Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine
Open accessAbstract
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 α-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 glucose-stimulated GLP-1 release in human ileal L cells.
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SGLT-1-based transport is critical for ex vivo release of GLP-1 in human ileum; blocking SGLT-1 with phlorizin or replacing extracellular sodium with N-methyl-D-glucamine abolishes this response.
“We have also established that SGLT-1-based transport is critical for ex vivo release of GLP-1 in human ileum, while blocking SGLT-1 with phlorizin or replacing extracellular Na + with N-methyl-D-glucamine abolishes this response (26).”
From Gut mechanisms linking intestinal sweet sensing to glycemic control (2018) · cites this paper as [26]
LCS evoke ex vivo GLP-1 release from human ileal tissue.
“To this end, we provided the first evidence that LCS evoke ex vivo GLP-1 release from human ileal tissue (26).”
From Gut mechanisms linking intestinal sweet sensing to glycemic control (2018) · cites this paper as [26]
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“We have also established that SGLT-1-based transport is critical for ex vivo release of GLP-1 in human ileum, while blocking SGLT-1 with phlorizin or replacing extracellular Na with N-methyl-D-glucamine abolishes this response (26).”
BackgroundSelf-citation
- Authors
- Sun, E. W., de Fontgalland, D., Rabbitt, P., Hollington, P., Sposato, L., Due, S. L., Wattchow, D. A., Rayner, C. K., Deane, A. M., Young, R. L., & Keating, D. J.
- Affiliations
- Flinders University (AU)
- Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia
- Royal Adelaide Hospital (AU)
- South Australian Health and Medical Research Institute (AU)
- Corresponding author
- Young, Richard L.
- Keating, Damien J.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-04-06
- Volume
- 66
- Issue
- 8
- Pages
- 2144-2149
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5860185
- OpenAlex
- W2604975434
- Cited by
- 152
- References
- 21
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 12 · 2023: 14 · 2022: 20 · 2021: 21 · 2020: 19 · 2019: 17 · 2018: 13 · 2017: 3
- FWCI
- 11.25
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Australian Research Council (LP150100419)
- National Health and Medical Research Council (APP1088737)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- glucagon-like peptide-1, GLP-1 secretion, incretins, L cells, ileum, duodenum, SGLT1, GLUT2, mitochondrial metabolism, membrane depolarization, ATP-sensitive potassium channels, phloridzin, sodium-glucose cotransport, human small intestine
- MeSH terms
- Dose-Response Relationship, Drug, Duodenum, Glucose, Glutamates, Humans, Ileum, Infusions, Parenteral, Methylglucosides, Mitochondria, Phlorhizin, Sweetening Agents, Calcium Channels, Sodium-Glucose Transporter 1, Glucose Transporter Type 2, Glucagon-Like Peptide 1
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