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Stenwall, A., Ingvast, S., Skog, O. & Korsgren, O. (2019). Characterization of host defense molecules in the human pancreas. Islets, 11(4), 89-101
Open this publication in new window or tab >>Characterization of host defense molecules in the human pancreas
2019 (English)In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 11, no 4, p. 89-101Article in journal (Refereed) Published
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 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.

Keywords
Islet of Langerhans, beta cell, defensin, bacteria, diabetes, pancreas
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Biology with specialization in Molecular Immunology
Identifiers
urn:nbn:se:uu:diva-358717 (URN)10.1080/19382014.2019.1585165 (DOI)000475247700001 ()31242128 (PubMedID)
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2019-08-19Bibliographically approved
Brandhorst, H., Johnson, P. R., Moench, J., Kurfuerst, M., Korsgren, O. & Brandhorst, D. (2019). Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation. Cell Transplantation, 28(2), 176-184
Open this publication in new window or tab >>Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation
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2019 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 2, p. 176-184Article in journal (Refereed) Published
Abstract [en]

Although human islet transplantation has been established as valid and safe treatment for patients with type 1 diabetes, the utilization rates of human pancreases for clinical islet transplantation are still limited and substantially determined by the quality and composition of collagenase blends. While function and integrity of collagenase has been extensively investigated, information is still lacking about the most suitable supplementary neutral proteases. The present study compared islet isolation outcome after pancreas digestion by means of collagenase used alone or supplemented with either neutral protease (NP), clostripain (CP), or both proteases. Decent amounts of islet equivalents (IEQ) were isolated using collagenase alone (3090 +/- 550 IEQ/g), or in combination with NP (2340 +/- 450 IEQ/g) or CP (2740 +/- 280 IEQ/g). Nevertheless, the proportion of undigested tissue was higher after using collagenase alone (21.1 +/- 1.1%, P < 0.05) compared with addition of NP (13.3 +/- 2.2%) or CP plus NP (13.7 +/- 2.6%). Likewise, the percentage of embedded islets was highest using collagenase only (13 +/- 2%) and lowest adding NP plus CP (4 +/- 1%, P < 0.01). The latter combination resulted in lowest post-culture overall survival (42.7 +/- 3.9%), while highest survival was observed after supplementation with CP (74.5 +/- 4.8%, P < 0.01). An insulin response toward glucose challenge was present in all experimental groups, but the stimulation index was significantly decreased using collagenase plus NP (2.0 +/- 0.12) compared with supplementation with CP (3.16 +/- 0.4, P < 0.001). This study demonstrates for the first time that it is possible to isolate significant numbers of human islets combining collagenase only with CP. The supplementation with CP is an effective means to substantially reduce NP activity, which significantly decreases survival and viability after culture. This will facilitate the manufacturing of enzyme blends with less harmful characteristics.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS INC, 2019
Keywords
clostripain, collagenase, neutral protease, human islet isolation, human islet transplantation
National Category
Endocrinology and Diabetes Cell Biology
Identifiers
urn:nbn:se:uu:diva-377679 (URN)10.1177/0963689718811614 (DOI)000457650600004 ()30419762 (PubMedID)
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-02-26Bibliographically approved
Nano, R., Kerr-Conte, J. A., Bosco, D., Karlsson, M., Lavallard, V., Melzi, R., . . . Piemonti, L. (2019). Islets for Research: Nothing Is Perfect, but We Can Do Better. Diabetes, 68(8), 1541-1543
Open this publication in new window or tab >>Islets for Research: Nothing Is Perfect, but We Can Do Better
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 8, p. 1541-1543Article in journal (Refereed) Published
Abstract [en]

In December 2018, Diabetes and Diabetologia began requiring authors of papers reporting data obtained from studies on human islets to report critical characteristics of the human islets used for research. The islet community was asked to provide feedback on it. Here is the contribution by the European Consortium for Islet Transplantation.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-391283 (URN)10.2337/db19-0367 (DOI)000476794600001 ()31331988 (PubMedID)
Available from: 2019-08-22 Created: 2019-08-22 Last updated: 2019-08-22Bibliographically approved
Skog, O., Klingel, K., Roivainen, M. & Korsgren, O. (2019). Large enteroviral vaccination studies to prevent type 1 diabetes should be well founded and rely on scientific evidence [Letter to the editor]. Diabetologia, 62(6), 1097-1099
Open this publication in new window or tab >>Large enteroviral vaccination studies to prevent type 1 diabetes should be well founded and rely on scientific evidence
2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 6, p. 1097-1099Article in journal, Letter (Other academic) Published
Keywords
Autoimmunity, Beta cells, DiViD study, Enterovirus, Pancreas, Prevention, Type 1 diabetes, Virus, VP1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-385780 (URN)10.1007/s00125-019-4841-1 (DOI)000467640700024 ()30810767 (PubMedID)
Funder
Swedish Child Diabetes Foundation
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Jonsson, A., Yngve, E., Karlsson, M., Ingvast, S., Skog, O. & Korsgren, O. (2019). Protein Kinase R Is Constitutively Expressed in the Human Pancreas. Journal of Histochemistry and Cytochemistry, 67(2), 99-105
Open this publication in new window or tab >>Protein Kinase R Is Constitutively Expressed in the Human Pancreas
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2019 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 67, no 2, p. 99-105Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2019
Keywords
immunohistochemistry, innate immunity, pancreas, PCR, type 1 diabetes, viral footprints, viral sensors
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-377210 (URN)10.1369/0022155418802838 (DOI)000457488700002 ()30265185 (PubMedID)
Funder
Swedish Child Diabetes Foundation
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
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
Gotthardt, M., Eizirik, D. L., Aanstoot, H.-J., Korsgren, O., Mul, D., Martin, F., . . . Brom, M. (2018). Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer. Diabetologia, 61(12), 2516-2519
Open this publication in new window or tab >>Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 12, p. 2516-2519Article in journal (Refereed) Published
Abstract [en]

In this issue of Diabetologia, Alavi and Werner (10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Clinical diabetes, Imaging, Islets, PET imaging
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-369382 (URN)10.1007/s00125-018-4745-5 (DOI)000449290200005 ()30284016 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically 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.

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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8524-9547

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