The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium

Abstract

OBJECTIVEIn mice, haploinsufficiency of the IGF-1 receptor (IGF-1R+/−), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαβ and one insulin receptor (IR), IRαβ complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO).RESEARCH DESIGN AND METHODSUsing a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.RESULTSIGF-1R+/− mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity.CONCLUSIONSThese data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.

Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects

“…As the IR was also found to be phosphorylated by IGF1 using western blot, we interpret this observation as an effect of insulin/IGF1 hybrid receptors where IGF1 binding to the IGF1R ab-dimer transphosphorylates the IR b-subunit (Ward et al 2007). This corroborates with the findings of Abbas et al (2011) who showed that reduction in the expression of IGF1R by siRNA, thus reducing the number of insulin/IGF1 hybrid receptors, increased the response to insulin in HUVECs.…”

Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism

“…Additionally, hyperinsulinemia stimulates theca-cell receptors via IGF-1 and causes ovarian hyperandrogenemia (22). Furthermore, in a recent study the IGF-1 receptor was found to play a critical negative regulator role in insulin sensitivity (23). Likewise, in the present study, IGF-1 levels were found to be higher in patients with insulin resistance.…”

Endothelial cells and the IGF system

“…Furthermore, endothelial cells have more IGF1 receptors than insulin receptors. Haploinsufficient Igf1r C/K mice had decreased IGF1 receptors, enhanced insulin-mediated glucose disposal, restored insulin-mediated aortic vasorelaxation, and increased insulin-stimulated endothelial cell NO release (Abbas et al 2011). Haploinsufficient Igf1r C/K mice also had fewer angiogenic progenitor cells than WT mice, but these cells had increased adhesion to fibronectin, increased IGF1 secretion and enhanced tube formation (Yuldasheva et al 2014).…”