Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression
Darrell D. Belke, … , C. Ronald Kahn, E. Dale Abel
Darrell D. Belke, … , C. Ronald Kahn, E. Dale Abel
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):629-639. https://doi.org/10.1172/JCI13946.
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Article Endocrinology

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

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.

Authors

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

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Cardiac metabolism in isolated working hearts, and in vivo glucose uptak...
Cardiac metabolism in isolated working hearts, and in vivo glucose uptake in CIRKO and control mice. Average rates of glycolysis, glucose oxidation, fatty acid oxidation, and glycogen content after 60 minutes of perfusion and in vivo cardiac 2-deoxyglucose uptake are shown in the panels as labeled. All studies were performed in 16- to 20-week-old male CIRKO mice and littermate controls. In the isolated heart studies, equal numbers of CIRKO and control mice were studied in each experiment. Numbers of animals studied are as follows. Without insulin: glucose oxidation and glycolysis, n = 5; fatty acid oxidation, n = 4; glycogen, n = 9. With insulin: glucose oxidation and glycolysis, n = 7; fatty acid oxidation, n = 6; glycogen, n = 13. For the in vivo 2-deoxyglucose uptake studies, numbers of mice are n = 4 and 5 (WT, basal and insulin, respectively) and n = 4 and 3 (CIRKO, basal and insulin, respectively). Data are means ± SE. *P < 0.05 vs. basal, †P < 0.05 vs. WT.