Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice
Abstract
Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose-induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg in the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose in the colon did not increase GIP or GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Coadministration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose in the upper intestine blocked glucose absorption and glucose-induced incretin secretion. α-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after a 2-h fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a noncalorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.
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Transport of SGLT-1 monosaccharide substrates triggers incretin hormone secretion, an action attenuated by phlorizin or genetic deletion in rodents.
“Importantly, transport of the monosaccharide substrates of SGLT-1 (e.g., glucose and galactose) triggers incretin hormone secretion (20), an action attenuated when SGLT-1 is pharmacologically inhibited with the competitive antagonist phlorizin, or absent through genetic deletion in rodents (42,43).”
From Gut mechanisms linking intestinal sweet sensing to glycemic control (2018) · cites this paper as [43]
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“, glucose and galactose) triggers incretin hormone secretion (20), an action attenuated when SGLT-1 is pharmacologically inhibited with the competitive antagonist phlorizin, or absent through genetic deletion in rodents (42, 43).”
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- Authors
- Moriya, R., Shirakura, T., Ito, J., Mashiko, S., & Seo, T.
- Affiliations
- Banyu Tsukuba Research Institute, Merck Research Laboratory, Tsukuba, Ibaraki, Japan
- Corresponding author
- Seo, Toru
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-12
- Volume
- 297
- Issue
- 6
- Pages
- E1358-E1365
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2163903330
- Cited by
- 156
- References
- 23
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 11 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 12 · 2015: 18 · 2014: 18 · 2013: 7 · 2012: 19
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SGLT1, incretin secretion, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, phloridzin, methyl α-D-glucopyranoside, hyperglycemia, glucose tolerance, type 2 diabetes, db/db mice, glucose absorption
- MeSH terms
- Animals, Blood Glucose, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Glucose, Glucose Tolerance Test, Hyperglycemia, Intestine, Large, Male, Methylglucosides, Mice, Inbred C57BL, Phlorhizin, Random Allocation, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sodium-Glucose Transporter 1, Mice, Glucagon-Like Peptide 1
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