| Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. | |
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MedLine Citation:
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PMID: 20407209 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-04-19 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-04 Completed Date: 2010-05-20 Revised Date: 2012-02-07 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 1506-14 Citation Subset: AIM; IM |
Affiliation:
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Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia Diabetes Mellitus, Type 1 / blood Heart Failure Insulin / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Myocardium / metabolism* Pressure Rats Rats, Inbred SHR Receptor, Insulin / biosynthesis Stress, Mechanical Systole* Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK092065-07/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Insulin; EC 2.7.10.1/Receptor, Insulin |
| Comments/Corrections | |
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