Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents
Ippei Shimizu, … , E. Dale Abel, Issei Komuro
Ippei Shimizu, … , E. Dale Abel, Issei Komuro
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1506-1514. https://doi.org/10.1172/JCI40096.
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Research Article Cardiology

Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents

Abstract

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch–induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload–induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.

Authors

Ippei Shimizu, Tohru Minamino, Haruhiro Toko, Sho Okada, Hiroyuki Ikeda, Noritaka Yasuda, Kaoru Tateno, Junji Moriya, Masataka Yokoyama, Aika Nojima, Gou Young Koh, Hiroshi Akazawa, Ichiro Shiojima, C. Ronald Kahn, E. Dale Abel, Issei Komuro

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Figure 1

Upregulation of cardiac insulin signals by pressure overload.

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Upregulation of cardiac insulin signals by pressure overload. (A) Mice w...
(A) Mice were subjected to TAC or sham operation (sham), and heart samples were obtained 2 weeks later. Mice were starved for 6 hours, and insulin or PBS was injected before sacrifice. pIrs1 and pAkt levels in the heart were examined by Western blot analysis. The graphs indicate relative expression levels of pIrs1 and pAkt. n = 3. TAC2w, 2 weeks after TAC. (B) Mice were subjected to TAC or sham operation and were sacrificed 2 weeks later. Components of the insulin signaling pathway in the heart were examined by Western blot analysis. The graphs indicate relative expression levels of these signaling molecules. n = 3. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01.