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Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors
L X Cubeddu1, H Bönisch, M Göthert
1Department of Pharmacology, School of Pharmacy, Central University of Venezuela.
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 microM) 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 microM) 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 microM), somatostatin (1 microM) 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 microM) 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.
Insights
Metformin causes gastrointestinal issues by triggering the release of serotonin (5-HT) from the gut. This serotonin release is independent of 5-HT3 receptors and involves both neuronal and non-neuronal pathways.
Area of Science:
- Gastroenterology
- Pharmacology
- Neuroscience
Background:
- Metformin is a common medication for type 2 diabetes.
- Nearly 30% of patients experience gastrointestinal side effects with metformin.
- Serotonin (5-HT) release in the intestine is linked to nausea, vomiting, and diarrhea.
Purpose of the Study:
- To investigate if metformin induces serotonin (5-HT) release from the human duodenal mucosa.
- To explore the mechanisms underlying metformin-induced 5-HT release.
- To determine if metformin directly interacts with 5-HT3 receptors.
Main Methods:
- Human duodenal biopsy specimens were exposed to varying concentrations of metformin.
- Serotonin (5-HT) outflow was measured.
- Experiments involved tetrodotoxin, somatostatin, and receptor antagonists.
- Receptor binding and functional assays were performed on murine neuroblastoma cells expressing 5-HT3 receptors.
Main Results:
- Metformin significantly increased 5-HT outflow in 40% of duodenal biopsy specimens.
- The effect was rapid, peaking at 10-15 minutes.
- Tetrodotoxin partially inhibited metformin-evoked 5-HT release, suggesting a neuronal component.
- Metformin did not directly bind to or activate 5-HT3 receptors.
Conclusions:
- Metformin induces 5-HT release from the human duodenal mucosa through 5-HT3 receptor-independent mechanisms.
- Both neuronal and non-neuronal pathways contribute to this release.
- Metformin-induced 5-HT release may explain some of the gastrointestinal side effects associated with its use.