Due to the fact that drugs which interfere with the serotonin (5-HT) uptake (doxepin, sertraline, fluvoxamine and fluoxetine), were able to minimize the insulin release from islet beta-cells and counteract hypoglycemia, we investigated the effects of tianeptine, a drug which enhances 5-HT uptake during the oral glucose tolerance test. We found that the drug triggered significant and sustained insulin rises which were opposite to the plasma glucose decreases. The fact that significant noradrenaline/adrenaline (NA/Ad) plasma ratio paralleled insulin rises throughout the test is consistent with the excitatory role played by the peripheral neural sympathetic activity. Additionally, the positive correlations registered between NA versus DA (dopamine) plasma levels indicate that the latter arose from sympathetic nerves rather than the adrenal glands. Furthermore, the significant reductions of both platelet and plasma 5-HT registered throughout the OGTT plus tianeptine test support the postulation that reduction of the parasympathetic drives is occurring. This parasympathetic drive is responsible for the secretion of 5-HT from the enterochromaffin cells. Finally, considering that circulating 5-HT excites alpha-cells and modulates beta-cells, it is possible to infer that minimization of this factor contributed to the insulinogenic effect displayed by the association of this drug to an oral glucose load. We also discussed the peripheral and central nervous system mechanisms responsible for the insulinogenic effect registered throughout the test.