Cited by 332Congenital heart defects researchCardiovascular Function and Risk FactorsCardiomyopathy and Myosin Studies

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Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression

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Belke, Darrell D., Betuing, Sandrine, Tuttle, Martin J., Graveleau, Christophe, Young, Martin E., Pham, Mark, Zhang, Dongfang, Cooksey, Robert C., McClain, Donald A., Litwin, Sheldon E., Taegtmeyer, Heinrich, Severson, David, Kahn, C. Ronald, Abel, E. Dale·2002·Journal of Clinical Investigation

DOI 10.1172/jci0213946

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Abstract

To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20–30% due to reduced cardiomyocyte size and had persistent expression of the fetal β-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial β-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.

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Additional file 8 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 3 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 4 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 10 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 9 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 7 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 6 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 5 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 2 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Additional file 1 of In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation
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Authors: Belke, D. D., Betuing, S., Tuttle, M. J., Graveleau, C., Young, M. E., Pham, M., Zhang, D., Cooksey, R. C., McClain, D. A., Litwin, S. E., Taegtmeyer, H., Severson, D., Kahn, C. R., & Abel, E. D.
Affiliations: University of Calgary (CA)
University of Utah (US)
Joslin Diabetes Center (US)
Corresponding author: Abel, E. Dale
ORCID: Belke, Darrell D.
Young, Martin E.
Zhang, Dongfang
McClain, Donald A.
Litwin, Sheldon E.
Taegtmeyer, Heinrich
Kahn, C. Ronald
Abel, E. Dale
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2002-03-01
Volume: 109
Issue: 5
Pages: 629-639
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci0213946
OpenAlex: W4236765824
Cited by: 330
References: 52
Citations by year: 2026: 4 · 2025: 3 · 2024: 14 · 2023: 7 · 2022: 9 · 2021: 14 · 2020: 15 · 2019: 8 · 2018: 9 · 2017: 19 · 2016: 12 · 2015: 15 · 2014: 12 · 2013: 18 · 2012: 13
FWCI: 5.68
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Funders: American Diabetes Association
National Institutes of Health (DK31036)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK033201)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords: insulin signaling, insulin receptor, heart development, cardiac hypertrophy, myosin heavy chain isoforms, glucose transporter 1, GLUT4, cardiac glucose uptake, glycolysis, fatty acid oxidation, mitochondrial beta-oxidation, glucose oxidation, glycogenolysis, cardiac contractility

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Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression

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