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.