Luminal glucose sensing in the rat intestine has characteristics of a sodium-glucose cotransporter

Freeman, Sara M.; Bohan, D; Darcel, Nicolas; Raybould, Helen E.

doi:10.1152/ajpgi.00079.2006

Cited by 71 publications

(69 citation statements)

References 31 publications

(36 reference statements)

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“…This possibility made us explore SGLT3, another putative glucose sensor. SGLT3 is a neuronally located member of the solute carrier family of proteins that appears to function as a sensor rather than a transporter of glucose (6,10). Binding of glucose (but not saccharin) to SGLT3 leads to membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Bhutta

Deelman

Roux

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bhutta HY, Deelman TE, le Roux CW, Ashley SW, Rhoads DB, Tavakkoli A. Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery. Am J Physiol Gastrointest Liver Physiol 307: G588 -G593, 2014. First published July 3, 2014 doi:10.1152/ajpgi.00405.2013.-Studies suggest that improvements in type 2 diabetes (T2D) post-Roux-en-Y gastric bypass (RYGB) surgery are attributable to decreased intestinal glucose absorption capacity mediated by exclusion of sweet taste-sensing pathways in isolated proximal bowel. We probed these pathways in rat models that had undergone RYGB with catheter placement in the biliopancreatic (BP) limb to permit post-RYGB exposure of isolated bowel to sweet taste stimulants. Lean Sprague Dawley (n ϭ 13) and obese Zucker diabetic fatty rats (n ϭ 15) underwent RYGB with BP catheter placement. On postoperative day 11 (POD 11), rats received catheter infusions of saccharin [sweet taste receptor (T1R2/3) agonist] or saline (control). Jejunum was analyzed for changes in glucose transporter/sensor mRNA expression and functional sodium-glucose transporter 1 (SGLT1)-mediated glucose uptake. Saccharin infusion did not alter glucose uptake in the Roux limb of RYGB rats. Intestinal expression of the glucose sensor T1R2 and transporters (SGLT1, glucose transporter 2) was similar in saccharin-vs. saline-infused rats of both strains. However, the abundance of SGLT3b mRNA, a putative glucose sensor, was higher in the common limb vs. BP/Roux limb in both strains of bypassed rats and was significantly decreased in the Roux limb after saccharin infusion. We concluded that failure of BP limb exposure to saccharin to increase Roux limb glucose uptake suggests that isolation of T1R2/3 is unlikely to be involved in metabolic benefits of RYGB, as restimulation failed to reverse changes in intestinal glucose absorption capacity. The altered expression pattern of SGLT3 after RYGB warrants further investigation of its potential involvement in resolution of T2D after RYGB.Roux-en-Y gastric bypass; obesity; type 2 diabetes mellitus; intestinal sweet taste sensor; sodium-glucose transporter 1 IN RECENT DECADES, BARIATRIC SURGERY has evolved into the foremost therapy for obesity. Moreover, one of the weight loss operations, Roux-en-Y Gastric Bypass surgery (RYGB), is associated with a high rate of remission of type 2 diabetes mellitus (T2D), with an early and weight-independent mechanism that improves glucose homeostasis (2, 17). However, the mechanisms mediating the resolution of T2D remain poorly understood.Intense investigation of contributory factors has implicated several mechanisms, including alterations in incretin levels, the gut microbiome, bile acids, and an area of interest to our lab, namely intestinal nutrient sensing. The surgical isolation of duodenum and proximal jejunum appear to be critical in mediating resolution of T2D, supported by outcomes following endoluminal sleeve device insertion and surgical procedures (e.g., RYGB, biliopancreatic diversion), which exclude a sim...

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Section: Discussionmentioning

confidence: 99%

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Bhutta

Deelman

Roux

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We hypothesize that vagal afferents may be detecting nutrient delivery, for example, through activation of SGLT1 or SGLT3 (12,17), intestinal sweet taste receptors such as T1R3 (23), or portal/hepatic glucoreceptors (26,32). An output pathway then leads to upregulation of SGLT protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na⁺/glucose cotransporter SGLT1

Stearns¹,

Balakrishnan²,

Rounds³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Stearns AT, Balakrishnan A, Rounds J, Rhoads DB, Ashley SW, Tavakkolizadeh A. Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na ϩ /glucose cotransporter SGLT1. Am J Physiol Gastrointest Liver Physiol 294: G1078-G1083, 2008. First published February 28, 2008 doi:10.1152/ajpgi.00591.2007.-Introduction: the intestinal Na ϩ /glucose cotransporter (SGLT1) displays rapid anticipatory diurnal rhythms in mRNA and protein expression. The vagus nerve has been implicated in the entrainment of some transporters. We aimed to clarify the influence of the vagus nerve on the diurnal entrainment pathway for SGLT1 and examine the role of vagal afferent fibers. Methods: male Sprague-Dawley rats were randomized to three groups, total subdiaphragmatic vagotomy, selective deafferentation of the vagus with capsaicin, or sham laparotomy. Postoperatively, animals were maintained in a 12-h light-dark cycle with food access limited to night. On the ninth postoperative day, animals were euthanized to harvest jejunal mucosa at 6-h intervals starting at 10 AM. Whole cell SGLT1 protein was measured by semiquantitative densitometry of immunoblots. Sglt1 and regulatory subunit RS1 mRNA was assessed by quantitative PCR. Fluorogold tracer technique was used to confirm adequacy of the vagotomy. Results: the diurnal rhythm in intestinal SGLT1, with a 5.3-fold increase in Sglt1 mRNA at 4 PM, was preserved in both vagotomy and capsaicin groups. However, the rhythmicity in SGLT1 protein expression (2.3-fold peak at 10 PM; P ϭ 0.041) was abolished following either total vagotomy or deafferentation. Lack of change in RS1 mRNA suggests this is independent of the RS1 regulatory pathway. Conclusion: SGLT1 transcription is independent of the vagus. However, dissociation of the protein rhythm from the underlying mRNA signal by vagotomy suggests the vagus may be involved in posttranscriptional regulation of SGLT1 in an RS1 independent pathway. Disruption following afferent ablation by capsaicin suggests this limb is specifically necessary. glucose transport; vagus; vagotomy THE APICAL na ϩ /glucose cotransporter (SGLT1), localized on the brush-border membrane of small bowel enterocytes, is responsible for all secondary active absorption of glucose from the small bowel (14,19). Dysregulation of SGLT1 is increasingly recognized in type 2 diabetes mellitus, with expression increasing up to fourfold in both patients and animal models (4, 7-9). Similarly, knockout of the SGLT1 regulatory subunit protein RS1 in mice leads to both SGLT1 overexpression and severe obesity (27). Therapy aimed at modulating SGLT1 expression may therefore have clinical benefits in diabetes and obesity through slowing of glucose absorption in a manner similar to amylase inhibitors (5) and through increased ileal glucose delivery (38). SGLT1 expression is regulated by several inputs, including diet composition (11) and the timing of food intake (28). Despite significant progress in characterizing the physiological signaling mechanisms regulating SGL...

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“…43) on the tongue insofar as the process of transporting molecules (in this case glucose and Na) into the enterocyte (or entero-endocrine cell) is also the event that depolarizes the cell (21). However, these transporters are highly specific to glucose and their effects appear to be sensory, insofar as nonmetabolizable glucose analogues likewise stimulate these transceptors (11,24). Previous studies on glucose transport have suggested that initial activity at the SGLTs (but also GLUTs) depolarizes the cell and, in doing so, activates nearby T1Rs (for a review see Ref.…”

Section: Methodsmentioning

confidence: 99%

Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise

Schier

Davidson

Powley

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Schier LA, Davidson TL, Powley TL. Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise. Am J Physiol Regul Integr Comp Physiol 302: R1351-R1363, 2012. First published March 14, 2012 doi:10.1152/ajpregu.00702.2011.-In a previous report (Schier et al., Am J Physiol Regul Integr Comp Physiol 301: R1557-R1568, 2011, we demonstrated with a new behavioral procedure that rats exhibit stimulus-bound suppression of intake in response to an intraduodenal (ID) bitter tastant predicting subsequent malaise. With the use of the same modified taste aversion procedure, the present experiments evaluated whether the sweet taste properties of ID stimuli are likewise detected and encoded. Thirsty rats licked at sipper spouts for hypotonic NaCl for 30 min and received brief (first 6 min) yoked ID infusions of either the same NaCl or an isomolar lithium chloride (LiCl) solution in each session. An intestinal taste cue was mixed directly into the LiCl infusate for aversion training. Results showed that rats failed to detect intestinal sweet taste alone (20 mM Sucralose) but clearly suppressed licking in response to a nutritive sweet taste stimulus (234 mM sucrose) in the intestine that had been repeatedly paired with LiCl. Rats trained with ID sucrose in LiCl subsequently generalized responding to ID Sucralose alone at test. Replicating this, rats trained with ID Sucralose in compound with 80 mM Polycose rapidly suppressed licking to the 20 mM Sucralose alone in a later test. Furthermore, ID sweet taste signaling did not support the rapid negative feedback of sucrose or Polycose on intake when their digestion and transport were blocked. Together, these results suggest that other signaling pathways and/or transporters engaged by caloric carbohydrate stimuli potentiate detection of sweet taste signals in the intestine.gastrointestinal; taste receptor; preabsorptive signals; artificial sweetener; food learning THE DISCOVERIES that putative chemoreceptive cells in the epithelium of the gastrointestinal (GI) tract express taste receptor molecules and intracellular signaling proteins (e.g., 3, 4, 10, 17-19, 22, 27, 28, 48, 53) as well as exhibit morphological features resembling those of taste cells on the tongue (e.g., 12, 18) have stimulated interest in how preabsorptive food-related signals arising from the lumen of the GI tract are transduced to affect digestion and ingestion (see, for example, the series of review articles entitled "Nutrient Tasting and Signaling Mechanisms in the Gut" published in American Journal of Physiology: Refs. 5,13,20,32,41). To address such questions, we recently developed and employed a new behavioral paradigm to demonstrate that a bitter tastant in the duodenum produces stimulus-bound reductions in ongoing ingestion (37). The present set of experiments addresses similar functional questions using the same behavioral paradigm to evaluate the effects of sweet tastants in the duodenum.

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Luminal glucose sensing in the rat intestine has characteristics of a sodium-glucose cotransporter

Cited by 71 publications

References 31 publications

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na⁺/glucose cotransporter SGLT1

Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise

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Luminal glucose sensing in the rat intestine has characteristics of a sodium-glucose cotransporter

Cited by 71 publications

References 31 publications

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na+/glucose cotransporter SGLT1

Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise

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Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na⁺/glucose cotransporter SGLT1