Modeling and NMR studies of GLP-1 suggest a b-turn between Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. Helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased both peptide helicity and cAMP potency. Strong correlation was observed for binding affinity with b-arrestin 2 signalling(rs = 0.94) than cAMP stimulation(rs = 0.64). Increased insulin secretion correlated well with helicity and cAMP activity rather than with b-arrestin 2 signaling.