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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, 1286-1292 p.Article 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: 2017-05-11Bibliographically 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, 418-427 p.Article 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
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
Kuric, E., Seiron, P., Krogvold, L., Edwin, B., Buanes, T., Hanssen, K. F., . . . Korsgren, O. (2017). Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes. American Journal of Pathology, 187(3), 581-588.
Open this publication in new window or tab >>Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes
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2017 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 3, 581-588 p.Article in journal (Refereed) Published
Abstract [en]

Subtypes of CD8(+) T cells in insulitic lesions in biopsy specimens from six subjects with recent-onset type 1 diabetes (T1D) and six nondiabetic matched controls were analyzed using simultaneous multicolor immunofluorescence. Also, insulitic islets based on accumulation of CD3(+) T cells were microdissected with laser-capture microscopy, and gene transcripts associated with inflammation and autoimmunity were analyzed. We found a substantial proportion, 43%, of the CD8(+) T cells in the insulitic lesions to display a tissue resident memory T cell (TRM) (CD8(+)CD69(+)CD103(+)) phenotype in T1D subjects. Most TRM cells were located in the insulitic lesion in the endocrine-exocrine interface. TRM cells were also sporadically found in islets of control subjects. Moreover, gene expression analysis showed a lack of active transcription of genes associated with acute inflammatory or cytotoxic T-cell responses. We present evidence that a substantial proportion of T cells in insulitic lesions of recent-onset T1D patients are TRM cells and not classic cytotoxic CD8(+) T cells. Our findings highlight the need for further analysis of the T cells involved in insulitis to elucidate their role in the etiology of T1D.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-318323 (URN)10.1016/j.ajpath.2016.11.002 (DOI)000394558200011 ()28212742 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 261441 PEVNETSwedish Research Council, VR K2015-54X-1221919-4 921-2014-7054Novo NordiskÅke Wiberg FoundationSwedish Diabetes AssociationSwedish Child Diabetes Foundation
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-04-19Bibliographically approved
Kabra, U. D., Pfuhlmann, K., Migliorini, A., Keipert, S., Lamp, D., Korsgren, O., . . . Jastroch, M. (2017). Direct Substrate Delivery into Mitochondrial-Fission Deficient Pancreatic Islets Rescues Insulin Secretion. Diabetes, 66(5), 1247-1257.
Open this publication in new window or tab >>Direct Substrate Delivery into Mitochondrial-Fission Deficient Pancreatic Islets Rescues Insulin Secretion
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, 1247-1257 p.Article in journal (Refereed) Published
Abstract [en]

In pancreatic beta cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion (GSIS). Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we here demonstrate that mitochondrial fission is necessary for GSIS in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fuelled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient beta cells, demonstrating that defective mitochondrial dynamics solely impact substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights in how mitochondrial dysfunction may cause pancreatic beta cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-318381 (URN)10.2337/db16-1088 (DOI)000399799800019 ()28174288 (PubMedID)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-05-11Bibliographically approved
Abadpour, S., Göpel, S. O., Schive, S. W., Korsgren, O., Foss, A. & Scholz, H. (2017). Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis. Scientific Reports, 7, Article ID 1575.
Open this publication in new window or tab >>Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 1575Article in journal (Refereed) Published
Abstract [en]

One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-325337 (URN)10.1038/s41598-017-01805-1 (DOI)000400874500015 ()28484241 (PubMedID)
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04Bibliographically approved
Lundberg, M., Seiron, P., Ingvast, S., Korsgren, O. & Skog, O. (2017). Insulitis in human diabetes: a histological evaluation of donor pancreases. Diabetologia, 60(2), 346-353.
Open this publication in new window or tab >>Insulitis in human diabetes: a histological evaluation of donor pancreases
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 2, 346-353 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis According to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when >= 15 CD45(+) cells are found within the parenchyma or in the islet-exocrine interface in >= 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals. Methods Insulitis was determined by examining CD45(+) cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3(+) cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA(1c) or autoantibody positivity were examined. Results Overall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had >= 15 CD3(+) cells in >= 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45(+) cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45(+) cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA(1c). Conclusions/interpretation The current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when >= 15 CD3(+) cells, not CD45(+) cells, are found in >= 3 islets.

Keyword
HLA, Inflammation, Insulin secretion, Insulitis, Islets, Macrophages, Tcells, Type 1 diabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-315054 (URN)10.1007/s00125-016-4140-z (DOI)000391359800016 ()27796420 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 261441 PEVNETNovo NordiskÅke Wiberg FoundationSwedish Diabetes Association
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-11-29Bibliographically approved
Korsgren, O. (2017). Islet Encapsulation: Physiological Possibilities and Limitations. Diabetes, 66(7), 1748-1754.
Open this publication in new window or tab >>Islet Encapsulation: Physiological Possibilities and Limitations
2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 7, 1748-1754 p.Article in journal (Refereed) Published
Abstract [en]

A logical cure for type 1 diabetes (T1D) involves replacing the lost insulin-producing cells with new ones, preferably cells from a well-characterized and unlimited source of human insulin-producing cells. This straightforward and simple solution to provide a cure for T1D is immensely attractive but entails at least two inherent and thus far unresolved hurdles: 1) provision of an unlimited source of functional human insulin-producing cells and 2) prevention of rejection without the side effects of systemic immunosuppression. Generation of transplantable insulin-producing cells from human embryonic stem cells or induced pluripotent stem cells is at present close to reality, and we are currently awaiting the first clinical studies. Focus is now directed to foster development of novel means to control the immune system to enable large-scale clinical application. Encapsulation introduces a physical barrier that prevents access of immune cells to the transplanted cells but also hinders blood vessel ingrowth. Therefore, oxygen, nutrient, and hormonal passage over the encapsulation membrane is solely dependent on diffusion over the immune barrier, contributing to delays in glucose sensing and insulin secretion kinetics. This Perspective focuses on the physiological possibilities and limitations of an encapsulation strategy to establish near-normoglycemia in subjects with T1D, assuming that glucose-responsive insulin-producing cells are available for transplantation.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-328989 (URN)10.2337/db17-0065 (DOI)000403778600003 ()28637827 (PubMedID)
Funder
Swedish Research Council, K2015-54X-12219-19-4, 921-2014-7054Novo NordiskSwedish Child Diabetes FoundationSwedish Diabetes Association
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved
Carlbom, L., Weis, J., Johansson, L., Korsgren, O. & Ahlström, H. (2017). Pre-transplantation ³¹P-magnetic resonance spectroscopy for quality assessment of human pancreatic grafts: A feasibility study. Magnetic Resonance Imaging, 39, 98-102.
Open this publication in new window or tab >>Pre-transplantation ³¹P-magnetic resonance spectroscopy for quality assessment of human pancreatic grafts: A feasibility study
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2017 (English)In: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 39, 98-102 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate the feasibility of using (31)P-MRS for objective non-invasive quality assessment of human pancreas grafts prior to transplantation or islet isolation.

Materials and methods: Pancreata from 5 human donors, 3 males and 2 females, aged 49-78years, with body mass index (BMI) 22-31kg/m(2), were included. Pancreata were perfused with histidine-tryptophan-ketoglutarate solution during procurement and stored in hypothermic condition (4°C) for 21-44h. During the period of hypothermic storage repeated spectra were obtained for each graft by (31)P-MRS (1.5Tesla) to measure the cold ischemia time (CIT) dependent changes of the phosphorous metabolites adenosine triphosphate (ATP), phosphomonoesters (PME), phosphodiesters (PDE) and inorganic phosphate (Pi), in the grafts. Graft temperature was measured immediately before and after MR-examination. Reference spectrum for non-viable tissue was obtained after graft exposure to room temperature.

Results: PME/Pi, PDE/Pi and ATP/Pi spectral intensities ratios decreased with increasing CIT, reflecting the decreased viability of the grafts. PME/Pi ratio was the most discriminatory variable at prolonged CIT. (31)P-MRS could be performed without significantly increasing graft temperature.

Conclusions: (31)P-MRS may provide quantitative parameters for evaluating graft viability ex vivo, and is a promising tool for objective non-invasive assessment of the quality of human pancreas grafts prior to transplantation or islet isolation.

Keyword
P-31-MR spectroscopy, Organ viability, Pancreas transplantation, Cold ischemia, ATP, PME
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-315894 (URN)10.1016/j.mri.2017.02.004 (DOI)000401051200012 ()28188872 (PubMedID)
Funder
Swedish Research Council, K2013-64X-08268-26-3Swedish Research Council, 921-2014-7054Swedish Research Council, K2015-54X-12219-19-4Swedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Note

Title in WOS: Pre-transplantation P-31-magnetic resonance spectroscopy for quality assessment of human pancreatic grafts - A feasibility study

Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2017-06-20Bibliographically approved
Lundberg, M., Seiron, P., Ingvast, S., Korsgren, O. & Skog, O. (2017). Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter]. [Letter to the editor]. Diabetologia, 60(4), 756-757.
Open this publication in new window or tab >>Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter].
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 4, 756-757 p.Article in journal, Letter (Other academic) Published
Keyword
CD45, Immunopathology, Inflammation, Insulitis, Islets, Macrophages, Pancreas, T cells, Type 1 diabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-318317 (URN)10.1007/s00125-017-4212-8 (DOI)000398046400018 ()28111711 (PubMedID)
Note

Funding: Work in the authors' laboratories was supported by the PEVNET Study Group funded by the European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreement number 261441 PEVNET, the Swedish Medical Research Council (K2015-54X-12219-19-4), the Diabetes Wellness Foundation, the Family Ernfors Foundation, the Novo Nordisk Foundation, the Ake Wiberg Foundation, the Tore Nilsson Foundation, the Swedish Diabetes Association, Gillbergska Stiftelsen, and Barndiabetesfonden. Human pancreatic biopsies and isolated islets were obtained from the Nordic Network for Clinical Islet Transplantation, supported by the Swedish national strategic research initiative Excellence of Diabetes Research in Sweden (EXODIAB) and the JDRF.

Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-05-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8524-9547

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