Endocrine Abstracts

Introduction: Accumulating evidence suggests a role for IGF1 in insulin resistance and cardiovascular disease. IGF1 enhances glucose uptake and nitric oxide (NO) production, via similar mechanisms to insulin. Previously we have reported a mouse model with global heterozygous knockout of the IGF1 receptor (IGF1RKO) that has enhanced insulin sensitivity and increased nitric oxide (NO) production in the vasculature.

Methods: To investigate this further we used two more mouse models; one with heterozygous endothelial cell specific knockout of the IGF1R (ECIGF1RKO) and another with heterozygous knockout of the insulin receptor (IR) and IGF1R (IRKOxIGF1RKO). Ex vivo assessment of vascular function was performed using murine thoracic aortic rings in an organ bath. Complementary studies were performed by disrupting IGF1R in HUVECs using siRNA and quantifying phosphorylated eNOS (pheNOS) expression.

Results: Aortic rings from ECIGF1RKO mice were hypocontractile to phenylepherine (PE) compared to those from wild-type littermates (WT) (E_max ECIGF1RKO=0.69±0.03 g n=8; E_max WT=0.85±0.06 g n=7, P=0.03). Addition of the NO synthase inhibitor L-NMMA abolished this difference (n=4, P=0.001).

Knockout of the IGF1R in IRKO mice (IRKOxIGF1RKO) mice restored vascular insulin sensitivity. Insulin led to a decrease in E_max 0.06±0.04 g (n=5) in IRKO aortic rings compared to a decrease in E_max 0.31±0.11 g (n=3) in IRKOxIGF1RKO aortic rings (P=0.04).

IGF1R knockdown, using siRNA in HUVECs, upregulated basal levels of pheNOS compared to control by 27.3±1.6% (n=3). Insulin-stimulated pheNOS expression was also increased by 28.3±4.9% with siRNA IGF1 R knockdown compared to insulin-stimulation alone (n=3, P=0.005).

Conclusion: Consistent with the favourable effects on endothelial function conferred by IGF1R knockdown, endothelial insulin sensitivity was restored by reducing IGF1R numbers in a murine model of insulin resistance. This novel interaction between the IR and IGF1R may account for the enhanced vascular NO production seen when IGF1R numbers are reduced.