Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by
pressure overload in rodents.
Authors Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, Tateno K, Moriya J,
Yokoyama M, Nojima A, Koh GY, Akazawa H, Shiojima I, Kahn CR, Abel ED, Komuro I
Submitted By E. Dale Abel on 4/25/2010
Status Published
Journal The Journal of clinical investigation
Year 2010
Date Published 5/1/2010
Volume : Pages 120 : 1506 - 1514
PubMed Reference 20407209
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.

Investigators with authorship
E. Dale AbelUniversity of Iowa


Insrinsulin receptor
Irs1insulin receptor substrate 1