Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor
Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhib...
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| creator | Ansarullah Lu, Yan Holstein, Martha DeRuyter, Brittany Rabinovitch, Alex Guo, Zhiguang |
| description | Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.
Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.
Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.
Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes. |
| doi_str_mv | 10.1371/journal.pone.0053345 |
| format | Article |
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Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.
Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.
Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0053345</identifier><identifier>PMID: 23382843</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids, Heterocyclic - administration & dosage ; Animals ; Biology ; Blood Glucose - drug effects ; Cell growth ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental ; Dipeptidyl Peptidase 4 - metabolism ; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage ; Drug dosages ; G protein-coupled receptors ; Glucagon ; Glucagon-Like Peptide 1 - blood ; Glucose ; Glucose tolerance ; Humans ; Inhibitors ; Insulin ; Insulin-Secreting Cells - cytology ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - metabolism ; Medical research ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD - genetics ; Mice, Inbred NOD - metabolism ; Oxadiazoles - administration & dosage ; Pancreas ; Pediatrics ; Pyrazines - administration & dosage ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - metabolism ; Regeneration ; Regeneration - drug effects ; Replication ; Rodents ; Sitagliptin Phosphate ; Streptozocin ; Therapy ; Triazoles - administration & dosage</subject><ispartof>PloS one, 2013, Vol.8 (1), p.e53345-e53345</ispartof><rights>2013 Ansarullah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Ansarullah et al 2013 Ansarullah et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-1966e64c4b95f8581252ce277b2c0b23da976fd149c81c206a50a6e4e2f51b583</citedby><cites>FETCH-LOGICAL-c526t-1966e64c4b95f8581252ce277b2c0b23da976fd149c81c206a50a6e4e2f51b583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558424/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558424/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,4012,23853,27910,27911,27912,53778,53780,79355,79356</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23382843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wagner, Bridget</contributor><creatorcontrib>Ansarullah</creatorcontrib><creatorcontrib>Lu, Yan</creatorcontrib><creatorcontrib>Holstein, Martha</creatorcontrib><creatorcontrib>DeRuyter, Brittany</creatorcontrib><creatorcontrib>Rabinovitch, Alex</creatorcontrib><creatorcontrib>Guo, Zhiguang</creatorcontrib><title>Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.
Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.
Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.
Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.</description><subject>Acids, Heterocyclic - administration & dosage</subject><subject>Animals</subject><subject>Biology</subject><subject>Blood Glucose - drug effects</subject><subject>Cell growth</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental</subject><subject>Dipeptidyl Peptidase 4 - metabolism</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - administration & dosage</subject><subject>Drug dosages</subject><subject>G protein-coupled receptors</subject><subject>Glucagon</subject><subject>Glucagon-Like Peptide 1 - blood</subject><subject>Glucose</subject><subject>Glucose tolerance</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Insulin</subject><subject>Insulin-Secreting Cells - cytology</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred NOD - genetics</subject><subject>Mice, Inbred NOD - metabolism</subject><subject>Oxadiazoles - administration & dosage</subject><subject>Pancreas</subject><subject>Pediatrics</subject><subject>Pyrazines - administration & dosage</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Regeneration</subject><subject>Regeneration - drug effects</subject><subject>Replication</subject><subject>Rodents</subject><subject>Sitagliptin Phosphate</subject><subject>Streptozocin</subject><subject>Therapy</subject><subject>Triazoles - administration & dosage</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1DAUtRCIlsIfIIjEhk0Gv-NskFApZaRKjHh0a9mOk_Eosad2QtXf4kP4JhwmrVrE6lr3nnPuwweAlwiuEKnQu12Yolf9ah-8XUHICKHsEThGNcElx5A8vvc-As9S2s0gwflTcIQJEVhQcgwuv41umHo1Ot8Vv3-VxvZ9EW1nvY05GXyhbwoTBu38jFDF-eYrQnWhuuBdGotrN25z9uNmU64vC-e3TrsxxOfgSav6ZF8s8QT8-HT2_fRzefHlfH364aI0DPOxRDXnllNDdc1awQTCDBuLq0pjAzUmjaor3jaI1kYggyFXDCpuqcUtQ5oJcgJeH3T3fUhyOUmSiOCqpohSnhHrA6IJaif30Q0q3signPybCLGTKo7O9Fay1kKKNcTaZmajVQ2hoEpoqJQmfO72fuk26cE2xvoxqv6B6MOKd1vZhZ-SMCYoplng7SIQw9Vk0ygHl-aTK2_DlOfOn8IxyyFD3_wD_f929IAyMaQUbXs3DIJytsktS842kYtNMu3V_UXuSLe-IH8AJBW6NA</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Ansarullah</creator><creator>Lu, Yan</creator><creator>Holstein, Martha</creator><creator>DeRuyter, Brittany</creator><creator>Rabinovitch, Alex</creator><creator>Guo, Zhiguang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>2013</creationdate><title>Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor</title><author>Ansarullah ; Lu, Yan ; Holstein, Martha ; DeRuyter, Brittany ; Rabinovitch, Alex ; Guo, Zhiguang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-1966e64c4b95f8581252ce277b2c0b23da976fd149c81c206a50a6e4e2f51b583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acids, Heterocyclic - administration & dosage</topic><topic>Animals</topic><topic>Biology</topic><topic>Blood Glucose - drug effects</topic><topic>Cell growth</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental</topic><topic>Dipeptidyl Peptidase 4 - metabolism</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - administration & dosage</topic><topic>Drug dosages</topic><topic>G protein-coupled receptors</topic><topic>Glucagon</topic><topic>Glucagon-Like Peptide 1 - blood</topic><topic>Glucose</topic><topic>Glucose tolerance</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Insulin</topic><topic>Insulin-Secreting Cells - cytology</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred NOD - genetics</topic><topic>Mice, Inbred NOD - metabolism</topic><topic>Oxadiazoles - administration & dosage</topic><topic>Pancreas</topic><topic>Pediatrics</topic><topic>Pyrazines - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ansarullah</au><au>Lu, Yan</au><au>Holstein, Martha</au><au>DeRuyter, Brittany</au><au>Rabinovitch, Alex</au><au>Guo, Zhiguang</au><au>Wagner, Bridget</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013</date><risdate>2013</risdate><volume>8</volume><issue>1</issue><spage>e53345</spage><epage>e53345</epage><pages>e53345-e53345</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.
Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.
Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.
Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23382843</pmid><doi>10.1371/journal.pone.0053345</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| subjects | Acids, Heterocyclic - administration & dosage Animals Biology Blood Glucose - drug effects Cell growth Diabetes Diabetes mellitus Diabetes Mellitus, Experimental Dipeptidyl Peptidase 4 - metabolism Dipeptidyl-Peptidase IV Inhibitors - administration & dosage Drug dosages G protein-coupled receptors Glucagon Glucagon-Like Peptide 1 - blood Glucose Glucose tolerance Humans Inhibitors Insulin Insulin-Secreting Cells - cytology Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Medical research Medicine Mice Mice, Inbred C57BL Mice, Inbred NOD - genetics Mice, Inbred NOD - metabolism Oxadiazoles - administration & dosage Pancreas Pediatrics Pyrazines - administration & dosage Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Regeneration Regeneration - drug effects Replication Rodents Sitagliptin Phosphate Streptozocin Therapy Triazoles - administration & dosage |
| title | Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T13%3A42%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Stimulating%20%CE%B2-cell%20regeneration%20by%20combining%20a%20GPR119%20agonist%20with%20a%20DPP-IV%20inhibitor&rft.jtitle=PloS%20one&rft.au=Ansarullah&rft.date=2013&rft.volume=8&rft.issue=1&rft.spage=e53345&rft.epage=e53345&rft.pages=e53345-e53345&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0053345&rft_dat=%3Cproquest_plos_%3E1284625128%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1327941446&rft_id=info:pmid/23382843&rft_doaj_id=oai_doaj_org_article_5fe042b02be446dba90084a8b0aab368&rfr_iscdi=true |