Objective-Advances in stent technology have enabled the delivery of drugs to improve outcomes after stent deployment.However, the optimal payloads for stents are not clear, and the appropriate stent-based therapies for high-risk patients, such as diabetics, have not been clearly established. Methods and Results-We used smooth muscle cell culture models to compare the activities of rapamycin and paclitaxel.Smooth muscle cells were grown in normal or high glucose to induce insulin resistance. Both paclitaxel and rapamycin activate mitogen-activated protein kinase pathways similarly. However, rapamycin potently activates AKT-dependent signaling, an effect that overrides the downregulation of this pathway by insulin resistance and that causes phosphorylation of the AKT-dependent transcription factor FOXO1. This effect is associated with attenuation of the anti-migratory effects of rapamycin under high glucose conditions that are not observed with paclitaxel, as well as with increased protection against ceramide-induced cytotoxicity, both of which are dependent on FOXO1 phosphorylation. Conclusions-Differences between the ability of rapamycin and paclitaxel to activate AKT may account for their differential cell survival and antichemotactic activities. These observations may provide a basis for understanding clinical differences between rapamycin-and paclitaxel-coated stents. The approaches used in these studies can be expanded to other candidate stent payloads as a method for triage in preclinical studies. Key Words: migration Ⅲ signaling Ⅲ smooth muscle Ⅲ stent Ⅲ viability C are for patients with symptomatic or unstable coronary artery disease has undergone a major evolution over the past 5 years, with shifts toward increased use of percutaneous stent implantation at the expense of thrombolytic therapy and coronary artery bypass grafting. Since the introduction of coronary artery angioplasty in the late 1970s by Andreas Greuntzig, the development of percutaneous coronary interventions has been punctuated by several major breakthroughs, including those that have transformed the field (eg, the use of stents to prevent vessel recoil) and some that have not (percutaneous atherectomy being a notable example). Although each of the major advances in interventional cardiology has been considered a threat to surgical approaches, only the introduction of drug-eluting stents to clinical practice has coincided with a reduction in coronary artery bypass procedures. 1 Nevertheless, with Ͼ1 million procedures performed per year and with stents being deployed in more patients and in more vessels per patient, the problem of restenosis has not been eliminated, and many questions remain about the optimal technology platform for percutaneous interventions.Restenosis after percutaneous interventions has 2 principle components: vessel remodeling and intimal hyperplasia. Stent deployment essentially obviates the problem of remodeling by preventing chronic recoil mechanisms. 2 Drug-eluting stents have been developed on the premise that ph...