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

Abstract

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 _½ 2.3±0.1 to 8.8±1.2 min; metabolic clearance rate [MCR] 20.4±3.4 to 4.8±0.4 ml·kg⁻¹· min⁻¹; pt _½ 1.4±0.1 to 1.6±0.1 min; MCR 47.9±8.0 to 38.8±5.0 ml·kg⁻¹·min⁻¹). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (ΔAUC_{min 27–87} 118±5 to 74±14 min·mmol·l⁻¹; glucose elimination rate [k] 6.6±0.5 to 8.6±0.5%; pt _½ 2.7±0.3 and 7.7±0.8 min; MCR 17.3±2.6 and 6.5±0.8 ml·kg⁻¹·min⁻¹ for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t _½ 2.8±0.3 and 7.5±0.6 min; MCR 18.3±0.6 and 9.4±0.9 ml·kg⁻¹·min⁻¹; pmin 27– 87 103±8 to 62±14 min·mmol·l⁻¹; k 6.8±0.4 to 11.4±1.4%; insulin ΔAUC_{min 27–87} 3,680±738 to 7,201±1,183 min·pmol·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.