Objectives: Inhibition of insulin-like growth factor (IGF-1) receptor has recently become a treatment
strategy in oncology for the suppression of growth and survival of many tumor types.
However, IGF-1 signaling is crucial for cardiac function. In this study, we evaluated
the effect of an inhibition of IGF-1 receptor (IGF-1R) and concomitant inhibition
of insulin receptor (InR) on cardiac function and glucose metabolism.
Methods: IGF-1R was inhibited by the small molecule NVP-AEW541 and examined in two age groups
of male Sprague Dawley rats: juvenile rats at 3 weeks and adult rats at 14 weeks.
Animals were treated with NVP-AEW541 orally at daily doses of 80, 160, or 240 mg/kg
dissolved in 25 mM L(+)-tartaric acid or with vehicle only. Insulin-dependent phosphorylation
of InR/IGF-1R and Akt was estimated by western blots. Fasting blood glucose and systemic
glucose tolerance were measured with glucose tolerance tests. Cardiac substrate oxidation
was characterized by isolated working heart perfusion. Cardiac contractile function
in vivo was monitored by echocardiography.
Results: IGF-1R inhibition had no effect on blood glucose levels but impaired glucose tolerance
dose dependently in juvenile rats indicated by delayed glucose removal. Likewise,
adult rats displayed significantly impaired glucose tolerance. Echocardiographic assessment
of cardiac function in vivo showed depression of systolic function indicated by reduced
left ventricular volume and a decline in ejection fraction and stroke volume after
only 14 days of treatment. IGF-1R inhibition led to markedly stunted body and organ
weights as well as tibia lengths in juvenile rats suggesting growth retardation. Resulting
ratios of heart weight to body weight and lung weight to body weight were elevated.
In contrast, IGF-1R inhibition had no effect on tibia lengths in fully grown adult
rats but reduced heart weight to tibia length as well as body and organ weights. IGF-1R
inhibition impaired insulin-stimulated glucose oxidation in isolated working hearts.
In line with that, IGF-1R inhibition reduced insulin-stimulated phosphorylation of
InsR/IGF-1R and Akt in cardiac tissue pointing to restricted insulin signaling.
Conclusion: Specific inhibition of IGF-1R by NVP-AEW541 significantly impairs insulin signaling
and glucose oxidation in the heart which was associated with reduced contractile function.
Depression of contractile function needs to be regarded if clinical application of
NVP-AEW541 is considered.
