Genetic loss of insulin receptors worsens cardiac efficiency in diabetes

被引:62
作者
Bugger, Heiko [1 ,2 ,3 ]
Riehle, Christian [1 ,2 ,3 ]
Jaishy, Bharat [1 ,2 ,3 ]
Wende, Adam R. [1 ,2 ,3 ]
Tuinei, Joseph [1 ,2 ,3 ]
Chen, Dong [4 ,5 ]
Soto, Jamie [1 ,2 ,3 ]
Pires, Karla M. [1 ,2 ,3 ]
Boudina, Sihem [1 ,2 ,3 ]
Theobald, Heather A. [1 ,2 ,3 ]
Luptak, Ivan [6 ]
Wayment, Benjamin [1 ,2 ,3 ]
Wang, Xiaohui [1 ,2 ,3 ]
Litwin, Sheldon E. [1 ,2 ,3 ]
Weimer, Bart C. [4 ,5 ]
Abel, E. Dale [1 ,2 ,3 ]
机构
[1] Univ Utah, Sch Med, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA
[2] Univ Utah, Sch Med, Program Mol Med, Salt Lake City, UT 84112 USA
[3] Univ Utah, Sch Med, Div Cardiol, Salt Lake City, UT 84112 USA
[4] Utah State Univ, Dept Nutr & Food Sci, Logan, UT 84322 USA
[5] Utah State Univ, Ctr Integrated BioSyst, Logan, UT 84322 USA
[6] Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA
基金
美国国家卫生研究院;
关键词
Insulin signaling; Cardiac efficiency; Mitochondria; Diabetes; Diabetic cardiomyopathy; FATTY-ACID OXIDATION; CONTRACTILE DYSFUNCTION; MITOCHONDRIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; RETICULUM CA2+-ATPASE; MOUSE HEARTS; CARDIOMYOPATHY; MICE; OBESITY; OVEREXPRESSION;
D O I
10.1016/j.yjmcc.2012.02.001
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims: To determine the contribution of insulin signaling versus systemic metabolism to metabolic and mitochondrial alterations in type 1 diabetic hearts and test the hypothesis that antecedent mitochondrial dysfunction contributes to impaired cardiac efficiency (CE) in diabetes. Methods and results: Control mice (WT) and mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO) were rendered diabetic with streptozotocin (WT-STZ and CIRKO-STZ, respectively), non-diabetic controls received vehicle (citrate buffer). Cardiac function was determined by echocardiography; myocardial metabolism, oxygen consumption (MVO2) and CE were determined in isolated perfused hearts; mitochondrial function was determined in permeabilized cardiac fibers and mitochondrial proteomics by liquid chromatography mass spectrometry. Pyruvate supported respiration and ATP synthesis were equivalently reduced by diabetes and genotype, with synergistic impairment in ATP synthesis in CIRKO-STZ. In contrast, fatty acid delivery and utilization was increased by diabetes irrespective of genotype, but not in non-diabetic CIRKO. Diabetes and genotype synergistically increased MVO2 in CIRKO-STZ, leading to reduced CE. Irrespective of diabetes, genotype impaired ATP/O ratios in mitochondria exposed to palmitoyl carnitine, consistent with mitochondrial uncoupling. Proteomics revealed reduced content of fatty acid oxidation proteins in CIRKO mitochondria, which were induced by diabetes, whereas tricarboxylic acid cycle and oxidative phosphorylation proteins were reduced both in CIRKO mitochondria and by diabetes. Conclusions: Deficient insulin signaling and diabetes mediate distinct effects on cardiac mitochondria. Antecedent loss of insulin signaling markedly impairs CE when diabetes is induced, via mechanisms that may be secondary to mitochondrial uncoupling and increased FA utilization. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1019 / 1026
页数:8
相关论文
共 35 条
[1]   Cardiac remodeling in obesity [J].
Abel, E. Dale ;
Litwin, Sheldon E. ;
Sweeney, Gary .
PHYSIOLOGICAL REVIEWS, 2008, 88 (02) :389-419
[2]   Role of changes in cardiac metabolism in development of diabetic cardiomyopathy [J].
An, Ding ;
Rodrigues, Brian .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2006, 291 (04) :H1489-H1506
[3]   Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression [J].
Belke, DD ;
Betuing, S ;
Tuttle, MJ ;
Graveleau, C ;
Young, ME ;
Pham, M ;
Zhang, DF ;
Cooksey, RC ;
McClain, DA ;
Litwin, SE ;
Taegtmeyer, H ;
Severson, D ;
Kahn, CR ;
Abel, ED .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (05) :629-639
[4]   Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity [J].
Boudina, S ;
Sena, S ;
O'Neill, BT ;
Tathireddy, P ;
Young, ME ;
Abel, ED .
CIRCULATION, 2005, 112 (17) :2686-2695
[5]   Mitochondrial energetics in the heart in obesity-related diabetes - Direct evidence for increased uncoupled respiration and activation of uncoupling proteins [J].
Boudina, Sihem ;
Sena, Sandra ;
Theobald, Heather ;
Sheng, Xiaoming ;
Wright, Jordan J. ;
Hu, Xia Xuan ;
Aziz, Salwa ;
Johnson, Josie I. ;
Bugger, Heiko ;
Zaha, Vlad G. ;
Abel, E. Dale .
DIABETES, 2007, 56 (10) :2457-2466
[6]   Diabetic cardiomyopathy revisited [J].
Boudina, Sihem ;
Abel, E. Dale .
CIRCULATION, 2007, 115 (25) :3213-3223
[7]   Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart [J].
Boudina, Sihem ;
Bugger, Heiko ;
Sena, Sandra ;
O'Neill, Brian T. ;
Zaha, Vlad G. ;
Ilkun, Olesya ;
Wright, Jordan J. ;
Mazumder, Pradip K. ;
Palfreyman, Eric ;
Tidwell, Timothy J. ;
Theobald, Heather ;
Khalimonchuk, Oleh ;
Wayment, Benjamin ;
Sheng, Xiaoming ;
Rodnick, Kenneth J. ;
Centini, Ryan ;
Chen, Dong ;
Litwin, Sheldon E. ;
Weimer, Bart E. ;
Abel, E. Dale .
CIRCULATION, 2009, 119 (09) :1272-U111
[8]   Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity [J].
Buchanan, J ;
Mazumder, PK ;
Hu, P ;
Chakrabarti, G ;
Roberts, MW ;
Yun, UJ ;
Cooksey, RC ;
Litwin, SE ;
Abel, ED .
ENDOCRINOLOGY, 2005, 146 (12) :5341-5349
[9]   Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3 [J].
Bugger, Heiko ;
Boudina, Sihem ;
Hu, Xiao Xuan ;
Tuinei, Joseph ;
Zaha, Vlad G. ;
Theobald, Heather A. ;
Yun, Ui Jeong ;
McQueen, Alfred P. ;
Wayment, Benjamin ;
Litwin, Sheldon E. ;
Abel, E. Dale .
DIABETES, 2008, 57 (11) :2924-2932
[10]   Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome [J].
Bugger, Heiko ;
Abel, E. Dale .
CLINICAL SCIENCE, 2008, 114 (3-4) :195-210