Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents
PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clona...
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| creator | Owolabi, Bosede O. Musale, Vishal Ojo, Opeolu O. Moffett, R. Charlotte McGahon, Mary K. Curtis, Tim M. Conlon, J. Michael Flatt, Peter R. Abdel-Wahab, Yasser H.A. |
| description | PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clonal β-cells without cytotoxicity at concentrations up to 3 μM. In contrast, the [A3K] analogue was cytotoxic at concentrations ≥ 30 nM. The potency and maximum rate of insulin release produced by the [A14K] and [A20K] peptides were significantly greater than produced by PGLa-AM1. [A14K]PGLa-AM1 also stimulated insulin release from mouse islets at concentrations ≥ 1 nM and from the 1.1B4 human-derived pancreatic β-cell line at concentrations > 30 pM. PGLa-AM1 (1 μM) produced membrane depolarization in BRIN-BD11 cells with a small, but significant (P |
| doi_str_mv | 10.1016/j.biochi.2017.04.004 |
| format | Article |
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•PGLa-AM1 and its [A14K] and [A20K] analogues stimulate insulin release from BRIN-BD11 cells, 1.1B4 cells and mouse islets.•PGLa-AM1 produces membrane depolarization in BRIN-BD11 but had no direct effect on KATP channels.•[A14K]PGLa-AM1 activates the protein kinase A pathway in BRIN-BD11 cells.•[A14K]PGLa-AM1 stimulates proliferation and protects against cytokine-induced apoptosis in BRIN-BD11 cells.•[A14K]PGLa-AM1 and [A20K]PGLa-AM1 improve glucose tolerance and stimulate insulin secretion in lean and high fat fed mice.</description><identifier>ISSN: 0300-9084</identifier><identifier>EISSN: 1638-6183</identifier><identifier>DOI: 10.1016/j.biochi.2017.04.004</identifier><identifier>PMID: 28392407</identifier><language>eng</language><publisher>France: Elsevier B.V</publisher><subject>Amphibian Proteins - therapeutic use ; Amphibian skin peptide ; Animals ; Anti-apoptotic peptide ; Antimicrobial Cationic Peptides - therapeutic use ; Calcium - metabolism ; Cell Line ; Cyclic AMP-Dependent Protein Kinases - drug effects ; Cyclic AMP-Dependent Protein Kinases - genetics ; Down-Regulation ; Humans ; Hypoglycemic Agents - therapeutic use ; Insulin - metabolism ; Insulin Secretion ; Insulin-release ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - metabolism ; Mice ; PGLa-AM1 ; Pipidae ; Rats ; Signal Transduction ; Type 2 diabetes ; Xenopus Proteins - therapeutic use ; β-Cell proliferation</subject><ispartof>Biochimie, 2017-07, Vol.138, p.1-12</ispartof><rights>2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)</rights><rights>Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-d5c642efc847f682d542f3c442e16795698e3319f7c55b422235780cdd7994513</citedby><cites>FETCH-LOGICAL-c408t-d5c642efc847f682d542f3c442e16795698e3319f7c55b422235780cdd7994513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0300908417300883$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28392407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Owolabi, Bosede O.</creatorcontrib><creatorcontrib>Musale, Vishal</creatorcontrib><creatorcontrib>Ojo, Opeolu O.</creatorcontrib><creatorcontrib>Moffett, R. Charlotte</creatorcontrib><creatorcontrib>McGahon, Mary K.</creatorcontrib><creatorcontrib>Curtis, Tim M.</creatorcontrib><creatorcontrib>Conlon, J. Michael</creatorcontrib><creatorcontrib>Flatt, Peter R.</creatorcontrib><creatorcontrib>Abdel-Wahab, Yasser H.A.</creatorcontrib><title>Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents</title><title>Biochimie</title><addtitle>Biochimie</addtitle><description>PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clonal β-cells without cytotoxicity at concentrations up to 3 μM. In contrast, the [A3K] analogue was cytotoxic at concentrations ≥ 30 nM. The potency and maximum rate of insulin release produced by the [A14K] and [A20K] peptides were significantly greater than produced by PGLa-AM1. [A14K]PGLa-AM1 also stimulated insulin release from mouse islets at concentrations ≥ 1 nM and from the 1.1B4 human-derived pancreatic β-cell line at concentrations > 30 pM. PGLa-AM1 (1 μM) produced membrane depolarization in BRIN-BD11 cells with a small, but significant (P < 0.05), increase in intracellular Ca2+ concentrations but the peptide had no direct effect on KATP channels. The [A14K] analogue (1 μM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of the peptide. [A14K]PGLa-AM1 (1 μM) protected against cytokine-induced apoptosis (p < 0.001) in BRIN-BD11 cells and augmented (p < 0.001) proliferation of the cells to a similar extent as GLP-1. Intraperitoneal administration of the [A14K] and [A20K] analogues (75 nmol/kg body weight) to both lean mice and high fat-fed mice with insulin resistance improved glucose tolerance with a concomitant increase in insulin secretion. The data provide further support for the assertion that host defense peptides from frogs belonging to the Pipidae family show potential for development into agents for the treatment of patients with Type 2 diabetes.
•PGLa-AM1 and its [A14K] and [A20K] analogues stimulate insulin release from BRIN-BD11 cells, 1.1B4 cells and mouse islets.•PGLa-AM1 produces membrane depolarization in BRIN-BD11 but had no direct effect on KATP channels.•[A14K]PGLa-AM1 activates the protein kinase A pathway in BRIN-BD11 cells.•[A14K]PGLa-AM1 stimulates proliferation and protects against cytokine-induced apoptosis in BRIN-BD11 cells.•[A14K]PGLa-AM1 and [A20K]PGLa-AM1 improve glucose tolerance and stimulate insulin secretion in lean and high fat fed mice.</description><subject>Amphibian Proteins - therapeutic use</subject><subject>Amphibian skin peptide</subject><subject>Animals</subject><subject>Anti-apoptotic peptide</subject><subject>Antimicrobial Cationic Peptides - therapeutic use</subject><subject>Calcium - metabolism</subject><subject>Cell Line</subject><subject>Cyclic AMP-Dependent Protein Kinases - drug effects</subject><subject>Cyclic AMP-Dependent Protein Kinases - genetics</subject><subject>Down-Regulation</subject><subject>Humans</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Insulin-release</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Mice</subject><subject>PGLa-AM1</subject><subject>Pipidae</subject><subject>Rats</subject><subject>Signal Transduction</subject><subject>Type 2 diabetes</subject><subject>Xenopus Proteins - therapeutic use</subject><subject>β-Cell proliferation</subject><issn>0300-9084</issn><issn>1638-6183</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtP3DAQgC3Uqmxp_wGqcuwl6fgZ-4IUIaCIreAAJ1RZXtsBr7LxYnuR-u9JdmmPvfgx882M_SF0iqHBgMWPdbMK0T6HhgBuG2ANADtCCyyorAWW9ANaAAWoFUh2jD7nvAYADkR9QsdEUkUYtAsUO1tCHHMV--ruamnq7heuzOiqUHL12GF283t_fewI7I9miE87n_fB8uxDmtdktn5Xgq22sfixBDNUZkZKqF0wKz-nzNOUyV_Qx94M2X9930_Qw-XF_fnPenl7dX3eLWvLQJbacSsY8b2VrO2FJI4z0lPLphgWreJCSU8pVn1rOV8xQgjlrQTrXKsU45ieoO-HvtsUX6b3Fr0J2fphMKOPu6yxlIJy4EpMKDugNsWck-_1NoWNSX80Bj2r1mt9UK1n1RqYnlRPZd_eJ-xWG-_-Ff11OwFnB8BP_3wNPulsgx-tdyF5W7SL4f8T3gCV746X</recordid><startdate>201707</startdate><enddate>201707</enddate><creator>Owolabi, Bosede O.</creator><creator>Musale, Vishal</creator><creator>Ojo, Opeolu O.</creator><creator>Moffett, R. Charlotte</creator><creator>McGahon, Mary K.</creator><creator>Curtis, Tim M.</creator><creator>Conlon, J. Michael</creator><creator>Flatt, Peter R.</creator><creator>Abdel-Wahab, Yasser H.A.</creator><general>Elsevier B.V</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>7X8</scope></search><sort><creationdate>201707</creationdate><title>Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents</title><author>Owolabi, Bosede O. ; Musale, Vishal ; Ojo, Opeolu O. ; Moffett, R. Charlotte ; McGahon, Mary K. ; Curtis, Tim M. ; Conlon, J. Michael ; Flatt, Peter R. ; Abdel-Wahab, Yasser H.A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-d5c642efc847f682d542f3c442e16795698e3319f7c55b422235780cdd7994513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amphibian Proteins - therapeutic use</topic><topic>Amphibian skin peptide</topic><topic>Animals</topic><topic>Anti-apoptotic peptide</topic><topic>Antimicrobial Cationic Peptides - therapeutic use</topic><topic>Calcium - metabolism</topic><topic>Cell Line</topic><topic>Cyclic AMP-Dependent Protein Kinases - drug effects</topic><topic>Cyclic AMP-Dependent Protein Kinases - genetics</topic><topic>Down-Regulation</topic><topic>Humans</topic><topic>Hypoglycemic Agents - therapeutic use</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Insulin-release</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Mice</topic><topic>PGLa-AM1</topic><topic>Pipidae</topic><topic>Rats</topic><topic>Signal Transduction</topic><topic>Type 2 diabetes</topic><topic>Xenopus Proteins - therapeutic use</topic><topic>β-Cell proliferation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Owolabi, Bosede O.</creatorcontrib><creatorcontrib>Musale, Vishal</creatorcontrib><creatorcontrib>Ojo, Opeolu O.</creatorcontrib><creatorcontrib>Moffett, R. Charlotte</creatorcontrib><creatorcontrib>McGahon, Mary K.</creatorcontrib><creatorcontrib>Curtis, Tim M.</creatorcontrib><creatorcontrib>Conlon, J. Michael</creatorcontrib><creatorcontrib>Flatt, Peter R.</creatorcontrib><creatorcontrib>Abdel-Wahab, Yasser H.A.</creatorcontrib><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>Biochimie</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Owolabi, Bosede O.</au><au>Musale, Vishal</au><au>Ojo, Opeolu O.</au><au>Moffett, R. Charlotte</au><au>McGahon, Mary K.</au><au>Curtis, Tim M.</au><au>Conlon, J. Michael</au><au>Flatt, Peter R.</au><au>Abdel-Wahab, Yasser H.A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents</atitle><jtitle>Biochimie</jtitle><addtitle>Biochimie</addtitle><date>2017-07</date><risdate>2017</risdate><volume>138</volume><spage>1</spage><epage>12</epage><pages>1-12</pages><issn>0300-9084</issn><eissn>1638-6183</eissn><abstract>PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clonal β-cells without cytotoxicity at concentrations up to 3 μM. In contrast, the [A3K] analogue was cytotoxic at concentrations ≥ 30 nM. The potency and maximum rate of insulin release produced by the [A14K] and [A20K] peptides were significantly greater than produced by PGLa-AM1. [A14K]PGLa-AM1 also stimulated insulin release from mouse islets at concentrations ≥ 1 nM and from the 1.1B4 human-derived pancreatic β-cell line at concentrations > 30 pM. PGLa-AM1 (1 μM) produced membrane depolarization in BRIN-BD11 cells with a small, but significant (P < 0.05), increase in intracellular Ca2+ concentrations but the peptide had no direct effect on KATP channels. The [A14K] analogue (1 μM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of the peptide. [A14K]PGLa-AM1 (1 μM) protected against cytokine-induced apoptosis (p < 0.001) in BRIN-BD11 cells and augmented (p < 0.001) proliferation of the cells to a similar extent as GLP-1. Intraperitoneal administration of the [A14K] and [A20K] analogues (75 nmol/kg body weight) to both lean mice and high fat-fed mice with insulin resistance improved glucose tolerance with a concomitant increase in insulin secretion. The data provide further support for the assertion that host defense peptides from frogs belonging to the Pipidae family show potential for development into agents for the treatment of patients with Type 2 diabetes.
•PGLa-AM1 and its [A14K] and [A20K] analogues stimulate insulin release from BRIN-BD11 cells, 1.1B4 cells and mouse islets.•PGLa-AM1 produces membrane depolarization in BRIN-BD11 but had no direct effect on KATP channels.•[A14K]PGLa-AM1 activates the protein kinase A pathway in BRIN-BD11 cells.•[A14K]PGLa-AM1 stimulates proliferation and protects against cytokine-induced apoptosis in BRIN-BD11 cells.•[A14K]PGLa-AM1 and [A20K]PGLa-AM1 improve glucose tolerance and stimulate insulin secretion in lean and high fat fed mice.</abstract><cop>France</cop><pub>Elsevier B.V</pub><pmid>28392407</pmid><doi>10.1016/j.biochi.2017.04.004</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amphibian Proteins - therapeutic use Amphibian skin peptide Animals Anti-apoptotic peptide Antimicrobial Cationic Peptides - therapeutic use Calcium - metabolism Cell Line Cyclic AMP-Dependent Protein Kinases - drug effects Cyclic AMP-Dependent Protein Kinases - genetics Down-Regulation Humans Hypoglycemic Agents - therapeutic use Insulin - metabolism Insulin Secretion Insulin-release Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Mice PGLa-AM1 Pipidae Rats Signal Transduction Type 2 diabetes Xenopus Proteins - therapeutic use β-Cell proliferation |
| title | Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents |
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