 (URN)10.1080/19382014.2018.1433980 (DOI)000428814700003 ()29446696 (PubMedID)
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 Association
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-08-30Bibliographically approved
Eriksson, O., Johnström, P., Cselenyi, Z., Jahan, M., Selvaraju, R. k., Jensen-Waern, M., . . . Korsgren, O. (2018). In Vivo Visualization of beta-Cells by Targeting of GPR44. Diabetes, 67(2), 182-192
Open this publication in new window or tab >>In Vivo Visualization of beta-Cells by Targeting of GPR44
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2018 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, no 2, p. 182-192Article in journal (Refereed) Published
Abstract [en]

GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342900 (URN)10.2337/db17-0764 (DOI)000426034500003 ()29208633 (PubMedID)
Funder
Swedish Research Council, K2015-54X-12219-19-4, K2013-64X-08268-26-3, K2013-55X-15043, 921-2014-7054Ernfors FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-05-09Bibliographically approved
Abadpour, S., Halvorsen, B., Sahraoui, A., Korsgren, O., Aukrust, P. & Scholz, H. (2018). Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT. Journal of Molecular Endocrinology, 60(3), 171-183
Open this publication in new window or tab >>Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT
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2018 (English)In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 60, no 3, p. 171-183Article in journal (Refereed) Published
Abstract [en]

Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found up-regulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20mM glucose) + LIGHT in vitro and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by up-regulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342896 (URN)10.1530/JME-17-0182 (DOI)000438183300006 ()29330151 (PubMedID)
Funder
Novo Nordisk, 36772Swedish Child Diabetes Foundation
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-09-20Bibliographically approved
Fuchs, A., Gliwiński, M., Grageda, N., Spiering, R., Abbas, A. K., Appel, S., . . . Trzonkowski, P. (2018). Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.. Frontiers in Immunology, 8, Article ID 1844.
Open this publication in new window or tab >>Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1844Article in journal (Refereed) Published
Abstract [en]

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Keywords
T regulatory cells, cell therapy, good manufacturing practice, immune tolerance, immunotherapy, minimum information model
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-342893 (URN)10.3389/fimmu.2017.01844 (DOI)000419897500001 ()29379498 (PubMedID)
Funder
EU, Horizon 2020
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-03-01Bibliographically approved
Kuric, E., Krogvold, L., Hanssen, K. F., Dahl-Jorgensen, K., Skog, O. & Korsgren, O. (2018). No Evidence for Presence of Mucosal-Associated Invariant T Cells in the Insulitic Lesions in Patients Recently Diagnosed with Type 1 Diabetes. American Journal of Pathology, 188(8), 1744-1748
Open this publication in new window or tab >>No Evidence for Presence of Mucosal-Associated Invariant T Cells in the Insulitic Lesions in Patients Recently Diagnosed with Type 1 Diabetes
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2018 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 188, no 8, p. 1744-1748Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-364915 (URN)10.1016/j.ajpath.2018.04.009 (DOI)000440773100002 ()29803829 (PubMedID)
Funder
Swedish Research Council, 65X-12219-15-6 K'2015-54X-12219-19-4Novo NordiskÅke Wiberg FoundationTore Nilsons Stiftelse för medicinsk forskningSwedish Child Diabetes FoundationSwedish Diabetes AssociationEU, FP7, Seventh Framework Programme, 26441 PEVNET
Available from: 2018-11-08 Created: 2018-11-08 Last updated: 2018-11-08Bibliographically approved
Vågesjö, E., Seignez, C., Christoffersson, G., Herrera Hidalgo, C., Giraud, A., Korsgren, O., . . . Phillipson, M. (2018). Perivascular macrophages regulate blood flow following tissue damage. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 44-45
Open this publication in new window or tab >>Perivascular macrophages regulate blood flow following tissue damage
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2018 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 44-45Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366622 (URN)10.1111/eci.12923 (DOI)000434100200105 ()
Conference
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Note

Meeting Abstract: W1-O2

Available from: 2018-11-23 Created: 2018-11-23 Last updated: 2018-12-10Bibliographically approved
Stenwall, A., Seiron, P., Lundberg, M., Esguerra, J., Volkov, P., Renström, E., . . . Korsgren, O. (2018). Transcriptional analysis of islets of Langerhans from organ donors of different ages.
Open this publication in new window or tab >>Transcriptional analysis of islets of Langerhans from organ donors of different ages
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2018 (English)In: Article in journal (Refereed) Submitted
Abstract [en]

Background: The incidence of type 2 diabetes increases with age because of impaired glucose homeostasis. In this study, we hypothesized that aging induces specific transcriptional changes in human islets.

Results: Full transcriptome analysis of laser-captured islets from 26 deceased organ donors aged 1-81 years revealed 20 genes that co-varied significantly with age; SGIP1, HIST1H3E, UST, LAD1, RORB, SSTR5-AS1, LDHB, KCNJ15, TRABD2B, GLUL, MBPL1P, EFCAB4B, PHLDA3, MAFB, DGKB, TNFRSF10C, C1ORF16B, CDKN2A, MAT1A and ITGB4. However, principal component analysis and hierarchical clustering of the full transcriptomes showed no obvious separation of donors based on age, and the expression of genes in key pathways of beta-cell function, replication, and senescence were not significantly affected by aging.

Conclusions: Our data from laser-captured islets confirm only partly the age-related differences reported from islets isolated by enzymatic digestion. The largely preserved transcriptomes and function of islets in elderly are surprising considering the enormous metabolic activity exerted by endocrine cells, and our data could be in line with a continuous renewal of islet cells.

Keywords
Diabetes, Islet of Langerhans, Beta-cell, Ageing
National Category
Medical and Health Sciences
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-358716 (URN)
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-08-30
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8524-9547

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