The Effects of Insulin and Insulin Sensitizers on Neointimal Formation after Arterial Injuries in Rodent Models

Restenosis, a common complication following angioplasty, is exacerbated in insulin resistant patients with or without diabetes. Our laboratory has previously shown that insulin decreases arterial injury induced neointimal hyperplasia in a rat model of restenosis, an effect abolished with a non-specific nitric oxide synthase (NOS) inhibitor. The vasculoprotective effect of insulin is also greatly diminished in high-fat fed rats, a model of insulin resistance. The first aim of this study is to further investigate the specific NOS isoform involved in insulin's action. The main finding was that insulin decreased iNOS expression but increased eNOS phosphorylation in injured vessels and this effect of insulin was associated with the improvement of endothelial-dependent vessel function. Furthermore, insulin also decreased neointimal hyperplasia induced by wire injury in mouse, an effect abolished in eNOS-null mice. Therefore, compounds, in particular metformin and resveratrol (RSV) that increase eNOS activation and improve insulin sensitivity, may potentially be beneficial. Metformin, the most commonly prescribed anti-diabetic drug, was found to improve insulin sensitivity but did not affect neointimal hyperplasia in rats fed normal or high-fat diet in the current study. Furthermore, AMPK activation, previously shown to protect against neointimal hyperplasia, was impaired in injured but not in uninjured vessels of metformin treated rats, which at least in part explains the ineffectiveness of metformin in our model. RSV, a polyphenol found in red wine, improved insulin sensitivity and decreased neointimal hyperplasia in high-fat fed rats. Further investigation of its mechanism of action found that the effect of RSV to decrease neointimal area was not mediated via SIRT1. Thus, a better understanding of the effects of insulin and insulin sensitizers in the vessel would be beneficial in bypassing vessel insulin resistance and further studies are still required to improve the outcomes especially for insulin resistant patients with or without diabetes.Ph.D.2016-11-30 00:00:0