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Efficacy of 1400W, a novel inhibitor of inducible nitric oxide synthase, in preventing interleukin-1β-induced suppression of pancreatic islet function in vitro and multiple low-dose streptozotocin-induced diabetes in vivo.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2002 In: European Journal of Endocrinology, ISSN 0804-4643, Vol. 147, no 4, 543-551 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 147, no 4, 543-551 p.
URN: urn:nbn:se:uu:diva-96374OAI: oai:DiVA.org:uu-96374DiVA: diva2:170929
Available from: 2007-11-09 Created: 2007-11-09Bibliographically approved
In thesis
1. Experimental Studies Aiming to Prevent Type 1 Diabetes Mellitus
Open this publication in new window or tab >>Experimental Studies Aiming to Prevent Type 1 Diabetes Mellitus
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which T-cells and macrophages invade the islets of Langerhans and selectively destroy the insulin producing β-cells, either directly or through the secretion of e.g. cytokines and nitric oxide (NO). This thesis has studied possible strategies to prevent T1DM. In β-cells and macrophages, NO is produced by inducible nitric oxide synthase (iNOS).

In the first study, we found that 1400W, a highly selective inhibitor of iNOS could prevent interleukin (IL)-1β induced suppression of rat islet function in vitro, but not diabetes induced by multiple low dose streptozotocin (MLDS), a well established animal model for autoimmune diabetes, in vivo.

Next, we wanted to test a new type of high affinity blocker of IL-1 action, called IL-1 trap, in vitro. Here we found that an IL-1 trap could prevent the suppressive effects by IL-1β on rat pancreatic islet function. Also, it was sufficient to block the action of IL-1β to prevent islet cell death induced by a combination of IL-1β, tumor necrosis factor-α and interferon-γ.

In study III, a murine IL-1 trap was found to prolong islet graft survival in the recurrence of disease (ROD) model, a T1DM model that involves syngeneic transplantation of healthy pancreatic islets to diabetic nonobese diabetic mice. Mice treated with IL-1 trap displayed an increased mRNA level of the cytokine IL-4 in isolated spleen cells. This suggests a shift towards Th2-cytokine production, which in part could explain the results.

Finally, simvastatin an anti-hypercholesterolemic drug that possesses anti-inflammatory properties e.g. by interfering with transendothelial migration of leukocytes to sites of inflammation was studied. We found that the administration of simvastatin could delay, and in some mice prevent, the onset of MLDS-diabetes, and prolong islet graft survival in the ROD model.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 288
Cell biology, Diabetes, Interleukin-1 trap, Simvastatin, Nitric oxide synthase, Cytokine, Pancreatic islet, Streptozotocin, Transplantation, Cellbiologi
urn:nbn:se:uu:diva-8292 (URN)978-91-554-7008-1 (ISBN)
Public defence
2007-11-30, C2:301, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-11-09 Created: 2007-11-09Bibliographically approved

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