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Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2001 In: Biochem. Biophys. Res. Commun., ISSN 0006-291, Vol. 281, no 2, 396-403 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2001. Vol. 281, no 2, 396-403 p.
URN: urn:nbn:se:uu:diva-90712OAI: oai:DiVA.org:uu-90712DiVA: diva2:163165
Available from: 2003-09-03 Created: 2003-09-03Bibliographically approved
In thesis
1. Role of Inducible Nitric Oxide Synthase and Melatonin in Regulation of β-cell Sensitivity to Cytokines
Open this publication in new window or tab >>Role of Inducible Nitric Oxide Synthase and Melatonin in Regulation of β-cell Sensitivity to Cytokines
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mechanisms of β-cell destruction leading to type 1 diabetes are complex and not yet fully understood, but infiltration of the islets of Langerhans by autoreactive immune cells is believed to be important. Activated macrophages and T-cells may then secrete cytokines and free radicals, which could selectively damage the β-cells. Among the cytokines, IL-1β, IFN-γ and TNF-α can induce expression of inducible nitric synthase (iNOS) and cyclooxygenase-2. Subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) formation may impair islet function.

In the present study, the ability of melatonin (an antioxidative and immunoregulatory hormone) to protect against β-cell damage induced by streptozotocin (STZ; a diabetogenic and free radical generating substance) or IL-1β exposure was examined. In vitro, melatonin counteracted STZ- but not IL-1β-induced islet suppression, indicating that the protective effect of melatonin is related to interference with free radical generation and DNA damage, rather than NO synthesis. In vivo, non-immune mediated diabetes induced by a single dose of STZ was prevented by melatonin.

Furthermore, the effects of proinflammatory cytokines were examined in islets obtained from mice with a targeted deletion of the iNOS gene (iNOS -/- mice) and wild-type controls. The in vitro data obtained show that exposure to IL-1β or (IL-1β + IFN-γ) induce disturbances in the insulin secretory pathway, which were independent of NO or PGE2 production and cell death. Initially after addition, in particular IL-1β seems to be stimulatory for the insulin secretory machinery of iNOS –/- islets, whereas IL-1β acts inhibitory after a prolonged period. Separate experiments suggest that the stimulatory effect of IL-1β involves an increased gene expression of phospholipase D1a/b. In addition, the formation of new insulin molecules appears to be affected, since IL-1β and (IL-1β + IFN-γ) suppressed mRNA expression of both insulin convertase enzymes and insulin itself.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 58 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1280
Cell biology, β-cell, Cyclooxygenase, Cytokine, Diabetes, IFN-γ, IL-1β, iNOS, Insulin, Melatonin, Nitric oxide, Pancreatic islets, Phospholipase D, Prostaglandin E2, Streptozotocin, Cellbiologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-3537 (URN)91-554-5704-5 (ISBN)
Public defence
2003-09-27, B22, Biomedical Centre (BMC), Uppsala, 10:15
Available from: 2003-09-03 Created: 2003-09-03Bibliographically approved

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