Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets.
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.
Maedler
Kathrin
K
Division of Endocrinology and Diabetes, University Hospital, CH8091 Zurich, Switzerland.
Sergeev
Pavel
P
Ehses
Jan A
JA
Mathe
Zoltan
Z
Bosco
Domenico
D
Berney
Thierry
T
Dayer
Jean-Michel
JM
Reinecke
Manfred
M
Halban
Philippe A
PA
Donath
Marc Y
MY
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020738:Leptin; D012795:Sialoglycoproteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases