LAUSR

&NA; The secretion of glucagon by islet &agr; 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 &agr; 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 &agr; cells, a defect of which may contribute to glucose intolerance in CF and other types of diabetes.