Restenosis following percutaneous transluminal angioplasty and stenting is increased in subjects with insulin resistance and diabetes. Our preclinical models of restenosis show that insulin treatment is vasculoprotective in insulin sensitive conditions but insulin's effect is diminished or lost in Western diet induced insulin resistant conditions. Accordingly, early insulin treatment has not proven to provide cardiovascular disease (CVD) protection in subjects with dysglycemia, while the effect of intensive insulin treatment of type 2 diabetes (T2D) is debated. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of antidiabetic drugs that reduce the CVD risk of T2D. Several animal studies have shown that GLP-1RA decrease neointimal growth in models of restenosis; however, the mechanisms of the CVD actions of these drugs remain elusive. GLP-1RA are insulin secretagogues, therefore their effect may be partly mediated by the insulin receptor (IR) . The objective of this study was to determine if insulin receptor (IR) deficiency in endothelial cells (EC) attenuates the effect of GLP-1RA to decrease neointimal growth after arterial injury. Endothelial deficient IR mice were generated by crossing IR floxed mice with mice expressing tamoxifen-inducible Cre recombinase under the control of Tie2 promoter. Mice were fed a low-fat (LFD) or a high-fat-high-sucrose (HFSD) Western diet and implanted with an osmotic pump delivering liraglutide, a GLP-1RA prototype (1mol/kg/day) , or vehicle prior to femoral artery wire injury. In LFD- as well as in HFSD-fed IR-floxed controls, liraglutide decreased neointimal area (NA) and intima-to-media ratio (I/M) . In LFD-fed endothelial IR deficient mice liraglutide had no effect. These data suggest that IR in ECs is important for the anti-restenotic effect of GLP1-RA, which is preserved in Western diet induced insulin resistant conditions unlike the effect of insulin. *First and second authors contributed equally


M.Gonzalez: None. Z.Liu: None. A.Giacca: None.

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