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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.

Keyword
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
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.

Keyword
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: 2018-06-04Bibliographically 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, Article ID JME-17-0182.
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, article id JME-17-0182Article in journal (Refereed) Epub ahead of print
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)29330151 (PubMedID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-03-14Bibliographically 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.

Keyword
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
Carlsson, P.-O., Espes, D., Sedigh, A., Rotem, A., Zimermann, B., Grinberg, H., . . . Korsgren, O. (2018). Transplantation of Macro-encapsulated Human Islets within the Bioartificial Pancreas β Air to Patients with Type 1 Diabetes Mellitus. American Journal of Transplantation
Open this publication in new window or tab >>Transplantation of Macro-encapsulated Human Islets within the Bioartificial Pancreas β Air to Patients with Type 1 Diabetes Mellitus
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2018 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143Article in journal (Refereed) Epub ahead of print
Abstract [en]

Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

National Category
Endocrinology and Diabetes Surgery Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-337701 (URN)10.1111/ajt.14642 (DOI)29288549 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-02-08Bibliographically approved
Carlbom, L., Espes, D., Lubberink, M., Martinell, M., Johansson, L., Ahlström, H., . . . Eriksson, O. (2017). [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes. Diabetes, 66(5), 1286-1292
Open this publication in new window or tab >>[(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, p. 1286-1292Article in journal (Refereed) Published
Abstract [en]

[(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) PET of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by non-invasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to non-diabetic individuals. The primary outcome was the [(11)C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass.We found that metabolic testing indicated a progressive loss of beta cell function, but that this was not mirrored by a decrease in [(11)C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased beta cell function. The results herein indicates that beta cell dedifferentiation, and not necessarily endocrine cell loss, constitute a major cause of beta cell failure in T2D.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-316831 (URN)10.2337/db16-1449 (DOI)000399799800022 ()28246291 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF), K2015-54X-12219-19-4 K2013-64X-08268-26-3 K2013-55X-15043 921-2014-7054Novo NordiskSwedish Child Diabetes Foundation
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2018-01-25Bibliographically approved
Radenkovic, M., Uvebrant, K., Skog, O., Sarmiento, L., Avartsson, J., Storm, P., . . . Cilio, C. M. (2017). Characterization of resident lymphocytes in human pancreatic islets. Clinical and Experimental Immunology, 187(3), 418-427
Open this publication in new window or tab >>Characterization of resident lymphocytes in human pancreatic islets
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2017 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 187, no 3, p. 418-427Article in journal (Refereed) Published
Abstract [en]

The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3(+) T cells with a remarkable bias towards CD8(+) cells. Central memory and effector memory phenotypes dominated within the CD8(+) and CD4(+) T cells and most CD8(+) T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45(+) cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8(+) T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes.

Keyword
T cells, diabetes, human, memory, pancreas
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-318324 (URN)10.1111/cei.12892 (DOI)000393976800010 ()27783386 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Child Diabetes FoundationNovo Nordisk
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-11-29Bibliographically approved
Skog, O. & Korsgren, O. (2017). Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-1345 [Letter to the editor]. Diabetes, 66(9), e8-e9
Open this publication in new window or tab >>Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-1345
2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 9, p. e8-e9Article in journal, Letter (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342885 (URN)10.2337/db17-0589 (DOI)28830917 (PubMedID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-03-16Bibliographically approved
Schive, S. W., Foss, A., Sahraoui, A., Kloster-Jensen, K., Hafsahl, G., Kvalheim, G., . . . Scholz, H. (2017). Cost and clinical outcome of islet transplantation in Norway 2010-2015. Clinical Transplantation, 31(1)
Open this publication in new window or tab >>Cost and clinical outcome of islet transplantation in Norway 2010-2015
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2017 (English)In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 31, no 1Article in journal (Refereed) Published
Abstract [en]

Islet transplantation is a minimally invasive -cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1nmolL(-1), and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347297 +/- 60588NOK, or 35424 +/- 6182EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.

Keyword
cost, islet transplantation, outcome, type 1 diabetes
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-316049 (URN)10.1111/ctr.12871 (DOI)000392436100011 ()
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8524-9547

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