Abstract 3682: Heterozygous Knockout of the Insulin-like Growth Factor 1 Receptor in Mice Leads to Enhanced Insulin Sensitivity and Increased Endothelial Nitric Oxide Production
Introduction Insulin like growth factor-1 (IGF-1) enhances glucose uptake and nitric oxide (NO) production, acting via similar signalling pathways to insulin. Several cross sectional and longitudinal studies have demonstrated an inverse relationship between IGF-1 bioactivity and cardiovascular disease. We assessed the hypothesis that a putative mechanism for these findings may be the modulation of endothelial NO bioavailability by IGF-1.
Methods and Results We investigated the effect of reduced IGF-1 bioactivity on metabolic and endothelial function in male mice, heterozygous for knockout of the IGF-1 receptor (IGF1RKO) and their wildtype littermates (WT). Glucose tolerance tests revealed impaired glucose handling in IGF1RKO mice compared to WT (mean AUC for IGF1RKO mice=1086 ± 26.82(mmol/L)minutes, mean AUC for WT mice=950.5 ± 22.5(mmol/L)minutes, n=5 in each group, p=0.005). However, using an insulin tolerance test, IGF1RKO mice were more insulin sensitive than controls (mean AUC for IGF1RKO=552.2 ± 25.18(mmol/L)minutes, n=10; mean AUC for WT=651.4 ± 22.26(mmol/ L)minutes, n=11, p=0.008). Ex-vivo assessment of vascular function was performed using thoracic aortic rings in an organ bath. Aortic rings from IGF1RKO mice were hypocontractile to phenylepherine compared to those from WT (mean Emax for IGF1RKO mice=0.60 ± 0.05g n=11 versus mean Emax for WT mice=0.79 ± 0.06g, n=10, p=0.03). Addition of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), led to a 65.40 ± 13.40% (n=9) increase in mean Emax in IGF1RKO mice compared to a 15.78 ± 12.00% (n=9) increase in WT mice (p=0.01). In addition IGF1RKO aortic rings were resistant to IGF-1 exposure compared to WT (percentage change in mean Emax for IGF1RKO mice=32.80 ± 11.01%, n=9 versus 66.28 ± 10.60% in WT mice, n=8, p=0.05), but maintained sensitivity to insulin.
Conclusion IGF1RKO mice demonstrate impaired glucose handling but enhanced sensitivity to insulin compared to WT. Aortic rings from IGF1RKO mice are hypocontractile to phenylepherine and have increased basal NO production. These data raise the possibility that reduced IGF-1 action in the endothelium may have a favourable effect on NO bioavailability, possibly by a novel interaction with insulin signalling.