Fluoxetine regulates glucose and lipid metabolism via the PI3K­AKT signaling pathway in diabetic rats.

ABSTRACT

Diabetes mellitus poses a major threat towards global heath due to a lack of effective treatment. Fluoxetine hydrochloride, a selective 5­hydroxytryptamine 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 proliferator­activated receptor γ, fatty acid synthase and lipoprotein lipase, and downregulated sterol regulatory element­binding protein 1­c were detected in rats with streptozotocin (STZ)­induced diabetes following treatment with fluoxetine. Furthermore, fluoxetine significantly inhibited the expression levels of glucose metabolism­associated proteins in liver tissues, including glycogen synthase kinase 3ß (GSK­3ß), glucose­6 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 STZ­induced diabetes. Additionally, fluoxetine could inhibit the phosphatidylinositol 3­kinase­protein kinase B (PI3K­AKT) signaling pathway, whereas LY294002, a specific inhibitor of PI3K, suppressed the function of PI3K­AKT signaling and suppressed the expression levels of glucose metabolism­associated proteins, including GSK­3ß, G6PC, PEPCK and FOXO1 in BRL­3A cells. The results of the present study revealed that fluoxetine may regulate glucose and lipid metabolism via the PI3K­AKT signaling pathway in diabetic rats.