Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice
Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin...
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Veröffentlicht in: | Journal of endocrinology 2000-09, Vol.166 (3), p.579-590 |
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creator | Dominici, FP Arostegui Diaz, G Bartke, A Kopchick, JJ Turyn, D |
description | Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity. |
doi_str_mv | 10.1677/joe.0.1660579 |
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In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.</description><identifier>ISSN: 0022-0795</identifier><identifier>EISSN: 1479-6805</identifier><identifier>DOI: 10.1677/joe.0.1660579</identifier><identifier>PMID: 10974652</identifier><identifier>CODEN: JOENAK</identifier><language>eng</language><publisher>Colchester: BioScientifica</publisher><subject>Analysis of Variance ; Animals ; Biological and medical sciences ; Endocrine pancreas ; Female ; Fundamental and applied biological sciences. Psychology ; Glucose - metabolism ; Hormones. Régulation ; Immunoblotting - methods ; Insulin - blood ; Insulin - metabolism ; Insulin Receptor Substrate Proteins ; Liver - metabolism ; Mice ; Mice, Knockout ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - metabolism ; Phosphorylation ; Receptor, Insulin - metabolism ; Receptors, Somatotropin - genetics ; Signal Transduction ; Tyrosine - metabolism ; Vertebrates: endocrinology</subject><ispartof>Journal of endocrinology, 2000-09, Vol.166 (3), p.579-590</ispartof><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b511t-5b91c372ea60b94c69e8b65c1f46d11282527b679ef2695018623a96f76ab4613</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=804885$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10974652$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dominici, FP</creatorcontrib><creatorcontrib>Arostegui Diaz, G</creatorcontrib><creatorcontrib>Bartke, A</creatorcontrib><creatorcontrib>Kopchick, JJ</creatorcontrib><creatorcontrib>Turyn, D</creatorcontrib><title>Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice</title><title>Journal of endocrinology</title><addtitle>J Endocrinol</addtitle><description>Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Endocrine pancreas</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glucose - metabolism</subject><subject>Hormones. Régulation</subject><subject>Immunoblotting - methods</subject><subject>Insulin - blood</subject><subject>Insulin - metabolism</subject><subject>Insulin Receptor Substrate Proteins</subject><subject>Liver - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Receptor, Insulin - metabolism</subject><subject>Receptors, Somatotropin - genetics</subject><subject>Signal Transduction</subject><subject>Tyrosine - metabolism</subject><subject>Vertebrates: endocrinology</subject><issn>0022-0795</issn><issn>1479-6805</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90EtLxDAUBeAgio6PpVsJCO6qSdokzVIGXyC40XVJM7cz0TYZk1Tx39vaQUTQVS7cLyfhIHRMyTkVUl48ezgfR0G4VFtoRgupMlESvo1mhDCWEan4HtqP8ZkQyqnMd9EeJUoWgrMZsnPfrcFFnXz4wLpNEHSy3kXsG2xd7FvrcLRLp1ucgnZx0ZtxP-xwa98gjG4Z_Hta4ZUPnXeAAxhYD3n4xXnz4vuEO2vgEO00uo1wtDkP0NP11eP8Nrt_uLmbX95nNac0ZbxW1OSSgRakVoURCspacEObQiwoZSXjTNZCKmiYUJzQUrBcK9FIoetC0PwAnU256-Bfe4ip6mw00Lbage9jJRkrcinLAWYTNMHHGKCp1sF2OnxUlFRjt9XQbTWOX90O_mQT3NcdLH7oqcwBnG6Ajka3zVCXsfHblaQoSz6oYlIru1y92wBVbX00FlyyjTX6z9fz6dov_f-fPwHyH6Vs</recordid><startdate>20000901</startdate><enddate>20000901</enddate><creator>Dominici, FP</creator><creator>Arostegui Diaz, G</creator><creator>Bartke, A</creator><creator>Kopchick, JJ</creator><creator>Turyn, D</creator><general>BioScientifica</general><general>Portland Press</general><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>20000901</creationdate><title>Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice</title><author>Dominici, FP ; Arostegui Diaz, G ; Bartke, A ; Kopchick, JJ ; Turyn, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b511t-5b91c372ea60b94c69e8b65c1f46d11282527b679ef2695018623a96f76ab4613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Endocrine pancreas</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glucose - metabolism</topic><topic>Hormones. Régulation</topic><topic>Immunoblotting - methods</topic><topic>Insulin - blood</topic><topic>Insulin - metabolism</topic><topic>Insulin Receptor Substrate Proteins</topic><topic>Liver - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Receptor, Insulin - metabolism</topic><topic>Receptors, Somatotropin - genetics</topic><topic>Signal Transduction</topic><topic>Tyrosine - metabolism</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dominici, FP</creatorcontrib><creatorcontrib>Arostegui Diaz, G</creatorcontrib><creatorcontrib>Bartke, A</creatorcontrib><creatorcontrib>Kopchick, JJ</creatorcontrib><creatorcontrib>Turyn, D</creatorcontrib><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>Journal of endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dominici, FP</au><au>Arostegui Diaz, G</au><au>Bartke, A</au><au>Kopchick, JJ</au><au>Turyn, D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice</atitle><jtitle>Journal of endocrinology</jtitle><addtitle>J Endocrinol</addtitle><date>2000-09-01</date><risdate>2000</risdate><volume>166</volume><issue>3</issue><spage>579</spage><epage>590</epage><pages>579-590</pages><issn>0022-0795</issn><eissn>1479-6805</eissn><coden>JOENAK</coden><abstract>Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.</abstract><cop>Colchester</cop><pub>BioScientifica</pub><pmid>10974652</pmid><doi>10.1677/joe.0.1660579</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Analysis of Variance Animals Biological and medical sciences Endocrine pancreas Female Fundamental and applied biological sciences. Psychology Glucose - metabolism Hormones. Régulation Immunoblotting - methods Insulin - blood Insulin - metabolism Insulin Receptor Substrate Proteins Liver - metabolism Mice Mice, Knockout Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - metabolism Phosphorylation Receptor, Insulin - metabolism Receptors, Somatotropin - genetics Signal Transduction Tyrosine - metabolism Vertebrates: endocrinology |
title | Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice |
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