A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats
The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study e...
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| Veröffentlicht in: | Biochemical pharmacology 2012-01, Vol.83 (2), p.241-252 |
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| creator | Akarte, Atul Sureshrao Srinivasan, B.P. Gandhi, Sonia |
| description | The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10
mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10
mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2
h and 10
h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1–10
mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1
mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes |
| doi_str_mv | 10.1016/j.bcp.2011.10.003 |
| format | Article |
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mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10
mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2
h and 10
h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1–10
mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1
mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2011.10.003</identifier><identifier>PMID: 22015634</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Adamantane - analogs & derivatives ; Adamantane - chemistry ; Adamantane - pharmacology ; Adamantane - therapeutic use ; Animals ; apoptosis ; Biological and medical sciences ; Blood Glucose - drug effects ; Blood Glucose - metabolism ; Cell Proliferation - drug effects ; Diabetes ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - enzymology ; Diabetes Mellitus, Experimental - pathology ; Diabetes. Impaired glucose tolerance ; Dipeptidyl peptidase-IV ; Dipeptidyl-Peptidase IV Inhibitors - chemistry ; Dipeptidyl-Peptidase IV Inhibitors - pharmacology ; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; gastric emptying ; Glucagon like peptide -1 ; glucose ; glucose tolerance tests ; glycation ; glycemic effect ; half life ; homeostasis ; Homeostasis - drug effects ; Homeostasis - physiology ; hypoglycemia ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; Hypoglycemic Agents - therapeutic use ; Insulin ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - enzymology ; Insulin-Secreting Cells - pathology ; Medical sciences ; Nitriles - chemistry ; Nitriles - pharmacology ; Nitriles - therapeutic use ; noninsulin-dependent diabetes mellitus ; patients ; pharmacology ; Pharmacology. Drug treatments ; Pyrrolidines - chemistry ; Pyrrolidines - pharmacology ; Pyrrolidines - therapeutic use ; Rats ; Rats, Wistar ; secretin ; streptozotocin ; therapeutics ; β-cell regeneration</subject><ispartof>Biochemical pharmacology, 2012-01, Vol.83 (2), p.241-252</ispartof><rights>2011 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-dd8f1f73f97898337392a228974c8f203553c25a1f9cc117de6f8fc62273acc83</citedby><cites>FETCH-LOGICAL-c406t-dd8f1f73f97898337392a228974c8f203553c25a1f9cc117de6f8fc62273acc83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bcp.2011.10.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25376167$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22015634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akarte, Atul Sureshrao</creatorcontrib><creatorcontrib>Srinivasan, B.P.</creatorcontrib><creatorcontrib>Gandhi, Sonia</creatorcontrib><title>A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10
mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10
mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2
h and 10
h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1–10
mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1
mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes</description><subject>Adamantane - analogs & derivatives</subject><subject>Adamantane - chemistry</subject><subject>Adamantane - pharmacology</subject><subject>Adamantane - therapeutic use</subject><subject>Animals</subject><subject>apoptosis</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - drug effects</subject><subject>Blood Glucose - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Experimental - enzymology</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Dipeptidyl peptidase-IV</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - chemistry</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>gastric emptying</subject><subject>Glucagon like peptide -1</subject><subject>glucose</subject><subject>glucose tolerance tests</subject><subject>glycation</subject><subject>glycemic effect</subject><subject>half life</subject><subject>homeostasis</subject><subject>Homeostasis - drug effects</subject><subject>Homeostasis - physiology</subject><subject>hypoglycemia</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Insulin</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - enzymology</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Medical sciences</subject><subject>Nitriles - chemistry</subject><subject>Nitriles - pharmacology</subject><subject>Nitriles - therapeutic use</subject><subject>noninsulin-dependent diabetes mellitus</subject><subject>patients</subject><subject>pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - pharmacology</subject><subject>Pyrrolidines - therapeutic use</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>secretin</subject><subject>streptozotocin</subject><subject>therapeutics</subject><subject>β-cell regeneration</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUuOEzEQhlsIxISBA7ABbxCrDn7Ejxar0cDAiJGIBMPWctzljCN3O9juSNyB03AQzoSbBNixKpfrq9_l-pvmKcFLgol4tVtu7H5JMSE1X2LM7jULoiRraSfU_WaBMRb1zOlZ8yjn3ZwqQR42Z7T2cMFWi-b7BRrjAQIKcdwiY4uv4c163V5_QX688xtfYkLrD1ctlbzFnKNc_DAFUyCjnz9aCyGgfYrBO0im-DiiBHkKv3X8iPxQiwfo0TZMNmZAd3GAmIvJPs_13psNFG9Rbc6PmwfOhAxPTvG8ub16-_nyfXvz8d315cVNa1dYlLbvlSNOMtdJ1SnGJOuooVR1cmWVo5hxzizlhrjOWkJkD8IpZwWlkhlrFTtvXh5162xfJ8hFDz7PPzEjxCnrjlBSV4VlJcmRtCnmnMDpffKDSd80wXr2QO909UDPHsxX1YPa8-ykPm0G6P92_Fl6BV6cAJOtCS6Z0fr8j-NMCiLmx58fOWeiNttUmdtPs0g1klKOeSVeHwmo2zp4SDpbD6OF3iewRffR_2fQX0CurZg</recordid><startdate>20120115</startdate><enddate>20120115</enddate><creator>Akarte, Atul Sureshrao</creator><creator>Srinivasan, B.P.</creator><creator>Gandhi, Sonia</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20120115</creationdate><title>A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats</title><author>Akarte, Atul Sureshrao ; Srinivasan, B.P. ; Gandhi, Sonia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-dd8f1f73f97898337392a228974c8f203553c25a1f9cc117de6f8fc62273acc83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adamantane - analogs & derivatives</topic><topic>Adamantane - chemistry</topic><topic>Adamantane - pharmacology</topic><topic>Adamantane - therapeutic use</topic><topic>Animals</topic><topic>apoptosis</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - drug effects</topic><topic>Blood Glucose - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Experimental - enzymology</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Dipeptidyl peptidase-IV</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - chemistry</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>gastric emptying</topic><topic>Glucagon like peptide -1</topic><topic>glucose</topic><topic>glucose tolerance tests</topic><topic>glycation</topic><topic>glycemic effect</topic><topic>half life</topic><topic>homeostasis</topic><topic>Homeostasis - drug effects</topic><topic>Homeostasis - physiology</topic><topic>hypoglycemia</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Hypoglycemic Agents - therapeutic use</topic><topic>Insulin</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - enzymology</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Medical sciences</topic><topic>Nitriles - chemistry</topic><topic>Nitriles - pharmacology</topic><topic>Nitriles - therapeutic use</topic><topic>noninsulin-dependent diabetes mellitus</topic><topic>patients</topic><topic>pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrrolidines - chemistry</topic><topic>Pyrrolidines - pharmacology</topic><topic>Pyrrolidines - therapeutic use</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>secretin</topic><topic>streptozotocin</topic><topic>therapeutics</topic><topic>β-cell regeneration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akarte, Atul Sureshrao</creatorcontrib><creatorcontrib>Srinivasan, B.P.</creatorcontrib><creatorcontrib>Gandhi, Sonia</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akarte, Atul Sureshrao</au><au>Srinivasan, B.P.</au><au>Gandhi, Sonia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2012-01-15</date><risdate>2012</risdate><volume>83</volume><issue>2</issue><spage>241</spage><epage>252</epage><pages>241-252</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10
mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10
mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2
h and 10
h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1–10
mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1
mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>22015634</pmid><doi>10.1016/j.bcp.2011.10.003</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Biochemical pharmacology, 2012-01, Vol.83 (2), p.241-252 |
| issn | 0006-2952 1873-2968 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Adamantane - analogs & derivatives Adamantane - chemistry Adamantane - pharmacology Adamantane - therapeutic use Animals apoptosis Biological and medical sciences Blood Glucose - drug effects Blood Glucose - metabolism Cell Proliferation - drug effects Diabetes Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - enzymology Diabetes Mellitus, Experimental - pathology Diabetes. Impaired glucose tolerance Dipeptidyl peptidase-IV Dipeptidyl-Peptidase IV Inhibitors - chemistry Dipeptidyl-Peptidase IV Inhibitors - pharmacology Dipeptidyl-Peptidase IV Inhibitors - therapeutic use Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance gastric emptying Glucagon like peptide -1 glucose glucose tolerance tests glycation glycemic effect half life homeostasis Homeostasis - drug effects Homeostasis - physiology hypoglycemia Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology Hypoglycemic Agents - therapeutic use Insulin Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - enzymology Insulin-Secreting Cells - pathology Medical sciences Nitriles - chemistry Nitriles - pharmacology Nitriles - therapeutic use noninsulin-dependent diabetes mellitus patients pharmacology Pharmacology. Drug treatments Pyrrolidines - chemistry Pyrrolidines - pharmacology Pyrrolidines - therapeutic use Rats Rats, Wistar secretin streptozotocin therapeutics β-cell regeneration |
| title | A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats |
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