Tropisetron modulates peripheral and central serotonin/insulin levels via insulin and nuclear factor kappa B/receptor for advanced glycation end products signalling to regulate type-2 diabetes in rats

Abstract

Despite its known central effect, 5% of serotonin is found centrally, while around 95% is found peripherally. Serotonin is stored and co-released with insulin upon pancreatic islets stimulation by glucose. This fact raises the curiosity regarding its possible role in diabetes. Hence, in this study, we assessed the possible modulatory effects of tropisetron, a 5-HT3 receptor antagonist, on type 2 diabetes mellitus models in rats. The rats were allocated into two groups: normal and diabetic. The latter group was treated with metformin (500 mg kg−1, p.o.), tropisetron (1 and 2 mg kg−1, i.p.), and a combination of metformin and tropisetron (1 mg kg−1). The different treatment regimens corrected glucose and lipid homeostasis manifested by the decrease in serum levels of glucose, fructosamine, homeostasis model of insulin resistance, triglycerides, total cholesterol, free fatty acid, as well as receptor for advanced glycation end products. Additionally, the treatments elevated levels of insulin, serotonin, and homeostasis model of β-cell function. On the molecular level, treatments corrected the altered insulin signaling cascade (phosphorylated insulin receptor substrate 1, phosphorylated protein kinase B, and glucose transporter 4), and inhibited β-catenin and phosphorylated nuclear factor kappa B p65 in the assessed soleus skeletal muscle. A similar pattern was duplicated in the hippocampus. This study provided evidence for the role of tropisetron on type 2 diabetes mellitus via modulating the insulin signaling cascade (insulin, phosphorylated insulin receptor substrate 1, phosphorylated protein kinase B, and glucose transporter 4), improving lipid/glucose profile, decreasing inflammatory markers (receptor for advanced glycation end products, and phosphorylated nuclear factor kappa B p65), as well as increasing 5-HT and reducing β-catenin.