Abstract 5847: IGF-1 Receptor and Insulin Receptor Stoichiometry is a Critical Determinant of Nitric Oxide Bioavailablity in vivo
Introduction Accumulating evidence suggests a role for Insulin-like growth factor 1 (IGF-1) in insulin resistance and cardiovascular disease. IGF-1 enhances glucose uptake and nitric oxide (NO) production, via similar mechanisms to insulin. We have previously reported a mouse model with global hemizygous knockout of the IGF-1 receptor (IGF1RKO) that has impaired glucose handling, enhanced insulin sensitivity and increased basal NO production in the vasculature. To dissect out the effect of the IGF-1 receptor (IGF-1R) at the endothelial level we used a mouse model with hemizygous endothelial cell specific knockout of the IGF-1R (ECIGF1RKO). To investigate the interaction between insulin receptors (IR) and IGF-1R we also used a mouse model with hemizygous knockout of the IR and IGF-1R (IRKOxIGF1RKO).
Results Metabolic assessment via tolerance testing with glucose or insulin showed no difference between ECIGF1RKO mice compared to their wild-type (WT) littermates, in contrast to results with IGF1RKO mice. Ex vivo assessment of vascular function was performed using murine thoracic aortic rings in an organ bath. ECIGF1RKO mice were hypocontractile to phenylepherine (PE) compared to those from WT (Emax ECIGF1RKO mice=0.67±0.06g; Emax for WT mice=0.88±0.08g, p=0.09). Addition of the NO synthase inhibitor L-NMMA led to a 89.7±10.0% increase in Emax in ECIGF1RKO mice compared to 29.4±2.6% increase in WT mice (p=0.01). When aortic rings from WT mice are exposed to insulin, they have blunted vasoconstriction to PE as a result of increased NO production. Aortae from mice with hemizygous knockout of the IR (IRKO) were resistant to the vascular effects of insulin. However knockout of the IGF-1 R in these mice (IRKOxIGF1RKO) restored vascular insulin sensitivity. Insulin led to a decrease in Emax 0.06±0.04g in IRKO compared to a decrease in Emax 0.31±.0.11g in IRKOxIGF1RKO mice (p=0.04); (n=4 – 8 in all experiments).
Conclusion ECIGF1RKO mice lose the metabolic phenotype seen in IGF1RKO mice. The restoration of vascular insulin sensitivity in IRKO mice by reducing IGF-1R numbers, suggests an important stoichiometry between the IR and IGF-1R, that may also explain the enhanced basal NO production present in both IGF1RKO and ECIGF1RKO models.