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β Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs β Cell Proliferation and Insulin Secretion

Published on Feb 1, 2018in Cell Reports7.815
· DOI :10.1016/j.celrep.2018.01.063
Marianne Böni-Schnetzler18
Estimated H-index: 18
(University of Basel),
Stéphanie P. Häuselmann5
Estimated H-index: 5
(University of Basel)
+ 10 AuthorsMarc Y. Donath60
Estimated H-index: 60
(University of Basel)
Sources
Abstract
Summary Interleukin-1 receptor antagonist (IL-1Ra) is elevated in the circulation during obesity and type 2 diabetes (T2D) but is decreased in islets from patients with T2D. The protective role of local IL-1Ra was investigated in pancreatic islet β cell (βIL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in β cells, but not in myeloid cells, resulted in diminished islet IL-1Ra expression. Myeloid cells were not the main source of circulating IL-1Ra in obesity. βIL-1Ra KO mice had impaired insulin secretion, reduced β cell proliferation, and decreased expression of islet proliferation genes, along with impaired glucose tolerance. The key cell-cycle regulator E2F1 partly reversed IL-1β-mediated inhibition of potassium channel Kir6.2 expression and rescued impaired insulin secretion in IL-1Ra knockout islets. Our findings provide evidence for the importance of β cell-derived IL-1Ra for the local defense of β cells to maintain normal function and proliferation.
  • References (52)
  • Citations (10)
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Summary Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stre...
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