This study evaluated the antidepressant-like effect of insulin compared to sertraline and a combination of insulin and sertraline in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats submitted to the forced swim test (FST). Male Wistar rats were daily treated for 21 days with insulin (1 or 2 IU/kg, i.p.), with the selective serotonin reuptake inhibitor (SSRI), sertraline (10 mg/kg, i.p.), or with a combination of insulin (1 or 2 IU/kg, i.p.) and sertraline (10 mg/kg, i.p.) and submitted to the FST. We also evaluated the water and food intake, urine volume and weight gain of the rats. Rats treated with STZ showed impaired glucose tolerance. Chronic treatment with sertraline showed an antidepressant-like effect in non-diabetic and diabetic rats. Furthermore, sertraline promoted lower weight gain in diabetic rats. Insulin reduced the immobility behaviour in T2DM rats with impaired glucose tolerance. In conclusion, our results showed that insulin has an antidepressant-like effect comparable to that of sertraline. Sertraline is effective as an antidepressant and reduces weight gain, which reinforces its superiority over other SSRIs in the treatment of major depression disorder in patients with T2DM.Global estimates indicate that approximately 382 million people worldwide have diabetes, 316 million have impaired glucose tolerance and 90% of patients are diagnosed with type 2 diabetes mellitus (T2DM) [1]. Major depressive disorder (MDD) is the most common psychiatric comorbidity diagnose in patients with T2DM [1], with a global prevalence ranging from 11% to 30% [2].MDD amplifies the perception of diabetes symptoms [3], worsens glycaemic control and increases the complications of diabetes such as retinopathy, neuropathy, sexual dysfunction and macrovascular complications [4]. The treatment of MDD is necessary to improve the quality of life and to increase the adherence to glycaemic control therapies in patients with diabetes. Currently, selective serotonin reuptake inhibitors (5-HT, SSRIs) are the main therapeutic option in the treatment of MDD in patients with or without diabetes due to low incidence of adverse effects compared to tricyclic antidepressants, such as anticholinergic effects, on the cardiovascular system and glycaemic control [5,6].Although the mechanisms involved in the relationship between T2DM and MDD are not yet fully understood, studies show the involvement of insulin on different cognitive brain functions such as learning and memory [7]. Insulin is a peptide hormone effective in the control and reduction of blood glucose and is widely used in the treatment of diabetes [8].Insulin also participates in the neurobiological processes related to hunger, reproduction and cognition by modulating neurotransmitter hormones such as 5-HT [9][10][11][12]. Furthermore, other studies show that the increase in 5-HT in the hypothalamus of rats, obtained by the administration of a release and inhibitor of 5-HT reuptake agent, dexfenfluramine, produces an immediate increase in insulin level...
