Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig.
OBJECTIVE
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) 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); 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.kg(-1).min(-1)). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (DeltaAUC(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%; 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.kg(-1).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.kg(-1).min(-1); p<0.02), potentiating the antihyperglycaemic/insulinotropic effects of GLP-1 (glucose deltaAUC(min 27- 87) 103+/-8 to 62+/-14 min.mmol.l(-1); k 6.8+/-0.4 to 11.4+/-1.4%; insulin deltaAUC(min 27-87) 3,680+/-738 to 7,201+/-1,183 min.pmol.l(-1); p<0.05).


CONCLUSIONS
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.
Plamboeck
A
A
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Holst
J J
JJ
Carr
R D
RD
Deacon
C F
CF
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D019540:Area Under Curve; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D007189:Indans / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D015260:Neprilysin / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D013552:Swine
D000959:Antihypertensive Agents; D007189:Indans; D007328:Insulin; D011422:Propionates; D005934:Glucagon; C062766:candoxatril; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin