Fluoxetine regulates glucose and lipid metabolism via the PI3K-AKT signaling pathway in diabetic rats

Diabetes mellitus poses a major threat towards global heath due to a lack of effective treatment. Fluoxetine hydrochloride, a selective 5-hydroxytryptamine reuptake inhibitor, is the most commonly used antidepressant in clinical therapy; however, the potential molecular mechanisms of fluoxetine in diabetes remain unknown. In the present study, reduced glucose, total cholesterol and triglyceride levels and lipid metabolism, as well as upregulated proliferator-activated receptor gamma, fatty acid synthase and lipoprotein lipase, and downregulated sterol regulatory element-binding protein 1-c were detected in rats with streptozotocin (STZ)-induced diabetes following treatment with fluoxetine. Furthermore, fluoxetine significantly inhibited the expression levels of glucose metabolism-associated proteins in liver tissues, including glycogen synthase kinase 3 beta (GSK-3 beta), glucose-6 phosphatase catalytic subunit (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and forkhead box protein O1 (FOXO1). In addition, fluoxetine treatment notably attenuated morphological liver damage in rats with STZ-induced diabetes. Additionally, fluoxetine could inhibit the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, whereas LY294002, a specific inhibitor of PI3K, suppressed the function of PI3K-AKT signaling and suppressed the expression levels of glucose metabolism-associated proteins, including GSK-3 beta, G6PC, PEPCK and FOXO1 in BRL-3A cells. The results of the present study revealed that fluoxetine may regulate glucose and lipid metabolism via the PI3K-AKT signaling pathway in diabetic rats.