title: Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine.
abstract: Intestinal glucose stimulates secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). The mechanisms underlying this pathway have not been fully investigated in humans. In this study, we showed that a 30-min intraduodenal glucose infusion activated half of all duodenal L cells in humans. This infusion was sufficient to increase plasma GLP-1 levels. With an ex vivo model using human gut tissue specimens, we showed a dose-responsive GLP-1 secretion in the ileum at ≥200 mmol/L glucose. In ex vivo tissue from the duodenum and ileum, but not the colon, 300 mmol/L glucose potently stimulated GLP-1 release. In the ileum, this response was independent of osmotic influences and required delivery of glucose via GLUT2 and mitochondrial metabolism. The requirement of voltage-gated Na+and Ca2+channel activation indicates that membrane depolarization occurs. KATPchannels do not drive this, as tolbutamide did not trigger release. The sodium-glucose cotransporter 1 (SGLT1) substrate α-MG induced secretion, and the response was blocked by the SGLT1 inhibitor phlorizin or by replacement of extracellular Na+withN-methyl-d-glucamine. This is the first report of the mechanisms underlying glucose-induced GLP-1 secretion from human small intestine. Our findings demonstrate a dominant role of SGLT1 in controlling glucose-stimulated GLP-1 release in human ileal L cells.
authors.affiliation: Discipline of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Emily W
authors.identifier: 0000-0001-5484-918X
authors.initials: EW
authors.lastname: Sun
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Dayan
authors.initials: D
authors.lastname: de Fontgalland
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Philippa
authors.initials: P
authors.lastname: Rabbitt
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Hollington
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sposato
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Due
authors.affiliation: Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Wattchow
authors.affiliation: Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.|National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia.|Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Rayner
authors.affiliation: Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.|National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia.|Intensive Care Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Deane
authors.affiliation: Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia damien.keating@flinders.edu.au richard.young@adelaide.edu.au.|National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia.|Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Young
authors.affiliation: Discipline of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia damien.keating@flinders.edu.au richard.young@adelaide.edu.au.|Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Keating
mesh_terms: D015220:Calcium Channels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage* / Q000502:physiology; D051273:Glucose Transporter Type 2 / Q000502:physiology; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007263:Infusions, Parenteral; D008757:Methylglucosides / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010695:Phlorhizin / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013549:Sweetening Agents / Q000008:administration & dosage*
chemical_list: D015220:Calcium Channels; D051273:Glucose Transporter Type 2; D005971:Glutamates; D008757:Methylglucosides; C495680:SLC2A2 protein, human; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D013549:Sweetening Agents; C014574:gamma-glutamylmethylamide; C027020:methylglucoside; D052216:Glucagon-Like Peptide 1; D010695:Phlorhizin; D005947:Glucose