Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala⁸-substituted analogues of GLP-1, (Abu⁸)GLP-1 and (Val⁸)GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu⁸)GLP-1 and (Val⁸)GLP-1 exhibited moderate affinities (IC₅₀: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC₅₀: 0.37 nM). (Abu⁸)GLP-1 and (Val⁸)GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val⁸)GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu⁸ )GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val⁸)GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala⁸ in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val⁸)GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.