Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig
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. The effect o...
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| Veröffentlicht in: | Diabetologia 2005-09, Vol.48 (9), p.1882-1890 |
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| creator | PLAMBOECK, A HOIST, J. J CARR, R. D DEACON, C. F |
| description | 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.
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.
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 |
| doi_str_mv | 10.1007/s00125-005-1847-7 |
| format | Article |
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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.
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).
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.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-005-1847-7</identifier><identifier>PMID: 16025254</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Antihypertensive Agents - pharmacology ; Area Under Curve ; Biological and medical sciences ; Diabetes ; Diabetes. Impaired glucose tolerance ; Dipeptidyl Peptidase 4 - metabolism ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Enzymes ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Glucagon ; Glucagon - blood ; Glucose ; Hogs ; Indans - pharmacology ; Insulin - blood ; Medical sciences ; Metabolic Clearance Rate ; Metabolism ; Models, Animal ; Neprilysin - metabolism ; Pharmacokinetics ; Physiology ; Polypeptides ; Propionates - pharmacology ; Swine</subject><ispartof>Diabetologia, 2005-09, Vol.48 (9), p.1882-1890</ispartof><rights>2005 INIST-CNRS</rights><rights>Springer-Verlag 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c399t-f259aaf37a323a19aa4fc46b8db8d9f714523b29aed02a1ca88cb678cd2bbc993</citedby><cites>FETCH-LOGICAL-c399t-f259aaf37a323a19aa4fc46b8db8d9f714523b29aed02a1ca88cb678cd2bbc993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17117274$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16025254$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PLAMBOECK, A</creatorcontrib><creatorcontrib>HOIST, J. J</creatorcontrib><creatorcontrib>CARR, R. D</creatorcontrib><creatorcontrib>DEACON, C. F</creatorcontrib><title>Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><description>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.
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.
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).
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.</description><subject>Animals</subject><subject>Antihypertensive Agents - pharmacology</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Dipeptidyl Peptidase 4 - metabolism</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Enzymes</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Glucagon</subject><subject>Glucagon - blood</subject><subject>Glucose</subject><subject>Hogs</subject><subject>Indans - pharmacology</subject><subject>Insulin - blood</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate</subject><subject>Metabolism</subject><subject>Models, Animal</subject><subject>Neprilysin - metabolism</subject><subject>Pharmacokinetics</subject><subject>Physiology</subject><subject>Polypeptides</subject><subject>Propionates - pharmacology</subject><subject>Swine</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkd9qFTEQxoMo9lh9AG8kCHq3NX832UspthaK3lTxLswm2dPUPcma7F70MfrGZj0LB4RAhvl-8zHMh9BbSi4oIepTIYQy2RAiG6qFatQztKOCs4YIpp-j3SpXpf11hl6V8kAI4VK0L9EZbQmTTIodevrmlznDiH10afLTHBwUj5m4oBRDdNiFY_dxxCf55ieG7HGf5nt88C7AnHLBacDzvcfO7zM4mEOKa2s_Lhb2KTZj-O03D48pDvEfDRF8qcUcind4CvvX6MUAY_Fvtv8c_bj6cnf5tbn9fn1z-fm2sbzr5mZgsgMYuALOONBai8GKtteuvm5QVEjGe9aBd4QBtaC17VulrWN9b7uOn6OPR98ppz9L3cEcQrF-HCH6tBTTaqnbesEKvv8PfEhLjnU3wyjXknC1QvQI2ZxKyX4wUw4HyI-GErOGZY5hmRqWWcMyqs6824yXvl7xNLGlU4EPGwDFwjhkiDaUE6coVUwJ_hdX7521</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>PLAMBOECK, A</creator><creator>HOIST, J. 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Target tissue resistance</topic><topic>Glucagon</topic><topic>Glucagon - blood</topic><topic>Glucose</topic><topic>Hogs</topic><topic>Indans - pharmacology</topic><topic>Insulin - blood</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate</topic><topic>Metabolism</topic><topic>Models, Animal</topic><topic>Neprilysin - metabolism</topic><topic>Pharmacokinetics</topic><topic>Physiology</topic><topic>Polypeptides</topic><topic>Propionates - pharmacology</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PLAMBOECK, A</creatorcontrib><creatorcontrib>HOIST, J. J</creatorcontrib><creatorcontrib>CARR, R. D</creatorcontrib><creatorcontrib>DEACON, C. 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J</au><au>CARR, R. D</au><au>DEACON, C. F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig</atitle><jtitle>Diabetologia</jtitle><addtitle>Diabetologia</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>48</volume><issue>9</issue><spage>1882</spage><epage>1890</epage><pages>1882-1890</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>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.
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.
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).
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.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>16025254</pmid><doi>10.1007/s00125-005-1847-7</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animals Antihypertensive Agents - pharmacology Area Under Curve Biological and medical sciences Diabetes Diabetes. Impaired glucose tolerance Dipeptidyl Peptidase 4 - metabolism Endocrine pancreas. Apud cells (diseases) Endocrinopathies Enzymes Etiopathogenesis. Screening. Investigations. Target tissue resistance Glucagon Glucagon - blood Glucose Hogs Indans - pharmacology Insulin - blood Medical sciences Metabolic Clearance Rate Metabolism Models, Animal Neprilysin - metabolism Pharmacokinetics Physiology Polypeptides Propionates - pharmacology Swine |
| title | 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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