Abstract: AIM To explore the effect of aerobic exercise on insulin resistance induced by sleep deprivation and the underlying mechanisms. METHODS A modified multiple platform method was used in a chronic sleep deprivation (CSD) model in rats. Thirty male 8-week-old Sprague-Dawley rats were randomized into a control group, CSD group, CSD with low-intensity aerobic exercise training (CSD+L) group, CSD with moderate intensity exercise training (CSD+M) group and CSD with high-intensity exercise training (CSD+H) group (n=6 per group). The intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), positron emission tomography (PET-CT) and insulin resistance index (HOMA-IR) were employed and the levels of IL-1β, IL-6, TNF-α and I-kappa B (I-κB) and NF-kappa B (NF-κB) in peripheral blood mononuclear cells (PBMCs) were assessed. Shortening fraction (FS) and left ventricular ejection fraction (LVEF) were measured by echocardiography after 8-week chronic sleep deprivation in all the groups with or without exercise. RESULTS Compared with those in the control group, CSD decreased HOMA-IR, insulin sensitivity and glucose tolerance as well as peripheral inflammation inhibitory cytokine (Iκ-B), reduced myocardial 18FDG uptake and LVEF but increased proinflammatory cytokine NF-κB. Compared with those in the CSD group, CSD+L resulted in no significant changes in the above indexes. CSD+M markedly lowered CSD induced insulin resistance, decreased the level of peripheral inflammatory cytokines and proinflammatory cytokine NF-κB and increased and myocardial 18FDG uptake and LVEF. CSD+H increased insulin resistance, serum inflammatory cytokines and proinflammatory cytokine NF-κB and decreased peripheral inflammation inhibitory cytokine Iκ-B, myocardial 18FDG uptake and LVEF. CONCLUSION CSD induced significant insulin resistance and systematic inflammation; however, moderate, not low or high, intensity aerobic exercise of aerobic exercise, improved insulin sensibility, at least partially by suppressing the serum inflammatory cytokines in response to CSD, indicating a proper intensity of aerobic exercise could improve LVEF and insulin resistance induced by chronic sleep deprivation.