Glucagon-like peptide 1-(7-37) [GLP-I-(7-37)] is a 31-amino acid hormone which may have an important role in the regulation of insulin secretion, It is processed from preproglucagon and found in the pancreas, brain, and, in highest quantity, intestine. In previous studies we found that GLP-I-(7-37) is a potent insulin secretagogue, and its effect was indistinguishable from that of GLP-I-(7-36) amide at concentrations of 10(-11) M. Herein we report insulinotropic effects of additional GLP-I analogs. GLP-I-(7-34) had no stimulatory effect on insulin release at 10(-10) M, but had a partial effect at 10(-9) M and was as active as GLP-I-(7-37) at 10(-8) M. GLP-I-(7-33) had no effect at any concentration tested. GLP-I-(8-37) caused no significant effect on insulin release at 10(-9) and 10(-8) M, but did have an effect at the high concentration of 10(-7) M. Similar results were found with cAMP formation in the beta TC1 line. In this system GLP-I-(7-34) was less potent than GLP-I-(7-37) at a concentration of 5 x 10(-9) M. GLP-I-(7-33) had only about 0.1% the potency of GLP-I-(7-37); thus, there is good agreement between cAMP formation in the beta-cell line and insulin secretion from the perfused pancreas experiments. We conclude that histidine in the 7 position in the N-terminus of GLP-I-(7-37) is crucial for cAMP formation and insulin secretion, and that removal of the last three C-terminus residues of GLP-I-(7-37) results in only partial loss of activity; the residue in the 34 position is, however, essential for the insulinotropic action.