T1R2 receptor-mediated glucose sensing in the upper intestine potentiates glucose absorption through activation of local regulatory pathways

Smith, Kathleen R.; Azari, Elnaz Karimian; LaMoia, Traci E.; Hussain, Tania; Vargova, Veronika; Károlyi, Katalin; Veldhuis, Paula P.; Arnoletti, J. Pablo; Fuente, Sebastián G. de la; Pratley, Richard E.; Osborne, Timothy F.; Kyriazis, George A.

doi:10.1016/j.molmet.2018.08.009

Cited by 36 publications

(53 citation statements)

References 54 publications

(79 reference statements)

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“…Although saccharin treatment was unsuccessful in modifying IGGTT responses, it may have induced localized intestinal changes that may contribute to long-term metabolic susceptibility. To address this possibility we assessed post-treatment ex vivo glucose transport using intact intestines (Ussing chamber) and found no effect of saccharin supplementation in the transport of the non-metabolizable glucose analog 3-O-methyl-glucose (3-OMG) ( Figure.2C), but we observed decreased glucose transport in T1R2-KO intestines, consistent with the IGGTT data and our previous studies [13]. In addition, saccharin supplementation did not change the expression of glucose transporters or of STRs (Supp.…”

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confidence: 89%

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High dose saccharin supplementation does not induce gut microbiota dysbiosis or glucose intolerance in healthy humans and mice

Serrano

Smith

Crouch

et al. 2020

Preprint

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Background : Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, saccharin and other NCAS have been reported to induce glucose intolerance in mice fed a high-fat diet and in a subset of humans by directly inducing unfavorable changes in gut microbiota. These findings have raised concerns about NCAS and called into question their broad use. Whether these results can be generalized to healthy populations consuming conventional diets is unknown. It is also unclear how different NCAS, that do not share a common chemical structure, can produce identical direct effects on gut microbiota. A common feature of all NCAS is their strong affinity for sweet taste receptors (STRs) which are expressed in the intestine. However, their role in mediating NCAS-induced effects has not been addressed. Results : We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of saccharin on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for two weeks. In parallel, we performed a ten-week study administering high-dose saccharin in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice alike, none of the interventions affected glucose or hormonal responses to a glucose tolerance test, nor ex vivo glucose absorption in mice. Similarly, saccharin supplementation did not alter microbial diversity or abundance at any taxonomic level in humans or mice. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance.

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supporting

confidence: 89%

“…However, we did observe age-dependent increases in intra-gastric GTT (IGGTT) responses in WT mice. Notably, these effects were absent in T1R2-KO mice, which also had reduced IGGTT responses compared to WT littermates [13] ( Figure.2A).…”

Section: Glucose Tolerance and Ex Vivo Intestinal Functionmentioning

confidence: 95%

High dose saccharin supplementation does not induce gut microbiota dysbiosis or glucose intolerance in healthy humans and mice

Serrano

Smith

Crouch

et al. 2020

Preprint

Self Cite

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“…In many species, intestinal SGLT1 expression levels control intestinal glucose absorption and is affected directly by dietary sugar in the lumen of the intestine (Dyer et al, 2007;Smith et al, 2018). In many species, intestinal SGLT1 expression levels control intestinal glucose absorption and is affected directly by dietary sugar in the lumen of the intestine (Dyer et al, 2007;Smith et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…3, decreased down to day 14 and were then maintained at a low expression level up to day 28. In many species, intestinal SGLT1 expression levels control intestinal glucose absorption and is affected directly by dietary sugar in the lumen of the intestine (Dyer et al, 2007;Smith et al, 2018). SGLT1 is likely to involve a G-protein-coupled second messenger pathway (Dyer, Vayro, King, & Shirazi-Beechey, 2003;Shirazi-Beechey, Moran, Batchelor, Daly, & Al-Rammahi, 2011).…”

Section: Discussionmentioning

confidence: 99%

Age‐related intestinal monosaccharides transporters expression and villus surface area increase in broiler and layer chickens

Cheng

Yuan

et al. 2019

Animal Physiology Nutrition

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In the chicken small intestine, glucose is mainly transported by the apically located sodium/glucose cotransporter 1 (SGLT1) and the basolaterally located glucose transporter 2 (GLUT2). Fructose is transported by the apically located glucose transporter 5 (GLUT5) and similarly by GLUT2. During the early post‐hatching period, the intestinal villus surface area (VSA) should be considered as an important factor related to the monosaccharide absorption capacity. Our objective here was to study intestinal monosaccharide absorption by analyzing the effects of age, diet, and breed on monosaccharide transporters and the VSA. The mRNA expression patterns of SGLT1, GLUT2 and GLUT5 genes in broiler and layer chickens were measured from the day of hatching to day 28 using the absolute quantitative real‐time PCR. Both the intestinal mRNA expression levels of these genes and the VSA were affected by age. The mRNA expression levels of SGLT1 and GLUT2 were significantly increased from day 1 to day 3 and then decreased from day 3 to day 28. The expression levels of GLUT5 decreased from day 1 to day 7. The broiler chickens VSAs were significantly larger than those of the layer chickens from days 7 to 28. The effect of diet on the gene expression patterns of these monosaccharide transporters and the VSA were not significant. Our results suggest that the expression levels of these monosaccharide transporters are increased rapidly at the beginning of intestinal growth to meet the demands for monosaccharides to support the fast growth of the chick before day 7. As intestinal maturation and VSA increased, the expression levels of these monosaccharide genes decreased to a certain expression level to maintain the intestinal transport capacity and the absorption balance of all other nutrients.

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“…The sweet taste receptor T1R2 + T1R3 is a heterodimer that detects sugars and LCSs and is expressed in many tissues beyond the mouth, including the intestine and the pancreas [4]. Activation of these sweet taste receptors in the intestine results in a faster rate of glucose absorption [5][6][7][8]13] and in the secretion of incretins [9], although data from studies in vivo suggest that the extent of incretin secretion varies with different sweet taste ligands [14,15]. In addition, activation of these receptors in the pancreas can result in increased insulin secretion [10][11][12] and in the mouth, it can elicit pre-ingestive cephalic-phase responses, including a cephalic-phase insulin response (CPIR), which are thought to prime the body to better absorb and use ingested nutrients [16,17].…”

Section: Introductionmentioning

confidence: 99%

Effects of Sucralose Ingestion versus Sucralose Taste on Metabolic Responses to an Oral Glucose Tolerance Test in Participants with Normal Weight and Obesity: A Randomized Crossover Trial

et al. 2019

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Here, we tested the hypothesis that sucralose differentially affects metabolic responses to labeled oral glucose tolerance tests (OGTTs) in participants with normal weight and obesity. Participants (10 with normal weight and 11 with obesity) without diabetes underwent three dual-tracer OGTTs preceded, in a randomized order, by consuming sucralose or water, or by tasting and expectorating sucralose (e.g., sham-fed; sweetness control). Indices of β-cell function and insulin sensitivity (S I ) were estimated using oral minimal models of glucose, insulin, and C-peptide kinetics. Compared with water, sucralose ingested (but not sham-fed) resulted in a 30 ± 10% increased glucose area under the curve in both weight groups. In contrast, the insulin response to sucralose ingestion differed depending on the presence of obesity: decreased within 20-40 min of the OGTT in normal-weight participants but increased within 90-120 min in participants with obesity. Sham-fed sucralose similarly decreased insulin concentrations within 60 min of the OGTT in both weight groups. Sucralose ingested (but not sham-fed) increased S I in normal-weight participants by 52 ± 20% but did not affect S I in participants with obesity. Sucralose did not affect glucose rates of appearance or β-cell function in either weight group. Our data underscore a physiological role for taste perception in postprandial glucose responses, suggesting sweeteners should be consumed in moderation.

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T1R2 receptor-mediated glucose sensing in the upper intestine potentiates glucose absorption through activation of local regulatory pathways

Cited by 36 publications

References 54 publications

High dose saccharin supplementation does not induce gut microbiota dysbiosis or glucose intolerance in healthy humans and mice

High dose saccharin supplementation does not induce gut microbiota dysbiosis or glucose intolerance in healthy humans and mice

Age‐related intestinal monosaccharides transporters expression and villus surface area increase in broiler and layer chickens

Effects of Sucralose Ingestion versus Sucralose Taste on Metabolic Responses to an Oral Glucose Tolerance Test in Participants with Normal Weight and Obesity: A Randomized Crossover Trial

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