Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig.

Abstract

Glucagon-like peptide 1 (GLP-1) has been proposed as a new therapeutic agent in the management of diabetes because of its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation in vivo by dipeptidyl peptidase IV (DPP IV). In nonfasted anesthetized pigs, valine-pyrrolidide (a stable and selective inhibitor of DPP IV), at a dose that reduced plasma DPP IV activity by more than 90%, increased both the amount of intact GLP-1 in the basal state (from 5 +/- 1 to 18 +/- 7 pmol/l; P < 0.05) and the proportion remaining undegraded during an infusion (from 21.0 +/- 1.3 to 102.3 +/- 4.5%; P < 0.0001). This was associated with a prolonged plasma half-life for the intact peptide (from 1.0 +/- 0.1 to 3.2 +/- 0.2 min; P < 0.0005). In the basal (nonfasted) state, valine-pyrrolidide potentiated the effect of intravenous GLP-1 on the incremental area under the curve (AUC) for glucose (-0.50 +/- 0.91 to -2.83 +/- 0.59 20 min x mmol x l(-1); P < 0.05) and insulin (23.8 +/- 30.5 to 332.5 +/- 99.6 20 min x pmol x l(-1); P < 0.05). When an intravenous glucose load was given during the GLP-1 infusion, valine-pyrrolidide augmented the insulin response (AUC, 2,086.2 +/- 600.9 to 6,247.0 +/- 1443.9 40 min x pmol x l(-1); P < 0.05). These results suggest that by reducing GLP-1 degradation, DPP IV inhibition potentiates the insulinotropic effect of GLP-1 and may, therefore, be a viable approach to the management of diabetes.