Abstract |
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 β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca(2+) oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-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 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.
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Authors | Jing Hui Guo, Hui Chen, Ye Chun Ruan, Xue Lian Zhang, Xiao Hu Zhang, Kin Lam Fok, Lai Ling Tsang, Mei Kuen Yu, Wen Qing Huang, Xiao Sun, Yiu Wa Chung, Xiaohua Jiang, Yoshiro Sohma, Hsiao Chang Chan |
Journal | Nature communications
(Nat Commun)
Vol. 5
Pg. 4420
(Jul 15 2014)
ISSN: 2041-1723 [Electronic] England |
PMID | 25025956
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Insulin
- Cystic Fibrosis Transmembrane Conductance Regulator
- Glucose
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Topics |
- Animals
- Cystic Fibrosis Transmembrane Conductance Regulator
(genetics, metabolism)
- Enzyme-Linked Immunosorbent Assay
- Glucose
(pharmacology)
- Insulin
(metabolism)
- Insulin Secretion
- Insulin-Secreting Cells
(drug effects, metabolism)
- Male
- Membrane Potentials
(drug effects)
- Mice
- Mice, Inbred C57BL
- Patch-Clamp Techniques
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