The secretion of glucagon by islet a 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 Cl2 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 KATPblockers are significantly greater in wild-Type/CFTR-overexpressed a cells compared with that in DF508/nonoverexpressed cells. KATPknockdown also reverses the suppressive effect of CFTR overexpression on glucagon secretion. The results reveal that by potentiating KATPchannels, CFTR acts as a glucosesensing negative regulator of glucagon secretion in a cells, a defect of which may contribute to glucose intolerance in CF and other types of diabetes.
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