Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression
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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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Deletion of insulin receptors in mouse cardiomyocytes is associated with reduced rates of fatty acid and glucose oxidation and reduced expression of FAO genes, consistent with mitochondrial dysfunction.
“Specifically, deletion of insulin receptors in the heart is associated with reduced rates of FA and glucose oxidation and reduced expression of FAO genes, consistent with mitochondrial dysfunction (26).”
From Cardiac remodeling in obesity (2008) · cites this paper as [26]
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Self-citationAdvanced glycation end products: role in pathology of diabetic cardiomyopathy
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The intrinsic circadian clock within the cardiomyocyte
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Self-citationMolecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome
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Self-citationActivated FOXO-mediated insulin resistance is blocked by reduction of TOR activity
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Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding
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Self-citationAbnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
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Mitochondrial NAD + /NADH Redox State and Diabetic Cardiomyopathy
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Diabetic Cardiomyopathy: Does the Type of Diabetes Matter?
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PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy
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Self-citationTelomeres and Mitochondria in the Aging Heart
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Self-citationNew insights into insulin resistance in the diabetic heart
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Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury
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Self-citationDilated Cardiomyopathy Resulting From High-Level Myocardial Expression of Cre-Recombinase
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FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model
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Self-citationNew Molecular Insights of Insulin in Diabetic Cardiomyopathy
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Self-citationSirt1 protects the heart from aging and stress
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Self-citationMolecular mechanisms of cardiac pathology in diabetes – Experimental insights
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Self-citationAre targeted therapies for diabetic cardiomyopathy on the horizon?
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Physiological myocardial hypertrophy: how and why?
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Insulin signaling in the heart
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Self-citationInsulin resistance protects the heart from fuel overload in dysregulated metabolic states
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Self-citationPTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance
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Self-citationAltered cardiac calcium handling in diabetes
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Self-citationIGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes
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Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts
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Cardiac metabolic remodelling in chronic kidney disease
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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
- Venue
- Journal of Clinical Investigation
- Published
- 2002-03-01
- Volume
- 109
- Issue
- 5
- Pages
- 629-639
- ISSN
- 0021-9738 (ISSN-L)
- 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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