Intestinal SGLT1 in metabolic health and disease
Abstract
The Na+-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na+ gradient created by Na+-K+-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC 50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na+ homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.
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NHE3 and SGLT1 have been shown to regulate one another in mammalian intestinal epithelial cell models, including rabbit and rat cells.
“The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells.”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [22]
The “GI Motility and Secretion Associated With SGLT1 Inhibition” section (page not provided) reports reciprocal regulation of SGLT1 and NHE3 in cell cultures: suppressing either enhances the other. The References identify the cited cell study as involving rat intestinal epithelial cells, but our copy does not establish the same compensatory regulation in rabbit cells. (LLM, conf=0.87)
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References 153 · Cited by 104
Research works printed but not linked: 1
- [2]2. Allen A, Bell A, Mantle M, Pearson JP. The structure and physiology of gastrointestinal mucus. Adv Exp Med Biol 144: 115-133, 1982.
- Authors
- Lehmann, A., & Hornby, P. J.
- Affiliations
- University of Gothenburg (SE)
- Cardiovascular and Metabolic Disease, Janssen Research and Development, LLC, Spring House, Pennsylvania
- Corresponding author
- Hornby, Pamela J.
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2016-06-01
- Volume
- 310
- Issue
- 11
- Pages
- G887-G898
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2304389785
- Cited by
- 104
- References
- 153
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 16 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 6 · 2016: 1
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- SGLT1, intestinal glucose transport, SGLT2 inhibitors, type 2 diabetes, canagliflozin, glucagon-like peptide-1, peptide YY, colonic microbiota, propionate, intestinal gluconeogenesis, incretin effect, ileal brake, dietary intake, diarrhea, Na+ homeostasis, Na+/K+-ATPase
- MeSH terms
- Animals, Gastrointestinal Motility, Humans, Intestinal Absorption, Intestinal Mucosa, Metabolic Diseases, Enteroendocrine Cells, Sodium-Glucose Transporter 1
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