期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5420
关键词
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资金
- National Major Basic Research Program of China [2012CB944903, 2013CB967404, 2013CB967401, 2013CB967403]
- Focused Investment Scheme of the Chinese University of Hong Kong [1907020]
- Lui Che Woo Foundation (SMART Program) [8303201, 8303202, 8303212]
- K.S. Lo Foundation [7104494]
- Grants-in-Aid for Scientific Research [25293049] Funding Source: KAKEN
The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in beta-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2+ oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse beta-cells or RINm5F beta-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 beta-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in beta-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.
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