Mechanisms Controlling Glucose-Induced Glp-1 Secretion in Human Small Intestine.

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 minute intraduodenal glucose infusion activated half of all duodenal L cells in humans. This infusion was sufficient to increase plasma GLP-1. With an ex vivo model using human gut tissue specimens, we showed a dose-responsive GLP-1 secretion in ileum at 200mM glucose or above. In ex vivo tissue from duodenum and ileum, but not colon, 300mM glucose potently stimulated GLP-1 release. In ileum, this response was independent of osmotic influences and required delivery of glucose via GLUT2 and mitochondrial metabolism. Requirement of voltage-gated Na + and Ca 2+ channel activation indicates that membrane depolarization occurs. K ATP channels do not drive this, as tolbutamide did not trigger release. The sodium glucose co-transporter 1 (SGLT1) substrate, α-MG, induced secretion, and the response was blocked by the SGLT1 inhibitor phlorizin or by replacement of extracellular Na + with NMDG. 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.