P41 Exploring the biological role of insulin and insulin-like growth factor-1 hybrid receptors in the endothelium

Abstract

Endothelial cells co-express insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) homodimers. Furthermore, association of insulin αβ half receptors and IGF-1 αβ half receptors also occur resulting in insulin/IGF-1 hybrid receptors. An abundance of hybrid receptors has been associated with reduced insulin sensitivity in metabolic tissue. The aim of this project is to study the differential expression of vascular derived insulin receptors, IGF-1 receptors and insulin/IGF-1 hybrids during insulin resistance in a diet-induced model of obesity (DIO). C57BL/6 mice were fed on high-fat or low-fat diets ad libitum for 16-weeks. Obese mice showed significant metabolic abnormalities indicative of insulin resistance when compared with lean littermates. A significant increase in hybrid receptor levels were observed in aorta from obese mice (immunoprecipitation and Western blotting). Total IR and IGF-1R protein levels were reduced in obese mice (Western blotting) however, no change was observed in IR and IGF-1R mRNA levels (real time-PCR). Insulin-stimulated (4.5 nmol/kg injected) in vivo serine phosphorylation of Akt was significantly blunted in aortae of obese mice, whereas IGF-1-stimulated (90 nmol/kg injected) remained unaffected. We have shown that IR and IGF1R homodimers are preferentially titrated into hybrid receptors in a model of DIO and this is accompanied with a reduction in insulin sensitivity but not IGF-1 sensitivity in the aorta. Hybrid receptors may provide a novel target for the prevention of CVD progression in vulnerable patients.