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Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors
Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated...
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Published in: | Endocrine Reviews 2014-12, Vol.35 (6), p.992-1019 |
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description | Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4. |
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Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://academic.oup.com/journals/pages/coronavirus .</rights><rights>Copyright © 2014 by the Endocrine Society 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6106-848c4836ad8798c64ad7a51c1e9471f1958fd0c858ca26867238f622a0dd671c3</citedby><cites>FETCH-LOGICAL-c6106-848c4836ad8798c64ad7a51c1e9471f1958fd0c858ca26867238f622a0dd671c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2406230326?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,315,786,790,798,891,27955,27957,27958,38551,43930</link.rule.ids><linktorsrc>$$Uhttps://www.proquest.com/docview/2406230326/abstract/?pq-origsite=primo$$EView_record_in_ProQuest$$FView_record_in_$$GProQuest</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25216328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mulvihill, Erin E</creatorcontrib><creatorcontrib>Drucker, Daniel J</creatorcontrib><title>Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors</title><title>Endocrine Reviews</title><addtitle>Endocr Rev</addtitle><description>Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.</description><subject>Animals</subject><subject>Clinical Trials as Topic</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Dipeptidyl Peptidase 4 - metabolism</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Humans</subject><subject>Mice</subject><subject>Reviews</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><issn>0163-769X</issn><issn>1945-7189</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>COVID</sourceid><recordid>eNptkU1vFSEYhYnR2Gt159pM4sZFqcAwfGxMmmo_kjbehUZ3hALToc7AFGZs7r-X6b22alxx4H04OW8OAK8xOsQEo_cuHRKEKcSobp6AFZa0gRwL-RSsEGY15Ex-3wMvcr5BCFEk5HOwRxpSRkSswLd1p9OgTezj9eagWneb7HdaB1tdOtPp4POQq9hWR2byMSzqox_dOHm76av1vdDZQVqdh85f-Smm_BI8a3Wf3avduQ--nnz6cnwGLz6fnh8fXUDDMGJQUGGoqJm2gkthGNWW6wYb7CTluMWyEa1FRjTCaMIE46QWLSNEI2sZx6beBx-2vuN8NThrXJiS7tWY_KDTRkXt1d-T4Dt1HX8qjpGgnBeDdzuDFG9nlyc1-Gxc3-vg4pwVZkQ0pKFcFvTtP-hNnFMo6ylCESM1qgkr1MGWMinmnFz7EAYjtTSmXFJLY2pprOBv_lzgAf5dUQHoFriL_eRS_tHPd8Whc7qfOlU6LS5SwsURk3KDy9MSo95-c8FGk3xwY3I5P0b-b5pfVKWxUA</recordid><startdate>201412</startdate><enddate>201412</enddate><creator>Mulvihill, Erin E</creator><creator>Drucker, Daniel J</creator><general>Endocrine Society</general><general>Copyright by The Endocrine Society</general><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>COVID</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201412</creationdate><title>Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors</title><author>Mulvihill, Erin E ; Drucker, Daniel J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6106-848c4836ad8798c64ad7a51c1e9471f1958fd0c858ca26867238f622a0dd671c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Clinical Trials as Topic</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Dipeptidyl Peptidase 4 - metabolism</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Humans</topic><topic>Mice</topic><topic>Reviews</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mulvihill, Erin E</creatorcontrib><creatorcontrib>Drucker, Daniel J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Coronavirus Research Database</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Endocrine Reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Mulvihill, Erin E</au><au>Drucker, Daniel J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors</atitle><jtitle>Endocrine Reviews</jtitle><addtitle>Endocr Rev</addtitle><date>2014-12</date><risdate>2014</risdate><volume>35</volume><issue>6</issue><spage>992</spage><epage>1019</epage><pages>992-1019</pages><issn>0163-769X</issn><eissn>1945-7189</eissn><notes>D.J.D. is supported by a Canada Research Chair in Regulatory Peptides and the Banting and Best Diabetes Center-Novo Nordisk Chair in Incretin Biology and Heart and Stroke Foundation of Canada Grant in Aid G-14–0005953 1417. E.E.M. has received postdoctoral fellowship funding from the Canadian Diabetes Association and Canadian Institute of Health Research.</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-3</notes><notes>content type line 23</notes><notes>ObjectType-Review-1</notes><abstract>Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>25216328</pmid><doi>10.1210/er.2014-1035</doi><tpages>28</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Clinical Trials as Topic Diabetes Mellitus, Type 2 - drug therapy Dipeptidyl Peptidase 4 - metabolism Dipeptidyl-Peptidase IV Inhibitors - pharmacology Dipeptidyl-Peptidase IV Inhibitors - therapeutic use Disease Models, Animal Humans Mice Reviews Signal Transduction - drug effects Signal Transduction - physiology |
title | Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors |
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