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  • 1.
    Andersson, Arne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology. Department of Medical Sciences.
    Carlsson, Carina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Olsson, Richard
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Nordin, Astrid
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Magnus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Tyrberg, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Tillman, Linda
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, NIls
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Mattsson, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Promoting islet cell function after transplantation2004In: Cell Biochem Biophys, no 40 (3 Suppl), p. 55-64Article in journal (Refereed)
  • 2.
    Barbu, Andreea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Bbirgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Börjesson, Joey Lau
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats: Effects of lactate and pyruvate2012In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, no 8, p. 1263-1271Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.

  • 3.
    Bergsten, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Westerlund, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, P
    Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Primary in vivo oscillations of metabolism in the pancreas.2002In: Diabetes, Vol. 51, p. 699-Article in journal (Refereed)
  • 4.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Uppsala University.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Pei, Yu
    Karolinska Institute, Stockholm, Sweden.
    Deng, Qiaolin
    Karolinska Institute, Stockholm, Sweden.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, p. 283-294Article in journal (Refereed)
    Abstract [en]

    The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

  • 5.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, p. 1968-1972Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.

    METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.

    RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.

    CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.

  • 6.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, p. 1286-1292Article in journal (Refereed)
    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.

  • 7.
    Carlsson, Per-Ola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    The renin-angiotensin system in the endocrine pancreas.2001In: JOOP, Vol. 2, p. 26-Article in journal (Refereed)
  • 8.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Cardiac natriuretic peptides and pancreatic islet blood flow inanesthetized rats.2001In: Horm Metab Res, Vol. 33, p. 181-Article in journal (Refereed)
  • 9.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Influence of age, hyperglycemia, leptin, and NPY on islet blood flow in obese-hyperglycemic mice1998In: Am J Physiol, Vol. 275, p. 594-Article in journal (Refereed)
  • 10.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Pancreatic islet blood flow in normal and obese-hyperglycemic (ob/ob) mice1996In: Am J Physiol, Vol. 271, p. 990-Article in journal (Refereed)
  • 11.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Carina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Hellerström, Claes
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Höglund, Erika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    King, Aileen
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, Per
    Mattsson, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Olsson, Richard
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Tyrberg, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Engraftment and growth of transplanted pancreatic islets.2000In: Ups J Med Sci, ISSN 0300-9734, Vol. 105, no 2, p. 107-23Article in journal (Other scientific)
  • 12.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Berne, Christian
    Department of Medical Sciences.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats1998In: Diabetologia, Vol. 41, p. 127-Article in journal (Refereed)
  • 13.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology. Department of Medical Sciences.
    Berne, Christian
    Department of Medical Sciences.
    Östenson, Claes-Göran
    Department of Medical Sciences.
    Andersson, Arne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Hypoglycaemia induces decreased islet blood perfusion mediated by thecentral nervous system in normal and Type 2 diabetic GK rats.2003In: Diabetologia, Vol. 46, no 8, p. 1124-30Article in journal (Refereed)
  • 14.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carbon monoxide and pancreatic islet blood flow in the rat: inhibition of haem oxygenase does not affect islet blood perfusion2006In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 66, no 7, p. 543-548Article in journal (Refereed)
    Abstract [en]

    Objective. To determine whether carbon monoxide, a known gaseous vasorelaxator, affects pancreatic islet blood flow in rats. Material and methods. Sprague-Dawley rats were anaesthetized with thiobutabarbital and injected intravenously with the haem oxygenase inhibitor tin-protoporphyrin IX dichloride ( SnPP; 4, 10 or 20 mg/kg body-weight). After 15 min, blood flow measurements were performed using a microsphere technique. Results. There was a slight increase in mean arterial blood pressure with the highest dose of SnPP. No effects on total pancreatic, islet, duodenal, colonic, renal or adrenal blood flow were seen with any of the applied doses. Conclusions. The findings of this study suggest that the haem oxygenase-carbon monoxide system is likely to be of limited importance in the regulation of blood perfusion to the pancreas, the islets of Langerhans or any of the other studied organs.

  • 15.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rotem, Avi
    Zimermann, Baruch
    Grinberg, Helena
    Goldman, Tali
    Barkai, Uriel
    Avni, Yuval
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlbom, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Mölndal, Sweden.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplantation of Macro-encapsulated Human Islets within the Bioartificial Pancreas β Air to Patients with Type 1 Diabetes Mellitus2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed)
    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.

  • 16.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Iwase, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Stimulation of intestinal glucoreceptors in rats increases pancreatic islet blood flow through vagal mechanisms1999In: Am J Physiol, Vol. 276, p. 233236-Article in journal (Refereed)
  • 17.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Whole pancreatic blood flow and islet blood flow after pancreatico-biliary diversion in rats1996In: Med Sci Res, Vol. 24, p. 11-Article in journal (Refereed)
  • 18.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ostenson, C-G
    Kallskog, Ö
    Department of Comparative Medicine.
    Islet capillary blood pressure increase mediated by hyperglycemia in NIDDM GK rats.1997In: Diabetes, Vol. 46, p. 947-Article in journal (Refereed)
  • 19.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Disruption of Insulin Receptor Signaling in Endothelial Cells Shows the Central Role of an Intact Islet Blood Flow for In Vivo beta-Cell Function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 3, p. 700-702Article in journal (Other academic)
  • 20.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Unaltered oxygen tension in rat pancreatic islets despite dissociation of insulin release and islet blood flow.2002In: Acta Physiol Scand, ISSN 0001-6772, Vol. 176, no 4, p. 275-81Article in journal (Other scientific)
  • 21.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Kallskog, O
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Multiple injections of coloured microspheres for islet blood flowmeasurements in anaesthetised rats: influence of microsphere size.2002In: Ups J Med Sci, Vol. 107, p. 111-Article in journal (Refereed)
  • 22.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Karlsson, Ella
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Mulder, Hindrik
    Gebre-Medhin, Samuel
    Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide deficient mice.2002In: Europ J Endocr, Vol. 146, p. 107-Article in journal (Refereed)
  • 23.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Kiuru, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Nordin, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Olsson, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Lin, JM
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Hillered, L
    Department of Neuroscience.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Microdialysis measurements demonstrate a shift to nonoxidative glucosemetabolism in rat pancreatic islets transplanted beneath the renalcapsule.2002In: Surgery, Vol. 132, p. 487-Article in journal (Refereed)
  • 24.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Mesenchymal Stromal Cells to Halt the Progression of Type 1 Diabetes?2015In: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 15, no 7, article id 46Article in journal (Refereed)
    Abstract [en]

    No treatment to halt the progressive loss of insulin-producing beta-cells in type 1 diabetes mellitus has yet been clinically introduced. Strategies tested have at best only transiently preserved beta-cell function and in many cases with obvious side effects of drugs used. Several studies have suggested that mesenchymal stromal cells exert strong immunomodulatory properties with the capability to prevent or halt diabetes development in animal models of type 1 diabetes. A multitude of mechanisms has been forwarded to exert this effect. Recently, we translated this strategy into a first clinical phase I/IIa trial and observed no side effects, and preserved or even increased C-peptide responses to a mixed meal tolerance test during the first year after treatment. Future blinded, larger studies, with extended follow-up, are clearly of interest to investigate this treatment concept.

  • 25.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, I
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Roomans, GM
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Changes in intracellular sodium, potassium, and calcium concentrations intransplanted mouse pancreatic islets.2003In: Transplantation, Vol. 75, p. 445-Article in journal (Refereed)
  • 26.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Lindberg, M
    Department of Medical Sciences.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Effects of the carbonic anhydrase inhibitor acetazolamide on splanchnic blood flow in anesthetized rats1998In: Acta Diabetol., Vol. 35, p. 215-Article in journal (Refereed)
  • 27.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, P
    Department of Oncology, Radiology and Clinical Immunology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Measurements of oxygen tension in native and transplanted pancreatic islets1998In: Diabetes, Vol. 47, p. 1027-Article in journal (Refereed)
  • 28.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Mattsson, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Oxygen tension and blood flow in relation to revascularization in transplanted adult and fetal rat pancreatic islets.2002In: Cell Transplant, Vol. 11, p. 813-Article in journal (Refereed)
  • 29.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Nordin, Astrid
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    pH is decreased in transplanted rat pancreatic islets.2003In: Am J Physiol Endocrinol Metab, ISSN 0193-1849, Vol. 284, no 3, p. E499-504Article in journal (Other scientific)
  • 30.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Olsson, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Kallskog, O
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose-induced islet blood flow increase in rats: interaction betweennervous and metabolic mediators.2002In: Am J Physiol Endocrinol Metab, Vol. 283, p. E457-Article in journal (Refereed)
  • 31.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ostenson, C-G
    Efendic, S
    Langel, ü
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Pituitary adenylate cyclase activating polypeptide (PACAP) redistributes the blood within the pancreas of anesthetized rats1996In: Regul Pept, Vol. 63, p. 123-Article in journal (Refereed)
  • 32.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pancreas transplants.2002In: Transpl Int, Vol. 15, p. 581-585Article in journal (Refereed)
  • 33.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Chronically decreased oxygen tension in rat pancreatic islets transplantedunder the kidney capsule2000In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 69, no 5, p. 761-766Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A factor of potential importance in the failure of islet grafts is poor or inadequate engraftment of the islets in the implantation organ. This study measured the oxygen tension and blood perfusion in 1-, 2-, and 9-month-old islet grafts. METHODS: The partial pressure of oxygen was measured in pancreatic islets transplanted beneath the renal capsule of diabetic and nondiabetic recipient rats with a modified Clark electrode (outer tip diameter 2-6 microm). The size of the graft (250 islets) was by purpose not large enough to cure the diabetic recipients. The oxygen tension in islets within the pancreas was also recorded. Blood perfusion was measured with the laser-Doppler technique. RESULTS: Within native pancreatic islets, the partial pressure of oxygen was approximately 40 mm Hg (n=8). In islets transplanted to nondiabetic animals, the oxygen tension was approximately 6-7 mm Hg 1, 2, and 9 months posttransplantation. No differences could be seen between the different time points after transplantation. In the diabetic recipients, an even more pronounced decrease in graft tissue oxygen tension was recorded. The mean oxygen tension in the superficial renal cortex surrounding the implanted islets was similar in all groups (approximately 15 mm Hg). Intravenous administration of glucose (0.1 gxkg(-1)x min(-1)) did not affect the oxygen tension in any of the investigated tissues. The islet graft blood flow was similar in all groups, measuring approximately 50% of the blood flow in the kidney cortex. CONCLUSION: The oxygen tension in islets implanted beneath the kidney capsule is markedly lower than in native islets up to 9 months after transplantation. Moreover, persistent hyperglycemia in the recipient causes an even further decrease in graft oxygen tension, despite similar blood perfusion. To what extent this may contribute to islet graft failure remains to be determined.

  • 34.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, Per
    Department of Oncology, Radiology and Clinical Immunology.
    Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site.2001In: Diabetes, ISSN 0012-1797, Vol. 50, no 3, p. 489-95Article in journal (Other scientific)
  • 35.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Mattsson, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Low revascularization of experimentally transplanted human pancreatic islets.2002In: J Clin Endocrino Metab, Vol. 87, no 12, p. 5418-5423Article in journal (Refereed)
  • 36.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Influence of the neurotoxin capsaicin on rat pancreatic islets in culture, and on the pancreatic islet blood flow of rats1996In: Eur J Pharmacol, Vol. 312, p. 75-Article in journal (Refereed)
  • 37.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Pancreatic islet blood perfusion in the nonobese diabetic mouse: Diabetes-prone female mice exhibit a higher blood flow compared with male mice in the prediabetic phase1998In: Endocrinology, Vol. 139, p. 3534-Article in journal (Refereed)
  • 38.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schwarcz, Erik
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Preserved Beta-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 2, p. 587-592Article in journal (Refereed)
    Abstract [en]

    The retention of endogenous insulin secretion in type 1 diabetes is an attractive clinical goal, which opens possibilities for long-term restoration of glucose metabolism. Mesenchymal stromal cells (MSCs) constitute, based on animal studies, a promising interventional strategy for the disease. This prospective clinical study describes the translation of this cellular intervention strategy to patients with recent onset type 1 diabetes. Twenty adult patients with newly diagnosed type 1 diabetes were enrolled and randomized to MSC treatment or to the control group. Residual beta-cell function was analyzed as C-peptide concentrations in blood in response to a mixed meal tolerance test (MMTT) at one-year follow-up. In contrast to the patients in the control arm, who showed loss in both C-peptide peak values and C-peptide when calculated as area under the curve during the first year, these responses were preserved or even increased in the MSC-treated patients. Importantly, no side effects of MSC treatment were observed. We conclude that autologous MSC treatment in new onset type 1 diabetes constitute a safe and promising strategy to intervene in disease progression and preserve beta-cell function.

  • 39.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Stridsberg, M
    Department of Medical Sciences.
    Jansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Influence of corticotropin-releasing factor on pancreatic islet blood flow in different regions of the rat pancreas.1995In: Digestion, Vol. 56, p. 242-Article in journal (Refereed)
  • 40. Carlsson, S.
    et al.
    Andersson, T.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Dorkhan, M.
    Groop, L.
    Lofvenborg, J. Edwall
    Hjort, R.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Rasouli, B.
    Storm, P.
    Tuomi, T.
    Family history of type 1 and type 2 diabetes and the risk of LADA-results from a population-based study of incident cases2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S80-S80Article in journal (Other academic)
  • 41.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Intramuscular islet transplantation promotes restored islet vascularity2011In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 3, no 2, p. 69-71Article in journal (Other academic)
    Abstract [en]

    In a recent publication, we reported that islets transplanted to mouse striated muscle became revascularized with intra-islet vessel densities comparable to native islets. Revascularization of islet grafts was completely dependent on recruited Gr-1+ leukocytes. Diabetic mice cured by transplantation of 300 islets into muscle handled glucose tolerance tests as healthy controls, whereas mice cured by intraportal islet transplantation into the liver had increased blood glucose values during the load. The translational impact of these observations were confirmed by magnetic resonance imaging of autotransplanted islets in the forearm muscle of pancreactomized patients, and higher blood perfusion of the grafts compared to adjacent muscle were found. In summary, the striated muscle is a promising site for islet transplantation which promotes full revascularization of implanted grafts. The proangiogenic role of recruited leukocytes during engraftment needs to be further characterized, and considered for immune suppression treatments.

  • 42.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Opdenakker, Ghislain
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 4, p. 1094-1103Article in journal (Refereed)
    Abstract [en]

    The availability of paracrine factors in the islets of Langerhans, and the constitution of the beta cell basement membrane can both be affected by proteolytic enzymes. This study aimed to investigate the effects of the extraceaular matrix-degrading enzyme gelatinase B/matrix metalloproteinase-9 (Mmp-9) on islet function in mice. Islet function of Mmp9-deficient (Mmp9(-/-)) mice and their wild-type Littermates was evaluated both in vivo and in vitro. The pancreata of Mmp9(-/-) mice did not differ from wild type in islet mass or distribution. However, Mmp9(-/-) mice had an impaired response to a glucose toad in vivo, with lower serum insulin levels. The glucose-stimulated insulin secretion was reduced also in vitro in isolated Mmp9(-/-) islets. The vascular density of Mmp9(-/-) islets was lower, and the capillaries had fewer fenestrations, whereas the islet blood flow was threefold higher. These alterations could partly be explained by compensatory changes in the expression of matrix-related proteins. This in-depth investigation of the effects of the loss of MMP9(-/-) function on pancreatic islets uncovers a deteriorated beta cell function that is primarily due to a shift in the beta cell phenotype, but also due to islet vascular aberrations. This likely reflects the importance of a normal islet matrix turnover exerted by MMP-9, and concomitant release of paracrine factors sequestered on the matrix.

  • 43. Chu, Kwan Yi
    et al.
    Lau, Tung
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Leung, Po Sing
    Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes2006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 2, p. 367-374Article in journal (Refereed)
    Abstract [en]

    We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.

  • 44.
    Cunha, D. A.
    et al.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Molkentin, J. D.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA..
    Bugliani, M.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Marchetti, P.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Eizirik, D. L.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Cnop, M.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Thrombospondin 1: a master regulator of the anti-oxidant defence in pancreatic beta cells2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S46-S46Article in journal (Other academic)
  • 45.
    Cunha, Daniel A.
    et al.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Cito, Monia
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vanderwinden, Jean-Marie
    Univ Libre Bruxelles, Light Microscopy Facil, B-1070 Brussels, Belgium..
    Molkentin, Jeffery D.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA..
    Bugliani, Marco
    Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy..
    Marchetti, Piero
    Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy..
    Eizirik, Decio L.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Cnop, Miriam
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium.;Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, B-1070 Brussels, Belgium..
    Thrombospondin 1 protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway2016In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 23, no 12, p. 1995-2006Article in journal (Refereed)
    Abstract [en]

    The failure of beta-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional beta-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in beta-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in beta-cell death. These findings shed light on the mechanisms leading to beta-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.

  • 46.
    Davies, Lindsay C.
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Alm, Jessica J.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Heldring, Nina
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Moll, Guido
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Gavin, Caroline
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Batsis, Ioannis
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Sigvardsson, Mikael
    Linkoping Univ, Inst Clin & Expt Med, Linkoping, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kyllonen, Lauri E.
    Helsinki Univ Hosp, Div Transplantat, Helsinki, Finland..
    Salmela, Kaija T.
    Helsinki Univ Hosp, Div Transplantat, Helsinki, Finland..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Type 1 Diabetes Mellitus Donor Mesenchymal. Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro2016In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 5, no 11, p. 1485-1495Article in journal (Refereed)
    Abstract [en]

    Bone marrow mesenchymal stromal cells (BM-MSCs) have been characterized and used in many clinical studies based on their immunomodulatory and regenerative properties. We have recently reported the benefit of autologous MSC systemic therapy in the treatment of type 1 diabetes mellitus (T1D). Compared with allogeneic cells, use of autologous products reduces the risk of eliciting undesired complications in the recipient, including rejection, immunization, and transmission of viruses and prions; however, comparable potency of autologous cells is required for this treatment approach to remain feasible. To date, no analysis has been reported that phenotypically and functionally characterizes MSCs derived from newly diagnosed and late-stage T1D donors in vitro with respect to their suitability for systemic immunotherapy. In this study, we used gene array in combination with functional in vitro assays to address these questions. MSCs from T1D donors and healthy controls were expanded from BM aspirates. BM mononuclear cell counts and growth kinetics were comparable between the groups, with equivalent colony-forming unit-fibroblast capacity. Gene microarrays demonstrated differential gene expression between healthy and late-stage T1D donors in relation to cytokine secretion, immunomodulatory activity, and wound healing potential. Despite transcriptional differences, T1D MSCs did not demonstrate a significant difference from healthy controls in immunosuppressive activity, migratory capacity, or hemocompatibility. We conclude that despite differential gene expression, expanded MSCs from T1D donors are phenotypically and functionally similar to healthy control MSCs with regard to their immunomodulatory and migratory potential, indicating their suitability for use in autologous systemic therapy.

  • 47.
    Drott, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Franzén, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ghrelin in rat pancreatic islets decreases islet blood flow and impairs insulin secretion2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S218-S218Article in journal (Other academic)
  • 48.
    Drott, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Emanuelsson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Christoffersson, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sustained Beta-Cell Dysfunction but Normalized Islet Mass in Aged Thrombospondin-1 Deficient Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47451-Article in journal (Refereed)
    Abstract [en]

    Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only similar to 15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  • 49.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 10, p. 3428-3437Article in journal (Refereed)
    Abstract [en]

    In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

  • 50.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Reinius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Severe diabetic ketoacidosis in combination with starvation and anorexia nervosa at onset of type 1 diabetes: A case report2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 2, p. 130-133Article in journal (Refereed)
    Abstract [en]

    We here report a case of diabetic ketoacidosis at onset of type 1 diabetes after a prolonged period of starvation due to anorexia nervosa. A 53-year-old female with a history of anorexia nervosa was admitted to the psychiatric clinic due to psychotic behaviour and inability to take care of herself. Twenty-four hours after admission she was transferred to the clinic of internal medicine due to altered mental status, and laboratory screening revealed a pH of 6.895 and blood glucose concentration of 40 mmol/L. Due to the unusual combination of prolonged starvation and diabetic ketoacidosis we implemented some modifications of existing treatment guidelines and some special considerations regarding nutrition in order to prevent a re-feeding syndrome.

1234 1 - 50 of 172
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