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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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Autores principales: Qi, Yajuan, Xu, Zihui, Zhu, Qinglei, Thomas, Candice, Kumar, Rajesh, Feng, Hao, Dostal, David E., White, Morris F., Baker, Kenneth M., Guo, Shaodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806607/
https://www.ncbi.nlm.nih.gov/pubmed/24159000
http://dx.doi.org/10.2337/db13-0095
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author Qi, Yajuan
Xu, Zihui
Zhu, Qinglei
Thomas, Candice
Kumar, Rajesh
Feng, Hao
Dostal, David E.
White, Morris F.
Baker, Kenneth M.
Guo, Shaodong
author_facet Qi, Yajuan
Xu, Zihui
Zhu, Qinglei
Thomas, Candice
Kumar, Rajesh
Feng, Hao
Dostal, David E.
White, Morris F.
Baker, Kenneth M.
Guo, Shaodong
author_sort Qi, Yajuan
collection PubMed
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.
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spelling pubmed-38066072014-11-01 Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance Qi, Yajuan Xu, Zihui Zhu, Qinglei Thomas, Candice Kumar, Rajesh Feng, Hao Dostal, David E. White, Morris F. Baker, Kenneth M. Guo, Shaodong Diabetes Original Research 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. American Diabetes Association 2013-11 2013-10-18 /pmc/articles/PMC3806607/ /pubmed/24159000 http://dx.doi.org/10.2337/db13-0095 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Qi, Yajuan
Xu, Zihui
Zhu, Qinglei
Thomas, Candice
Kumar, Rajesh
Feng, Hao
Dostal, David E.
White, Morris F.
Baker, Kenneth M.
Guo, Shaodong
Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title_full Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title_fullStr Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title_full_unstemmed Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title_short Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
title_sort myocardial loss of irs1 and irs2 causes heart failure and is controlled by p38α mapk during insulin resistance
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806607/
https://www.ncbi.nlm.nih.gov/pubmed/24159000
http://dx.doi.org/10.2337/db13-0095
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