Kuhre RE, Bechmann LE, Wewer Albrechtsen NJ, Hartmann B, Holst JJ. Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2, leading to cell depolarization and calcium influx. Am J Physiol Endocrinol Metab 308: E1123-E1130, 2015. First published April 21, 2015 doi:10.1152/ajpendo.00012.2015.-Neurotensin (NT) is a neurohormone produced in the central nervous system and in the gut epithelium by the enteroendocrine N cell. NT may play a role in appetite regulation and may have potential in obesity treatment. Glucose ingestion stimulates NT secretion in healthy young humans, but the mechanisms involved are not well understood. Here, we show that rats express NT in the gut and that glucose gavage stimulates secretion similarly to oral glucose in humans. Therefore, we conducted experiments on isolated perfused rat small intestine with a view to characterize the cellular pathways of secretion. Luminal glucose (20% wt/vol) stimulated secretion but vascular glucose (5, 10, or 15 mmol/l) was without effect. The underlying mechanisms depend on membrane depolarization and calcium influx, since the voltage-gated calcium channel inhibitor nifedipine and the KATP channel opener diazoxide, which causes hyperpolarization, eliminated the response. Luminal inhibition of the sodium-glucose cotransporter 1 (SGLT1) (by phloridzin) eliminated glucose-stimulated release as well as secretion stimulated by luminal methyl-␣-D-glucopyranoside (20% wt/vol), a metabolically inactive SGLT1 substrate, suggesting that glucose stimulates secretion by initial uptake by this transporter. However, secretion was also sensitive to GLUT2 inhibition (by phloretin) and blockage of oxidative phosphorylation (2-4-dinitrophenol). Direct K ATP channel closure by sulfonylureas stimulated secretion. Therefore, glucose stimulates NT secretion by uptake through SGLT1 and GLUT2, both causing depolarization either as a consequence of sodium-coupled uptake (SGLT1) or by closure of K ATP channels (GLUT2 and SGLT1) secondary to the ATP-generating metabolism of glucose.neurotensin; mechanisms of secretion; SGLT1; GLUT2 NEUROTENSIN (NT) is a 13-amino acid peptide neuromodulator, first isolated from bovine intestine and brain tissue (3,14). It is stored in secretory vesicles in enteroendocrine N cells in the intestine and in neuronal vesicles in the CNS. NT is released from the intestine in response to nutrient stimulation and may play a role in satiety regulation, as centrally administered NT decreases food intake in rodents (19,20). A few reports have shown that glucose stimulates NT secretion in healthy young humans (18) and from isolated perfused rat small intestine (4), but the underlying mechanisms of secretion are not well understood. Studies of secretion of the gut hormone glucagonlike peptide-1 (GLP-1) have indicated that glucose-stimulated secretion of this hormone involves electrogenic sodium uptake through sodium-glucose transporter 1 (SGLT1) as well as closure of ATP-sensitive potassium (K ATP ) channel...
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