Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells
The incretin hormone glucagon-like peptide-1 augments islet cell mass in vivo by increasing proliferation and decreasing apoptosis of the beta cells. However, the signalling pathways that mediate these effects are mostly unknown. Using a clonal rat pancreatic beta cell line (INS-1), we examined the...
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| Veröffentlicht in: | Diabetologia 2004-03, Vol.47 (3), p.478-487 |
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| creator | WANG, Q LI, L XU, E WONG, V RHODES, C BRUBAKER, P. L |
| description | The incretin hormone glucagon-like peptide-1 augments islet cell mass in vivo by increasing proliferation and decreasing apoptosis of the beta cells. However, the signalling pathways that mediate these effects are mostly unknown. Using a clonal rat pancreatic beta cell line (INS-1), we examined the role of protein kinase B in mediating beta-cell growth and survival stimulated by glucagon-like peptide-1.
Immunoblot analysis was used to detect active (phospho-) and total protein kinase B. Proliferation was assessed using (3)H-thymidine incorporation, while apoptosis was quantitated using 4'-6-diamidino-2-phenylindole staining and APO percentage apoptosis assay. Kinase-dead and wild-type protein kinase B was introduced into cells using adenoviral vectors.
Glucagon-like peptide-1 rapidly activated protein kinase B in INS-1 cells (by 2.7+/-0.7-fold, p |
| doi_str_mv | 10.1007/s00125-004-1327-5 |
| format | Article |
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Immunoblot analysis was used to detect active (phospho-) and total protein kinase B. Proliferation was assessed using (3)H-thymidine incorporation, while apoptosis was quantitated using 4'-6-diamidino-2-phenylindole staining and APO percentage apoptosis assay. Kinase-dead and wild-type protein kinase B was introduced into cells using adenoviral vectors.
Glucagon-like peptide-1 rapidly activated protein kinase B in INS-1 cells (by 2.7+/-0.7-fold, p<0.05). This effect was completely abrogated by inhibition, with wortmannin, of the upstream activator of protein kinase B, phosphatidylinositol-3-kinase. Glucagon-like peptide-1 also stimulated INS-1 cell proliferation in a dose-dependent manner (by 1.8+/-0.5-fold at 10(-7) mol/l, p<0.01), and inhibited staurosporine-induced apoptosis (by 69+/-12%, p<0.05). Both of these effects were also prevented by wortmannin treatment. Ablation of protein kinase B by adenovirus-mediated overexpression of the kinase-dead form of protein kinase Balpha prevented protein kinase B phosphorylation and completely abrogated both cellular proliferation ( p<0.05) and protection from drug-induced cellular death ( p<0.01) induced by glucagon-like peptide-1.
These results identify protein kinase B as an essential mediator linking the glucagon-like peptide-1 signal to the intracellular machinery that modulates beta-cell growth and survival.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-004-1327-5</identifier><identifier>PMID: 14762654</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Adenoviruses ; Animals ; Antidiabetics ; Apoptosis ; Apoptosis - drug effects ; Biological and medical sciences ; Cell cycle ; Cell Division - drug effects ; Cell growth ; Cell Line ; Diabetes ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Glucagon ; Glucagon - pharmacology ; Glucagon-Like Peptide 1 ; Glucose ; Insulin - analysis ; Insulin - metabolism ; Insulin resistance ; Insulin Secretion ; Islets of Langerhans - cytology ; Islets of Langerhans - drug effects ; Islets of Langerhans - physiology ; Kinases ; Medical sciences ; Peptide Fragments - pharmacology ; Peptides ; Phosphorylation ; Protein Precursors - pharmacology ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Reverse Transcriptase Polymerase Chain Reaction ; Staurosporine - pharmacology</subject><ispartof>Diabetologia, 2004-03, Vol.47 (3), p.478-487</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright Springer-Verlag 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-ceae279293f294da1a52027016164c7ede3c798322c6fc04ede599132b3b4c143</citedby><cites>FETCH-LOGICAL-c428t-ceae279293f294da1a52027016164c7ede3c798322c6fc04ede599132b3b4c143</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=15597189$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14762654$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>WANG, Q</creatorcontrib><creatorcontrib>LI, L</creatorcontrib><creatorcontrib>XU, E</creatorcontrib><creatorcontrib>WONG, V</creatorcontrib><creatorcontrib>RHODES, C</creatorcontrib><creatorcontrib>BRUBAKER, P. L</creatorcontrib><title>Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><description>The incretin hormone glucagon-like peptide-1 augments islet cell mass in vivo by increasing proliferation and decreasing apoptosis of the beta cells. However, the signalling pathways that mediate these effects are mostly unknown. Using a clonal rat pancreatic beta cell line (INS-1), we examined the role of protein kinase B in mediating beta-cell growth and survival stimulated by glucagon-like peptide-1.
Immunoblot analysis was used to detect active (phospho-) and total protein kinase B. Proliferation was assessed using (3)H-thymidine incorporation, while apoptosis was quantitated using 4'-6-diamidino-2-phenylindole staining and APO percentage apoptosis assay. Kinase-dead and wild-type protein kinase B was introduced into cells using adenoviral vectors.
Glucagon-like peptide-1 rapidly activated protein kinase B in INS-1 cells (by 2.7+/-0.7-fold, p<0.05). This effect was completely abrogated by inhibition, with wortmannin, of the upstream activator of protein kinase B, phosphatidylinositol-3-kinase. Glucagon-like peptide-1 also stimulated INS-1 cell proliferation in a dose-dependent manner (by 1.8+/-0.5-fold at 10(-7) mol/l, p<0.01), and inhibited staurosporine-induced apoptosis (by 69+/-12%, p<0.05). Both of these effects were also prevented by wortmannin treatment. Ablation of protein kinase B by adenovirus-mediated overexpression of the kinase-dead form of protein kinase Balpha prevented protein kinase B phosphorylation and completely abrogated both cellular proliferation ( p<0.05) and protection from drug-induced cellular death ( p<0.01) induced by glucagon-like peptide-1.
These results identify protein kinase B as an essential mediator linking the glucagon-like peptide-1 signal to the intracellular machinery that modulates beta-cell growth and survival.</description><subject>Adenoviruses</subject><subject>Animals</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Cell cycle</subject><subject>Cell Division - drug effects</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Glucagon</subject><subject>Glucagon - pharmacology</subject><subject>Glucagon-Like Peptide 1</subject><subject>Glucose</subject><subject>Insulin - analysis</subject><subject>Insulin - metabolism</subject><subject>Insulin resistance</subject><subject>Insulin Secretion</subject><subject>Islets of Langerhans - cytology</subject><subject>Islets of Langerhans - drug effects</subject><subject>Islets of Langerhans - physiology</subject><subject>Kinases</subject><subject>Medical sciences</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Protein Precursors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Staurosporine - pharmacology</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU1rFTEUhoMo9rb6A9xIECpuojn5mEyWWuwHFF2o4C7kZs6UtHNnxiRT6Mq_boZ7oeCiqxxynnN4z_sS8gb4R-DcfMqcg9CMc8VACsP0M7IBJQXjSrTPyWZtM2ib30fkOOdbzrnUqnlJjkCZRjRabcjfi2EJ_mYa2RDvkM44l9ghA5rwZhl8wUznNA2xx-RLnEbqx476eZrLlGOm99FTH0q83zenfqULxpHexdFnpF9orWc_hoQVCfTq24-6fIvF04DDkF-RF70fMr4-vCfk1_nXn2eX7Pr7xdXZ52sW6imFBfQojBVW9sKqzoPXggvDoYFGBYMdymBsK4UITR-4qh_a2mrKVm5VqJ6ckPf7vVXfnwVzcbuYVwV-xGnJzoCxXEhTwQ9PgtBaIy1wgIq--w-9nZY01jOcANlqJVRTIdhDIU05J-zdnOLOpwcH3K0pun2Krqbo1hSdrjNvD4uX7Q67x4lDbBU4PQA-Bz_0qRoc8yOntTVVqPwHsHykHg</recordid><startdate>20040301</startdate><enddate>20040301</enddate><creator>WANG, Q</creator><creator>LI, L</creator><creator>XU, E</creator><creator>WONG, V</creator><creator>RHODES, C</creator><creator>BRUBAKER, P. 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Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Glucagon</topic><topic>Glucagon - pharmacology</topic><topic>Glucagon-Like Peptide 1</topic><topic>Glucose</topic><topic>Insulin - analysis</topic><topic>Insulin - metabolism</topic><topic>Insulin resistance</topic><topic>Insulin Secretion</topic><topic>Islets of Langerhans - cytology</topic><topic>Islets of Langerhans - drug effects</topic><topic>Islets of Langerhans - physiology</topic><topic>Kinases</topic><topic>Medical sciences</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Protein Precursors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Staurosporine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WANG, Q</creatorcontrib><creatorcontrib>LI, L</creatorcontrib><creatorcontrib>XU, E</creatorcontrib><creatorcontrib>WONG, V</creatorcontrib><creatorcontrib>RHODES, C</creatorcontrib><creatorcontrib>BRUBAKER, P. 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L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells</atitle><jtitle>Diabetologia</jtitle><addtitle>Diabetologia</addtitle><date>2004-03-01</date><risdate>2004</risdate><volume>47</volume><issue>3</issue><spage>478</spage><epage>487</epage><pages>478-487</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>The incretin hormone glucagon-like peptide-1 augments islet cell mass in vivo by increasing proliferation and decreasing apoptosis of the beta cells. However, the signalling pathways that mediate these effects are mostly unknown. Using a clonal rat pancreatic beta cell line (INS-1), we examined the role of protein kinase B in mediating beta-cell growth and survival stimulated by glucagon-like peptide-1.
Immunoblot analysis was used to detect active (phospho-) and total protein kinase B. Proliferation was assessed using (3)H-thymidine incorporation, while apoptosis was quantitated using 4'-6-diamidino-2-phenylindole staining and APO percentage apoptosis assay. Kinase-dead and wild-type protein kinase B was introduced into cells using adenoviral vectors.
Glucagon-like peptide-1 rapidly activated protein kinase B in INS-1 cells (by 2.7+/-0.7-fold, p<0.05). This effect was completely abrogated by inhibition, with wortmannin, of the upstream activator of protein kinase B, phosphatidylinositol-3-kinase. Glucagon-like peptide-1 also stimulated INS-1 cell proliferation in a dose-dependent manner (by 1.8+/-0.5-fold at 10(-7) mol/l, p<0.01), and inhibited staurosporine-induced apoptosis (by 69+/-12%, p<0.05). Both of these effects were also prevented by wortmannin treatment. Ablation of protein kinase B by adenovirus-mediated overexpression of the kinase-dead form of protein kinase Balpha prevented protein kinase B phosphorylation and completely abrogated both cellular proliferation ( p<0.05) and protection from drug-induced cellular death ( p<0.01) induced by glucagon-like peptide-1.
These results identify protein kinase B as an essential mediator linking the glucagon-like peptide-1 signal to the intracellular machinery that modulates beta-cell growth and survival.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>14762654</pmid><doi>10.1007/s00125-004-1327-5</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoviruses Animals Antidiabetics Apoptosis Apoptosis - drug effects Biological and medical sciences Cell cycle Cell Division - drug effects Cell growth Cell Line Diabetes Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Glucagon Glucagon - pharmacology Glucagon-Like Peptide 1 Glucose Insulin - analysis Insulin - metabolism Insulin resistance Insulin Secretion Islets of Langerhans - cytology Islets of Langerhans - drug effects Islets of Langerhans - physiology Kinases Medical sciences Peptide Fragments - pharmacology Peptides Phosphorylation Protein Precursors - pharmacology Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Reverse Transcriptase Polymerase Chain Reaction Staurosporine - pharmacology |
| title | Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells |
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