title: Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine.
abstract: Glucose is an important stimulus for glucagon-like peptide 1 (GLP-1) secretion, but the mechanisms of secretion have not been investigated in integrated physiological models. We studied glucose-stimulated GLP-1 secretion from isolated perfused rat small intestine. Luminal glucose (5% and 20% w/v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration (20%) of the nonmetabolizable sodium-glucose transporter 1 (SGLT1) substrate, methyl-α-D-glucopyranoside (α-MGP), stimulated release, whereas the SGLT1 inhibitor phloridzin (luminally) abolished responses to α-MGP and glucose. Furthermore, in the absence of luminal NaCl, luminal glucose (20%) did not stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal α-MGP in matched concentrations. Glucose transported by GLUT2 may act after metabolization, closing KATP channels similar to sulfonylureas, which also stimulated secretion. Our data indicate that SGLT1 activity is the driving force for glucose-stimulated GLP-1 secretion and that KATP-channel closure is required to stimulate a full-blown glucose-induced response.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rune E
authors.initials: RE
authors.lastname: Kuhre
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Frost
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Svendsen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark jjholst@sund.ku.dk.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D015640:Ion Channel Gating; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008757:Methylglucosides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D008757:Methylglucosides; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D008353:Mannitol; D052216:Glucagon-Like Peptide 1; D012964:Sodium; D005947:Glucose