mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia and hypertriglyceridemia, which are due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPAR activity. Herein we tested the hypothesis that pharmacological PPAR activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg/kg/day) in combination or not with the PPAR ligand rosiglitazone (15 mg/kg/day) for 15 days were evaluated for insulin secretion, glucose, insulin and pyruvate tolerances, skeletal muscle and adipose tissue glucose uptake and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser473 phosphorylation. The rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol, however, were unaffected by rosiglitazone. Our findings indicate that PPAR activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.