Huang Wen Qing, Guo Jing Hui, Zhang Xiao Hu, Yu Mei Kuen, Chung Yiu Wa, Ruan Ye Chun, Chan Hsiao Chang
Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, People's Republic of China.
Endocrinology. 2017 Oct 1;158(10):3188-3199. doi: 10.1210/en.2017-00282.
The secretion of glucagon by islet α cells is normally suppressed by high blood glucose, but this suppressibility is impaired in patients with diabetes or cystic fibrosis (CF), a disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate-activated Cl- channel. However, precisely how glucose regulates glucagon release remains controversial. Here we report that elevated glucagon secretion, together with increased glucose-induced membrane depolarization and Ca2+ response, is found in CFTR mutant (DF508) mice/islets compared with the wild-type. Overexpression of CFTR in AlphaTC1-9 cells results in membrane hyperpolarization and reduced glucagon release, which can be reversed by CFTR inhibition. CFTR is found to potentiate the adenosine triphosphate-sensitive K+ (KATP) channel because membrane depolarization and whole-cell currents sensitive to KATP blockers are significantly greater in wild-type/CFTR-overexpressed α cells compared with that in DF508/non-overexpressed cells. KATP knockdown also reverses the suppressive effect of CFTR overexpression on glucagon secretion. The results reveal that by potentiating KATP channels, CFTR acts as a glucose-sensing negative regulator of glucagon secretion in α cells, a defect of which may contribute to glucose intolerance in CF and other types of diabetes.
胰岛α细胞分泌胰高血糖素通常会受到高血糖的抑制，但在糖尿病患者或囊性纤维化（CF）患者中这种抑制能力受损。CF是一种由编码CF跨膜电导调节因子（CFTR）的基因突变引起的疾病，CFTR是一种环磷酸腺苷激活的氯离子通道。然而，葡萄糖究竟如何调节胰高血糖素的释放仍存在争议。在此我们报告，与野生型相比，在CFTR突变（DF508）小鼠/胰岛中发现胰高血糖素分泌增加，同时葡萄糖诱导的膜去极化和Ca2+反应增强。在AlphaTC1-9细胞中过表达CFTR会导致膜超极化并减少胰高血糖素释放，而CFTR抑制可使其逆转。发现CFTR增强了三磷酸腺苷敏感性钾（KATP）通道，因为与DF508/未过表达细胞相比，野生型/过表达CFTR的α细胞中的膜去极化和对KATP阻滞剂敏感的全细胞电流明显更大。敲低KATP也可逆转CFTR过表达对胰高血糖素分泌的抑制作用。结果表明，通过增强KATP通道，CFTR在α细胞中作为胰高血糖素分泌的葡萄糖感应负调节因子发挥作用，其缺陷可能导致CF和其他类型糖尿病中的葡萄糖不耐受。
