title: Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR.
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.
authors.affiliation: 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, Hong Kong, China.
authors.forename: Jing Hui
authors.initials: JH
authors.lastname: Guo
authors.affiliation: 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, Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1] 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, Hong Kong, China [2] Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education of China, West China Second University Hospital, Sichuan University, Chengdu 610041, China [3] Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ye Chun
authors.initials: YC
authors.lastname: Ruan
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
authors.forename: Xue Lian
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: 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, Hong Kong, China.
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: 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, Hong Kong, China.
authors.forename: Kin Lam
authors.initials: KL
authors.lastname: Fok
authors.affiliation: 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, Hong Kong, China.
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.affiliation: 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, Hong Kong, China.
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.affiliation: 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, Hong Kong, China.
authors.forename: Wen Qing
authors.initials: WQ
authors.lastname: Huang
authors.affiliation: 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, Hong Kong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Sun
authors.affiliation: 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, Hong Kong, China.
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Chung
authors.affiliation: 1] 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, Hong Kong, China [2] Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education of China, West China Second University Hospital, Sichuan University, Chengdu 610041, China [3] Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Sohma
authors.affiliation: 1] 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, Hong Kong, China [2] Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education of China, West China Second University Hospital, Sichuan University, Chengdu 610041, China [3] Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques
chemical_list: D007328:Insulin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005947:Glucose