The impact of paroxetine on insulin secretion and sensitivity through AKT/GLUT4 axis.

Selective serotonin reuptake inhibitors (SSRIs) are reported to be implicated in altering glucose homeostasis and inducing hypoglycemia in diabetic patients and mice. Herein, the effects of paroxetine on glucose homeostasis, insulin secretion, and insulin sensitivity were investigated in both healthy and streptozotocin-induced-insulin deficient mouse model. Mice were administered with paroxetine (1, 10, and 50 mg/kg) and fasting insulin levels and glucose-stimulated insulin secretion were assessed in healthy mice, whereas the glycemic profile in diabetic mice was evaluated after glucose or insulin challenge. Muscle mRNA expression of insulin signaling-relevant genes was analyzed, in addition to protein kinase B (PKB/Akt) activity and glucose transporter 4 (GLUT4) plasma membrane expression assessed in C2C12 myotubes. Paroxetine modulated glucose homeostasis and reduced the spike in blood glucose in diabetic mice in a dose-dependent manner after a glucose tolerance test. On the other hand, a reverse relationship was observed in the insulin tolerance test, with no evidence of acute hypoglycemia, suggesting that paroxetine did not further exacerbate insulin-induced glucose lowering under the tested conditions. Paroxetine (50 mg/kg) significantly increased fasting insulin secretion and upregulated genes involved in insulin receptor and Akt signaling, while reducing Glut4 mRNA expression. At 10 mg/kg, paroxetine significantly elevated Akt phosphorylation (p < 0.01). Paroxetine enhanced GLUT4 translocation and Akt phosphorylation in C2C12 myotubes. These findings suggest that paroxetine influences glucose homeostasis in diabetic conditions without causing acute hypoglycemia. Nevertheless, further preclinical and clinical investigations are warranted to clarify its metabolic effects and to determine the clinical implications for glycemic management in diabetic patients receiving paroxetine.