Comparison of the effect of native glucagon-like peptide I and dipeptidyl peptidase IV-resistant analogues on insulin release from rat pancreatic islets

Background Glucagon-like peptide I (GLP-1) stimulates insulin secretion and may improve glycaemic control in type 2 diabetes. Therapeutic use is limit ed by its rapid degradation, primarily by dipeptidyl peptidase TV. Materials and methods Five GLP-1 analogues with alterations at cleavage pos itions were synthesized according to the Fmoc strategy and tested for metab olic stability by incubation with rat kidney membranes containing dipeptidy l peptidase IV activity Their insulinotropic effect was compared in isolate d rat pancreatic islets after 24 h maintenance in tissue culture. Ten islet s per vial were incubated for 30 min; insulin was measured radioimmunologic ally. Each analogue was compared with GLP-1 in the same experiment. Results All analogues were biologically active in isolated islets in the po tency order da2d8 = da2 > d2d9 > da2ds8 > desamino. Ar 16.7 mmolL(-1) gluco se, GLP-1 and GLP-1 analogues altered as position 2, or 2 and 8 significant ly (P < 0.05) increased insulin release at 10(-9) molL(-1). N-terminal modi fication of GLP-1 confers resistance to dipeptidyl peptidase IV degradation in rat kidney membranes in vitro. Conclusions The analogues tested are biologically active and resistant to d egradation by dipeptidyl peptidase TV. Their greater metabolic stability ma y help to realize the potential of GLP-I analogues in diabetes therapy.