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The potent role of the anti-inflammatory cytokine Interleukin-1 Receptor Antagonist to improve beta-cell function and survival in obesity and diabetes

English title The potent role of the anti-inflammatory cytokine Interleukin-1 Receptor Antagonist to improve beta-cell function and survival in obesity and diabetes
Applicant Sauter Nadine
Number 117035
Funding scheme Fellowships for prospective researchers
Research institution Division of Endocrinology and Diabetes David Geffen School of Medicine University of California UCLA
Institution of higher education Institution abroad - IACH
Main discipline Endocrinology
Start/End 01.01.2007 - 30.06.2008
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All Disciplines (3)

Discipline
Endocrinology
Molecular Biology
Cellular Biology, Cytology

Keywords (5)

diabetes; apoptosis; cytokines; interleukin-1 receptor antagonist; obesity

Lay Summary (English)

Lead
Lay summary
Chronic exposure of human pancreatic islets to elevated glucose concentrations induces beta-cell apoptosis and impaired beta-cell function. Hyperglycemia has been implicated in the progression of diabetes, accelerating beta-cell death and decreasing secretory function. The mechanisms of beta-cell destruction in a diabetic milieu are complex. We previously reported that the deleterious effects of glucose are partly mediated by the production and secretion of the pro-inflammatory cytokine Interleukin-1beta (IL-1beta) by beta-cells themselves. Interleukin-1 Receptor Antagonist (IL-1Ra) is a naturally occurring antagonist to IL-1beta and prevents glucose and IL-1beta-induced beta-cell failure in vitro. We found that IL-1Ra is able to protect from high fat diet (HFD)-induced diabetes in vivo by improving glucose tolerance and insulin secretion. The insulin transcription factor pancreatic duodenal homeobox-1 (PDX-1) translocates from the nucleus to the cytoplasm in mice under the high fat diet. This export is prevented in HFD-mice treated with IL-1Ra together with improved insulin production and secretion. Using isolated human islets, we confirmed that elevated glucose and IL-1beta induces shuttling of PDX-1 and that addition of IL-1Ra maintains its nuclear localization. Our aim is to further characterize the mechanisms of IL-1Ra-mediated ?-cell protection at a cellular level. We hypothesize an involvement of the JNK-Foxo1-pathway in the regulation of PDX-1 cellular localization. Taken together, our studies investigate the mechanisms of IL-1Ra-mediated beta-cell protection to elucidate its possible role in the future treatment of diabetes.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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