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
Hauptverfasser: YAJUAN QI, ZIHUI XU, QINGLEI ZHU, THOMAS, Candice, KUMAR, Rajesh, HAO FENG, DOSTAL, David E, WHITE, Morris F, BAKER, Kenneth M, SHAODONG GUO
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container_end_page 3900
container_issue 11
container_start_page 3887
container_title Diabetes (New York, N.Y.)
container_volume 62
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). 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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&amp;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. 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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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