Manipulation of the insulin-like growth factor 1 receptor on the vascular endothelium: the effect on whole body and endothelial specific insulin sensitivity

Endothelial dysfunction is associated with the onset of atherosclerosis and cardiovascular disease. Whole body and endothelial cell insulin resistance results in reduced nitric oxide (NO) bioavailability; this is a prominent feature of endothelial dysfunction. Recent work published by our group has suggested that expression of insulin like growth factor-1 receptors (IGF-1R) in the endothelium may play a role in determining both endothelial cell insulin sensitivity and NO bioavailability. We have generated a transgenic mouse which expresses a non-functional mutation of the IGF-1R solely on the vascular endothelium (MIGFREO) under control of the Tie2 promoter. In vivo metabolic tests have shown that MIGFREO mice have enhanced whole body insulin sensitivity and significant reduction in plasma free fatty acid level in keeping with enhanced whole body insulin sensitivity. In contrast, MIGFREO mice have endothelial cell insulin resistance; measured by significant reduction in the vasodilatory response to insulin, and markedly reduced insulin stimulated NO production in pulmonary endothelial cells (PECs). In addition, the MIGFREO PECs are also resistant to IGF-1 as measured by significantly reduced IGF-1 stimulated NO production. In order to investigate a potential mechanism we assessed production of the reactive oxygen species H2O2, production of which has been demonstrated to enhance insulin signalling. Vascular tissue from the MIGFREO mice has elevated basal levels of H2O2 in comparison wt. counterparts; measured by response to catalase in the organ bath, and by direct measurement of H2O2 in aortae. Mutation of the IGF-1R specific to the vascular endothelium has divergent effects on whole body and endothelial cell specific insulin resistance. Furthermore, there is evidence of excess production of H2O2 in MIGFREO vascular tissues; this may provide a mechanistic link for observed finding of divergent whole body and endothelial cell insulin sensitivity seen in the MIGFREO mice.