Insulin controls hyperglycemia after severe burns, and its use opposes the hypermetabolic response. Underlying molecular mechanisms are poorly understood and previous research in this area has been limited due to the inadequacy of animal models to mimic the physiologic effects seen in humans with burns. Using a recently published rat model the combines both burn and disuse components, we compare the effects of insulin treatment versus vehicle on glucose tolerance, hypermetabolic response, muscle loss, and circadian-metabolic protein expression after burns. Male Sprague Dawley rats were assigned to three groups: cage-controls (n=6); vehicle-treated (VBH; n=11) and insulin-treated (IBH; n=9). With the exception of cage-controls, rats underwent a 40% TBSA burn with hindlimb unloading, then IBH rats received 12 days of subcutaneous insulin injections (5 units/kg/day), and VBH rats received an equivalent dose of vehicle. Glucose tolerance testing was performed on day 14, after which blood and tissues were collected for analysis. Body mass loss was attenuated by insulin treatment (VBH=265±17 g versus IBH=283±14 g, p=0.016) and glucose clearance capacity was increased. Soleus and gastrocnemius muscle loss was decreased in the IBH group. IRS-1, AKT, FOXO-1, Caspase-3, and PER1 phosphorylation was altered by injury and disuse, with levels restored by insulin treatment in almost all cases. Insulin treatment after burn and disuse attenuated the hypermetabolic response, increased glucose clearance , and normalized circadian-metabolic protein expression patterns. Therapies aimed at targeting downstream effectors may provide the beneficial effects of insulin without hypoglycemic risk.