Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine

Emily Sun, Dayan De Fontgalland, Philippa Rabbitt, Paul Hollington, Luigi Sposato, Steven Due, David Wattchow, Christopher Rayner, Adam Deane, Richard Young, Damien Keating

Research output: Contribution to journalArticle

35 Citations (Scopus)

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. KATP channels do not drive this, as tolbutamide did not trigger release. The sodium-glucose cotransporter 1 (SGLT1) substrate a-MG induced secretion, and the response was blocked by the SGLT1 inhibitor phlorizin or by replacement of extracellular Na+ with N-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 glucosestimulated GLP-1 release in human ileal L cells.

Original languageEnglish
Pages (from-to)2144-2149
Number of pages6
JournalDiabetes
Volume66
Issue number8
DOIs
Publication statusPublished - 2017

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