Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling c...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2013-11, Vol.62 (11), p.3887-3900 |
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creator | YAJUAN QI ZIHUI XU QINGLEI ZHU THOMAS, Candice KUMAR, Rajesh HAO FENG DOSTAL, David E WHITE, Morris F BAKER, Kenneth M SHAODONG GUO |
description | Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes. |
doi_str_mv | 10.2337/db13-0095 |
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Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db13-0095</identifier><identifier>PMID: 24159000</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Animals ; Biological and medical sciences ; Cardiology. Vascular system ; Cholesterol ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Energy Metabolism - genetics ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Genetic aspects ; Heart ; Heart failure ; Heart Failure - etiology ; Heart failure, cardiogenic pulmonary edema, cardiac enlargement ; Hyperinsulinism - physiopathology ; Insulin ; Insulin - physiology ; Insulin Receptor Substrate Proteins - deficiency ; Insulin Resistance - physiology ; Medical sciences ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase 14 - physiology ; Original Research ; Phosphorylation ; Physiological aspects ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Receptors ; Risk factors ; Signal Transduction - drug effects</subject><ispartof>Diabetes (New York, N.Y.), 2013-11, Vol.62 (11), p.3887-3900</ispartof><rights>2014 INIST-CNRS</rights><rights>COPYRIGHT 2013 American Diabetes Association</rights><rights>2013 by the American Diabetes Association. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c544t-985dc75be02e57f38174f3e137acc458256c3b3422b799e39be74c52eee4ce563</citedby><cites>FETCH-LOGICAL-c544t-985dc75be02e57f38174f3e137acc458256c3b3422b799e39be74c52eee4ce563</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/PMC3806607/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806607/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27894892$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24159000$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YAJUAN QI</creatorcontrib><creatorcontrib>ZIHUI XU</creatorcontrib><creatorcontrib>QINGLEI ZHU</creatorcontrib><creatorcontrib>THOMAS, Candice</creatorcontrib><creatorcontrib>KUMAR, Rajesh</creatorcontrib><creatorcontrib>HAO FENG</creatorcontrib><creatorcontrib>DOSTAL, David E</creatorcontrib><creatorcontrib>WHITE, Morris F</creatorcontrib><creatorcontrib>BAKER, Kenneth M</creatorcontrib><creatorcontrib>SHAODONG GUO</creatorcontrib><title>Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Cholesterol</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Energy Metabolism - genetics</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Genetic aspects</subject><subject>Heart</subject><subject>Heart failure</subject><subject>Heart Failure - etiology</subject><subject>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</subject><subject>Hyperinsulinism - physiopathology</subject><subject>Insulin</subject><subject>Insulin - physiology</subject><subject>Insulin Receptor Substrate Proteins - deficiency</subject><subject>Insulin Resistance - physiology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitogen-Activated Protein Kinase 14 - physiology</subject><subject>Original Research</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Receptors</subject><subject>Risk factors</subject><subject>Signal Transduction - drug effects</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkt2KEzEUxwdR3HX1wheQgAh6MWs-m8nNQqnubrGLsip4FzKZMzWSJjWZEftYvojPZErraqGci3yc3_nnkPOvqqcEn1PG5OuuJazGWIl71SlRTNWMyi_3q1OMCa2JVPKkepTzN4zxpMTD6oRyIlQ5nlbxZhOtSZ0zHi1izij2aH77kSATuu2GopkZM2R0DSYN6NI4PybYZTOaxTCk6D10qN2gNWt-_0I30w_v0JsxubBE85BH7wK6hezyYIKFx9WD3vgMT_brWfX58u2n2XW9eH81n00XtRWcD7VqRGelaAFTELJnDZG8Z0CYNNZy0VAxsaxlnNJWKgVMtSC5FRQAuAUxYWfVxU53PbYr6CyURo3X6-RWJm10NE4fZoL7qpfxh2YNnkywLAIv9wIpfh8hD3rlsgXvTYA4Zk04F6r0Q3hBn-_QpfGgXehjUbRbXE-ZwIxxIZpC1UeoJQQoz8cAvSvXB_z5Eb5EBytnjxa8OigozAA_h2WZX9bN1eIoa1MZeoL-7mcI1ltP6a2n9NZThX32_1fekX9NVIAXe8Bka3yfyqBd_sfJRvFGUfYHLfTQSQ</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>YAJUAN QI</creator><creator>ZIHUI XU</creator><creator>QINGLEI ZHU</creator><creator>THOMAS, Candice</creator><creator>KUMAR, Rajesh</creator><creator>HAO FENG</creator><creator>DOSTAL, David E</creator><creator>WHITE, Morris F</creator><creator>BAKER, Kenneth M</creator><creator>SHAODONG GUO</creator><general>American Diabetes Association</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>8GL</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20131101</creationdate><title>Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance</title><author>YAJUAN QI ; ZIHUI XU ; QINGLEI ZHU ; THOMAS, Candice ; KUMAR, Rajesh ; HAO FENG ; DOSTAL, David E ; WHITE, Morris F ; BAKER, Kenneth M ; SHAODONG GUO</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c544t-985dc75be02e57f38174f3e137acc458256c3b3422b799e39be74c52eee4ce563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Cholesterol</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Energy Metabolism - genetics</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Genetic aspects</topic><topic>Heart</topic><topic>Heart failure</topic><topic>Heart Failure - etiology</topic><topic>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</topic><topic>Hyperinsulinism - physiopathology</topic><topic>Insulin</topic><topic>Insulin - physiology</topic><topic>Insulin Receptor Substrate Proteins - deficiency</topic><topic>Insulin Resistance - physiology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mitogen-Activated Protein Kinase 14 - physiology</topic><topic>Original Research</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Receptors</topic><topic>Risk factors</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>YAJUAN QI</creatorcontrib><creatorcontrib>ZIHUI XU</creatorcontrib><creatorcontrib>QINGLEI ZHU</creatorcontrib><creatorcontrib>THOMAS, Candice</creatorcontrib><creatorcontrib>KUMAR, Rajesh</creatorcontrib><creatorcontrib>HAO FENG</creatorcontrib><creatorcontrib>DOSTAL, David E</creatorcontrib><creatorcontrib>WHITE, Morris F</creatorcontrib><creatorcontrib>BAKER, Kenneth M</creatorcontrib><creatorcontrib>SHAODONG GUO</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>Gale In Context: High School</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>YAJUAN QI</au><au>ZIHUI XU</au><au>QINGLEI ZHU</au><au>THOMAS, Candice</au><au>KUMAR, Rajesh</au><au>HAO FENG</au><au>DOSTAL, David E</au><au>WHITE, Morris F</au><au>BAKER, Kenneth M</au><au>SHAODONG GUO</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>62</volume><issue>11</issue><spage>3887</spage><epage>3900</epage><pages>3887-3900</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>24159000</pmid><doi>10.2337/db13-0095</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biological and medical sciences Cardiology. Vascular system Cholesterol Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Energy Metabolism - genetics Etiopathogenesis. Screening. Investigations. Target tissue resistance Genetic aspects Heart Heart failure Heart Failure - etiology Heart failure, cardiogenic pulmonary edema, cardiac enlargement Hyperinsulinism - physiopathology Insulin Insulin - physiology Insulin Receptor Substrate Proteins - deficiency Insulin Resistance - physiology Medical sciences Mice Mice, Knockout Mitogen-Activated Protein Kinase 14 - physiology Original Research Phosphorylation Physiological aspects Proto-Oncogene Proteins c-akt - metabolism Rats Receptors Risk factors Signal Transduction - drug effects |
title | Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance |
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