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Helker, C. S., Mullapudi, S.-T., Mueller, L. M., Preussner, J., Tunaru, S., Skog, O., . . . Stainier, D. Y. (2019). A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.. Development, 146(14), Article ID dev172569.
Open this publication in new window or tab >>A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.
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2019 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 14, article id dev172569Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Pdx1, Small molecule screen, Transdifferentiation, α-Cells, β-Cells
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-392522 (URN)10.1242/dev.172569 (DOI)000478027300013 ()31142539 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602587
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-09Bibliographically approved
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
Korsgren, O., Skyler, J. S., Skog, O., Sundberg, F., Forsander, G. & Ludvigsson, J. (2019). Imagining a better future for all people with type 1 diabetes mellitus. Nature Reviews Endocrinology, 15(11), 623-624
Open this publication in new window or tab >>Imagining a better future for all people with type 1 diabetes mellitus
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2019 (English)In: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 15, no 11, p. 623-624Article in journal, Editorial material (Other academic) Published
Abstract [en]

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.

National Category
Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-392521 (URN)10.1038/s41574-019-0257-8 (DOI)000489751400001 ()31471596 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-11-08Bibliographically 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
von Zur-Mühlen, B., Lundgren, T., Bayman, L., Berne, C., Bridges, N., Eggerman, T., . . . Korsgren, O. (2019). Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation. Transplantation, 103(3), 630-637
Open this publication in new window or tab >>Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation
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2019 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 3, p. 630-637Article in journal (Refereed) Published
Abstract [en]

Background. When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods. The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 +/- 10 seconds and 50 +/- 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results. Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 +/- 5 days after the first transplant) between the 2 arms (1.33 +/- 1.10 versus 1.56 +/- 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. Conclusions. Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-393536 (URN)10.1097/TP.0000000000002425 (DOI)000480678600034 ()30211831 (PubMedID)
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically 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
Weis, J., Ahlström, H. & Korsgren, O. (2019). Proton MR spectroscopy of human pancreas allografts. Magnetic Resonance Materials in Physics, Biology and Medicine, 32(4), 511-517
Open this publication in new window or tab >>Proton MR spectroscopy of human pancreas allografts
2019 (English)In: Magnetic Resonance Materials in Physics, Biology and Medicine, ISSN 0968-5243, E-ISSN 1352-8661, Vol. 32, no 4, p. 511-517Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To estimate pancreas graft relaxation times and concentrations of total fat, and the intracellular lipids of non-adipose pancreatic cells (NAPC) using proton (1H) magnetic resonance spectroscopy (MRS) during cold preservation.

MATERIALS AND METHODS: Grafts from 11 human donors were investigated. Each pancreas was perfused in situ with histidine-tryptophan-ketoglutarate (HTK) or with University of Wisconsin solution and placed into a transport container. Temperature of the grafts was maintained at 4 ± 2 °C during transport to our hospital and MR scanning. A 1.5 T clinical scanner was used for the measurements. Single-voxel PRESS spectra were acquired using transmit-receiver head coil.

RESULTS: Relaxation times were measured for lipid (-CH2-)n (T1, 287 ± 60 ms; T2, 27 ± 4 ms), and tissue water (T1, 670 ± 69 ms; T2, 77 ± 17 ms). Average total fat, and intracellular lipids of NAPC concentrations were 79.2 ± 100.8 (range 2.4-304.4), and 2.9 ± 1.2 mmol/kg ww, respectively.

CONCLUSION: We have shown that 1H-MRS is a useful tool for the estimation of pancreas graft lipid concentrations. Total pancreatic fat and especially content of intracellular lipids of NAPC are valuable measures for inspection of graft quality prior to transplantation or islet of Langerhans isolation.

Keywords
1H-MRS, Intracellular fat, Pancreas graft, Relaxation times, Total fat
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-382935 (URN)10.1007/s10334-019-00740-8 (DOI)000476510700009 ()30937576 (PubMedID)
Funder
Swedish Research Council, VR K2013-64X-08268-26-3Swedish Research Council, 921-2014-7054Swedish Research Council, K2015-54X-12219-19-4Ernfors FoundationSwedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-09-20Bibliographically approved
Eriksson, J., Roy, T., Sawadjoon, S., Bachmann, K., Sköld, C., Larhed, M., . . . Odell, L. R. (2019). Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass. Nuclear Medicine and Biology, 71, 1-10
Open this publication in new window or tab >>Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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2019 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed) Published
Abstract [en]

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Funder
Swedish Research Council, 2018-05133Knut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-09-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8524-9547

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