Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

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 and Hsiao Chang Chan ()
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Jing Hui Guo: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Hui Chen: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Ye Chun Ruan: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Xue Lian Zhang: Beijing Tongren Hospital, Capital Medical University
Xiao Hu Zhang: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Kin Lam Fok: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Lai Ling Tsang: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Mei Kuen Yu: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Wen Qing Huang: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Xiao Sun: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Yiu Wa Chung: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Xiaohua Jiang: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong
Yoshiro Sohma: Keio University School of Medicine, Shinjuku
Hsiao Chang Chan: Epithelial Cell Biology Research Center, Key Laboratory of Regenerative Medicine of Ministry of Education of China, CUHK—SJTU Joint Center for Human Reproduction and Related Disease, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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, Ca2+ 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.

Date: 2014
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DOI: 10.1038/ncomms5420

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