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Scientific article
English

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

Publication date2004
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 effects
  • Caspase 3
  • Caspases/metabolism
  • Cell Survival/drug effects
  • Diabetes Mellitus, Type 2/genetics/metabolism/pathology
  • Down-Regulation/drug effects
  • Gene Expression Regulation/ drug effects
  • Humans
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1/antagonists & inhibitors/metabolism/ secretion
  • Islets of Langerhans/ drug effects/enzymology/metabolism/pathology
  • Leptin/antagonists & inhibitors/ pharmacology
  • Sialoglycoproteins/antagonists & inhibitors/genetics/ metabolism/pharmacology
  • Signal Transduction/drug effects
Citation (ISO format)
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 of the United States of America, 2004, vol. 101, n° 21, p. 8138–8143. doi: 10.1073/pnas.0305683101
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ISSN of the journal0027-8424
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