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Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets

Maedler, Kathrin
Sergeev, Pavel
Ehses, J. A.
Mathe, Zoltan
Reinecke, Manfred
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Published in Proceedings of the National Academy of Sciences. 2004, vol. 101, no. 21, p. 8138-8143
Abstract High concentrations of glucose induce beta cell production of IL-1beta, leading to impaired beta cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1beta and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1beta and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic beta cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased beta cell production of IL-1Ra and induced IL-1beta release from the islet preparation, leading to impaired beta cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired beta cell function. Moreover, siIL-1Ra enhanced glucose-induced beta cell apoptosis. These findings demonstrate expression of IL-1Ra in the human beta cell, providing localized protection against leptin- and glucose-induced islet IL-1beta.
Keywords Apoptosis/drug effectsCaspase 3Caspases/metabolismCell Survival/drug effectsDiabetes Mellitus, Type 2/genetics/metabolism/pathologyDown-Regulation/drug effectsGene Expression Regulation/ drug effectsHumansInterleukin 1 Receptor Antagonist ProteinInterleukin-1/antagonists & inhibitors/metabolism/ secretionIslets of Langerhans/ drug effects/enzymology/metabolism/pathologyLeptin/antagonists & inhibitors/ pharmacologySialoglycoproteins/antagonists & inhibitors/genetics/ metabolism/pharmacologySignal Transduction/drug effects
PMID: 15141093
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Research groups La transplantation d'îlots de Langerhans (623)
Fonction de l'îlot de Langerhans (324)
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MAEDLER, Kathrin et al. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. In: Proceedings of the National Academy of Sciences, 2004, vol. 101, n° 21, p. 8138-8143. https://archive-ouverte.unige.ch/unige:8876

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Deposited on : 2010-07-12

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