title: Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2, leading to cell depolarization and calcium influx.
abstract: 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-α-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 KATP 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 KATP channels (GLUT2 and SGLT1) secondary to the ATP-generating metabolism of glucose.
authors.affiliation: NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rune Ehrenreich
authors.initials: RE
authors.lastname: Kuhre
authors.affiliation: NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Louise Ellegaard
authors.initials: LE
authors.lastname: Bechmann
authors.affiliation: NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicolai Jacob
authors.initials: NJ
authors.lastname: Wewer Albrechtsen
authors.affiliation: NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark jjholst@sund.ku.dk.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage*; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009496:Neurotensin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051273:Glucose Transporter Type 2; C495683:Slc2a2 protein, rat; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D009496:Neurotensin; D005947:Glucose; D002118:Calcium
keywords: GLUT2; SGLT1; mechanisms of secretion; neurotensin