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

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Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. / Plamboeck, A; Holst, Jens Juul; Carr, R D; Deacon, C F.

In: Diabetologia, Vol. 48, No. 9, 09.2005, p. 1882-90.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Plamboeck, A, Holst, JJ, Carr, RD & Deacon, CF 2005, 'Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig', Diabetologia, vol. 48, no. 9, pp. 1882-90. https://doi.org/10.1007/s00125-005-1847-7

APA

Plamboeck, A., Holst, J. J., Carr, R. D., & Deacon, C. F. (2005). Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia, 48(9), 1882-90. https://doi.org/10.1007/s00125-005-1847-7

Vancouver

Plamboeck A, Holst JJ, Carr RD, Deacon CF. Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia. 2005 Sep;48(9):1882-90. https://doi.org/10.1007/s00125-005-1847-7

Author

Plamboeck, A ; Holst, Jens Juul ; Carr, R D ; Deacon, C F. / Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. In: Diabetologia. 2005 ; Vol. 48, No. 9. pp. 1882-90.

Bibtex

@article{0b3ad1553a1440c0a424c0ec345a2e22,
title = "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(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/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.",
keywords = "Animals, Antihypertensive Agents, Area Under Curve, Dipeptidyl Peptidase 4, Glucagon, Indans, Insulin, Metabolic Clearance Rate, Models, Animal, Neprilysin, Propionates, Swine",
author = "A Plamboeck and Holst, {Jens Juul} and Carr, {R D} and Deacon, {C F}",
year = "2005",
month = "9",
doi = "10.1007/s00125-005-1847-7",
language = "English",
volume = "48",
pages = "1882--90",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",
number = "9",

}

RIS

TY - JOUR

T1 - Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

AU - Plamboeck, A

AU - Holst, Jens Juul

AU - Carr, R D

AU - Deacon, C F

PY - 2005/9

Y1 - 2005/9

N2 - 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) 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/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.

AB - 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) 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/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.

KW - Animals

KW - Antihypertensive Agents

KW - Area Under Curve

KW - Dipeptidyl Peptidase 4

KW - Glucagon

KW - Indans

KW - Insulin

KW - Metabolic Clearance Rate

KW - Models, Animal

KW - Neprilysin

KW - Propionates

KW - Swine

U2 - 10.1007/s00125-005-1847-7

DO - 10.1007/s00125-005-1847-7

M3 - Journal article

C2 - 16025254

VL - 48

SP - 1882

EP - 1890

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -

ID: 132053583