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PMID: 15141093 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 21 ·2004-05-25 ·Pages 8138-43

Maedler K, Sergeev P, Ehses JA, Mathe Z, Bosco D, Berney T, Dayer JM, Reinecke M, Halban PA, Donath MY

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.

MeSH Terms
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 Islets of Langerhans/drug effects,enzymology,metabolism,pathology Leptin/antagonists & inhibitors,pharmacology Sialoglycoproteins/antagonists & inhibitors,genetics,metabolism,pharmacology Signal Transduction/drug effects
Chemicals
IL1RN protein, human Interleukin 1 Receptor Antagonist Protein Interleukin-1 Leptin Sialoglycoproteins CASP3 protein, human Caspase 3 Caspases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Maedler Kathrin
Division of Endocrinology and Diabetes, University Hospital, CH8091 Zurich, Switzerland.
Sergeev Pavel
Ehses Jan A
Mathe Zoltan
Bosco Domenico
Berney Thierry
Dayer Jean-Michel
Reinecke Manfred
Halban Philippe A
Donath Marc Y
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0305683101
Published
2004-05-25
Epub
2004-00-12
Pages
8138-43
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC419570
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0305683101 PMC Full Text View journal details
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