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 overloadinduced 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.

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

“…Conversely, suppression of cellular senescence in adipose tissue ameliorates inflammation and systemic metabolic dysfunction, inhibiting the progression of heart failure and the development of diabetes via modulation of insulin signaling. 15,16) In addition to WAT, other types of fat are known to be involved in regulating metabolic homeostasis. Brown adipose tissue (BAT) is highly vascular and abundant in mitochondria that are rich in uncoupling protein-1 (UCP-1), which produce heat by uncoupling the respiratory chain involved in ATP synthesis.…”

Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice

“…We previously reported that HF is associated with impaired glucose tolerance in mice and dogs, and that correction of impaired glucose tolerance with voglibose or metformin reduces HF severity (26, 27, 41). Shimizu et al (46) reported that systolic dysfunction induced by pressure overload exacerbates plasma glucose and hepatic insulin resistance via Akt and insulin signaling in rodents. In humans, chronic HF is associated with hyperinsulinemia (36,51).…”

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

“…Whether myostatin from the heart is also responsible for the insulin resistance or the fiber type switching (toward more slow fibers) reported to occur in heart failure was not yet examined, but both effects have been ascribed to myostatin (Fig. 4) (27,52,73,77). Interestingly, elimination of cardiac myostatin did only influence skeletal muscle mass after aortic constriction but not at baseline or after sham operation.…”