Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid beta, isoform 42 (A beta 42) deposition in rats with diet-induced insulin resistance (IR). Diet-induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal fluid insulin levels were measured; in addition, hippocampal tissues were collected for immunohistochemical analysis of A beta 42 expression. The levels of insulin-degrading enzyme (IDE) and peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA and protein expression were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. In addition, the activation of glycogen synthase kinase 3 beta (GSK3 beta) induced by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet-induced IR model rats. Treatment with pioglitazone ameliorated A beta 42 deposition in the hippocampus by increasing IDE and PPAR gamma expression. Notably, activation of the PI3K/AKT/GSK3 beta pathway was also demonstrated to serve a role in pioglitazone-induced A beta 42 degradation, which was abrogated by the PPAR gamma antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate A beta 42 accumulation in rats with diet-induced IR by regulating AKT/GSK3 beta activation, suggesting that pioglitazone may be a promising drug for AD treatment.