Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Aims/hypothesis: The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear. Methods: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/ pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs. Results: During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t(1/2).3 +/- 0.1 to 8.8 +/- 1.2 min; metabolic clearance rate [MCR] 20.4 +/- 3.4 to 4.8 +/- 0.4 ml center dot kg(-1) center dot min(-1); p< 0.01), but had no effect upon intact GLP-1 (t(1/2) 1.4 +/- 0.1 to 1.6 +/- 0.1 min; MCR 47.9 +/- 8.0 to 38.8 +/- 5.0 ml center dot kg(-1) center dot min(-1)). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (Delta AUC(min 27 - 87) 118 +/- 5 to 74 +/- 14 min center dot mmol center dot l(-1); glucose elimination rate [k] 6.6 +/- 0.5 to 8.6 +/- 0.5%; p< 0.05). When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t(1/2) 2.7 +/- 0.3 and 7.7 +/- 0.8 min; MCR 17.3 +/- 2.6 and 6.5 +/- 0.8 ml center dot kg(-1) center dot min(-1) for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t(1/2) 2.8 +/- 0.3 and 7.5 +/- 0.6 min; MCR 18.3 +/- 0.6 and 9.4 +/- 0.9 ml center dot kg(-1) center dot min(-1); p< 0.02), potentiating the antihyperglycaemic/ insulinotropic effects of GLP-1 ( glucose Delta AUC(min 27 - 87) 103 +/- 8 to 62 +/- 14 min center dot mmol center dot l(-1); k 6.8 +/- 0.4 to 11.4 +/- 1.4%; insulin Delta AUC(min 27 - 87) 3,680 +/- 738 to 7,201 +/- 1,183 min center dot pmol center dot l(-1); p< 0.05). Conclusions/interpretation: This study confirms a role for NEP-24.11 in GLP-1 metabolism in vivo, suggesting that up to 50% of GLP-1 entering the circulation may be degraded by NEP-24.11. Furthermore, combined inhibition of DPP-IV and NEP-24.11 is superior to DPP-IV inhibition alone in preserving intact GLP-1, which raises the possibility that the combination has therapeutic potential.