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Intestinal SGLT1 in metabolic health and disease

Review article
Authors Anders Lehmann
Pamela J. Hornby
Published in American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume 310
Pages G887-G898
ISSN 0193-1857
Publication year 2016
Published at Institute of Neuroscience and Physiology, Department of Physiology
Pages G887-G898
Language en
Links doi.org/10.1152/ajpgi.00068.2016
Keywords Diarrhea, Gluconeogenesis, Glucose tolerance, Ileal brake, Incretin, Microbiome, Monosaccharide, SLC5A1, Sodium/hydrogen exchanger isoform 3, Taste receptors
Subject categories Physiology

Abstract

© 2016 the American Physiological Society. 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 IC50 + 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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