期刊
CELL REPORTS
卷 9, 期 6, 页码 2219-2232出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.11.033
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资金
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Agence Nationale pour la Recherche [ANR 11 BSV1 003-01]
- Fondation pour la Recherche Medicale [FRM DEQ20110421295]
- Ministere de la Recherche
- Fondation ARC pour la recherche sur le Cancer
- MRC (UK) [MR/J0003042/1]
- BBSRC (UK [BB/J015873/1]
- Royal Society for a Wolfson Research Merit Award
- Wellcome Trust for a Senior Investigator Award [WT098424AIA]
- BBSRC [BB/J015873/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J015873/1] Funding Source: researchfish
Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature b cells in mice. Rfx6 loss in adult b cells leads to glucose intolerance, impaired beta cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of K-ATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of disallowed'' genes, a group usually specifically repressed in adult b cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to b cell failure in humans.
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