| Authors |
Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, Zhang D, Cooksey
RC, McClain DA, Litwin SE, Taegtmeyer H, Severson D, Kahn CR, Abel ED.
|
| Submitted By |
E. Dale Abel on 3/3/2004 |
| Status |
Published |
| Journal |
The Journal of clinical investigation |
| Year |
2002 |
| Date Published |
3/1/2002 |
| Volume : Pages |
109 : 629 - 639 |
| PubMed Reference |
|
| 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
beta-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 beta-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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