Fluoxetine improves glucose metabolism and regulates hepatic and neural gene expression in diabetic mice

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired glucose metabolism, and is frequently associated with depression. This exploratory study investigated the effects of fluoxetine on fasting blood glucose (FBG) levels and on the expression of depression- and metabolism-related genes in the brain and liver of streptozotocin (STZ)-induced diabetic mice. Male Balb/c mice ( n = 5 per group) were assigned to four groups: control (C), fluoxetine-treated non-diabetic (C + Fl), untreated diabetic (D), and fluoxetine-treated diabetic (D + Fl). Fluoxetine was administered orally at a dose of 25 mg/kg/day for 15 days. The expression levels of glucose transporter type 4 (GLUT4), insulin receptor (INSR), AKT serine/threonine kinase 1 (AKT1), sirtuin 1 (SIRT1), long non-coding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1), and maternally expressed gene 3 (MEG3) were analyzed using real-time PCR (RT-PCR). Kidney tissues were also evaluated histologically. Fluoxetine treatment was associated with reduced FBG levels in diabetic mice ( p < 0.001), although AKT1 expression remained unchanged. Hepatic GLUT4 and INSR expression levels were increased in fluoxetine-treated diabetic mice compared with untreated diabetics ( p < 0.01). In the brain, fluoxetine restored SIRT1 expression ( p < 0.01), decreased lncRNA NEAT1 levels ( p < 0.05), and increased lncRNA MEG3 levels ( p < 0.01) in diabetic mice. Histological analysis indicated that fluoxetine partially attenuated diabetic kidney alterations; however, the improvement was modest and did not restore renal histology to control levels. These preliminary findings suggest that fluoxetine primarily exerts metabolic and neuroregulatory effects rather than structural protection. Fluoxetine was associated with reduced fasting blood glucose levels and modulation of hepatic and neuronal gene expression in this exploratory mouse model. These exploratory findings provide preliminary evidence supporting further investigation of fluoxetine as a potential therapeutic strategy for comorbid depression and diabetes. Larger studies incorporating comprehensive metabolic phenotyping and protein-level validation are needed to validate these observations and clarify the underlying mechanisms.