Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT₃ receptors

Abstract.

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 µM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10–15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 µM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT₃ receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 µM), somatostatin (1 µM) further reduced metformin-induced 5-HT release by 15–20%.

In view of the 5-HT releasing effects of selective 5-HT₃ receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT₃ receptors. Receptor binding (inhibition of [³H]-GR65630 binding) and agonist effects (stimulation of [¹⁴C]-guanidinium influx) at 5-HT₃ receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT₃ receptors. Metformin up to 0.3 mM failed to inhibit [³H]-GR65630 binding and to modify displacement of [³H]-GR65630 binding induced by 5-HT. 5-HT (3 µM) stimulated the influx of [¹⁴C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [¹⁴C]-guanidinium. Our results indicate that metformin induces 5-HT₃ receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.