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 β, isoform 42 (Aβ42) 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 Aβ42 expression. The levels of insulin‑degrading enzyme (IDE) and peroxisome proliferator‑activated receptor γ (PPARγ) 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 3β (GSK3β) 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 Aβ42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3β pathway was also demonstrated to serve a role in pioglitazone‑induced Aβ42 degradation, which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aβ42 accumulation in rats with diet‑induced IR by regulating AKT/GSK3β activation, suggesting that pioglitazone may be a promising drug for AD treatment.