The beneficial effect of angiotensin(1-7), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how angiotensin(1-7) or MAS-1 affects insulin secretion remains elusive and whether endogenous level of angiotensin(1-7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of CFTR, a cAMP-activated Cl- channel, in regulation of insulin secretion. Here, we tested possible involvement of CFTR in mediating angiotensin(1-7)'s effect on insulin secretion and measured the level of angiotensin(1-7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes.Angiotensin(1-7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, western blotting as well as insulin ELISA in a pancreatic β cell line, RINm5F. Human blood samples were collected from 333 individuals with (n=197) and without (n=136) type 2 diabetes. Angiotensin(1-7), MAS-1 and CFTR level in the human blood were determined by ELISA.In RINm5F cells, angiotensin(1-7) induced intracellular cAMP increase, CREB activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not angiotensin(1-7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2-diabetic but not non-diabetic subjects.These results suggested MAS-1 and CFTR as key players in mediating angiotensin(1-7)-promoted insulin secretion in pancreatic β cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.