Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control

Copyright © 2018 Kreuch, Keating, Wu, Horowitz, Rayner and Young. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes

Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control

Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes

Gut mechanisms linking low-calorie sweeteners to impaired glycaemic control

Habitual high consumption of beverages and foods containing low-calorie sweeteners (LCS) has been linked to an increased risk of developing type 2 diabetes (T2D) in humans, however the underlying mechanisms are unknown. It is known that sweet stimuli, including LCS, are sensed at broadly tuned sweet taste receptors (STRs) located on taste cells of the tongue, and in extra-oral sites including enteroendocrine cell (EEC) populations in the proximal intestine. Activation of STRs in intestinal cell lines and preclinical models triggers a signalling cascade leading to the release of gut hormones, including the ‘incretin’ hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which augment pancreatic insulin release, as well as the intestinotrophic peptide glucagon-like peptide-2 (GLP-2). STR-dependent release of gut GLP-2 augments levels and function of the primary apical glucose transporter, sodium-glucose cotransporter 1 (SGLT-1), acting to increase the rate of glucose absorption; this evidence is, however, equivocal in humans. The potential for sweet stimuli (and LCS) to modify glucose absorption and disposal, and disrupt gut bacterial communities, is high, and habitual high intake of LCS, particularly in subjects with T2D, may exaggerate postprandial hyperglycemia and blood glucose excursions. Work in this thesis aimed to determine the glycaemic and thyroid hormone consequences of sub-acute LCS supplementation and acute STR blockade in healthy subjects, and the molecular pathways subserving LCS signals in human intestinal tissues. A clinical study was first undertaken to evaluate the impact of two-week, high dose LCS supplementation in capsules (combined sucralose and acesulfame-K) on glycaemic control in health. LCS supplementation augmented glucose absorption, disrupted glycaemic responses to intestinal glucose, tended to reduce glucoseevoked L-cell release of GLP-1, GLP-2 and peptide tyrosine-tyrosine (PYY) and had modest effects on the balance of thyroid hormones. Glycaemic changes were linked to shifts in microbiome composition and function toward microbiome features seen in T2D, while specific microbiome mediators (e.g., Eubacterium rectale) and moderators (e.g., Bacteroidetes uniformis) were identified. These provided first evidence that an individual’s basal microbiome composition, as well as LCS-induced changes, contributed to shifts in glycaemic response to LCS supplementation. A separate ex vivo study utilising a novel human intestinal tissue platform developed to interrogate LCS molecular signals, then added support that combined sucralose and acesulfame-K evoked more powerful GLP-1 release from the ileum than duodenum in humans, a response that was lower in the presence than absence of the STR blocker, lactisole. Finally, a clinical study was then undertaken to determine acute effects of the STR blocker, lactisole, on glycaemic responses to intraduodenal glucose infusion in healthy subjects, to evaluate any potential for postprandial benefits. Lactisole co-infusion augmented the rate of glucose absorption and attenuated late phase glucose-evoked GLP-1 release in health but had no effect on T1R2, SGLT-1 or GLUT2 transcript expression levels in the duodenum. Lactisole had none of these effects in subjects with T2D. These findings add support that intestinal STRs are acutely dysregulated and decoupled from absorptive function in the context of T2D, a finding that demands validation in a more chronic setting. Together, findings in this thesis highlight the fact that combined acesulfame-K and sucralose are not inert and can negatively impact glycaemic control via intestinal STR and, potentially, microbiome mechanisms. This evidence informs the public health debate over the merits of substituting these LCS for added sugar as well as the development of new targets for ‘next-generation’ anti-diabetic therapies that target gut control of glucose absorption/glycemia or the gut microbiome (precision pre- or pro-biotics), to optimise glycaemic control.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202