Can restoration of endothelial insulin sensitivity rescue vascular function and repair in systemic insulin resistance?

Diabetes and insulin resistance are prominent cardiovascular risk factors and are projected to affect more than 500 million individuals worldwide in the next few decades. Managing hyperglycaemia is not sufficient to reduce the cardiovascular risk that these diseases confer, and there is increasing awareness of insulin resistance as an independent predictor of morbidity and mortality. Animal models partially recapitulate this profile: mice with insulin receptor knockout (IRKO) show elements of human metabolic syndrome, such as hypertension and endothelial dysfunction. These mice also exhibit impaired vascular repair after arterial injury and associated defects in the number and function of endothelial progenitor cells and mature endothelial cells. These impairments appear to relate to reduced nitric oxide bioavailability and oxidative stress. Loss of intact endothelial insulin signalling seems to play a key pathogenetic role. In this work, we describe a murine model with global insulin receptor knockout and concomitant rescue of endothelial insulin receptor expression (HIRECOxIRKO). In order to achieve this, we have targeted expression of a human insulin receptor transgene to vascular endothelial cells using a Tie-2 promoter. This manipulation results in a viable mouse with preserved glucoregulation. We have confirmed endothelium-specific expression of the human insulin receptor transgene in HIRECOxIRKO mice. These animals display restoration of normal blood pressure, endothelial function and vascular repair after arterial injury, as compared with IRKO littermates, often with recovery to wild-type levels. We have observed augmented endothelial cell migration and, perhaps, proliferation, which may mediate increased vascular repair. We also present evidence of increased nitric oxide bioavailability, which may underpin the rescue of vasomotor function. Much work remains, but this project supports the pursuit of endothelial insulin sensitisation as a potential therapeutic target in insulin resistance