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Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels. In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion.
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... Furthermore, the data available suggest that SGLT1 and GLUT2 play a crucial role in glucose-dependent stimulation of GLP-1 and GIP secretion in the small intestine [40,41]. Thus, we studied the expression of intestinal SGLT1 and GLUT2 to determine how AE affected these intestinal glucose transporters, which may help to explain the observed stimulation effect of AE on incretin hormones. ...
... Several studies have shown the importance of GLUT2 in stimulating GLP-1 and/or GIP secretion at very high glucose concentrations in the intestinal lumen [41,43]. However, a study by Roder et al. [40] found no significant differences in GIP and GLP-1 secretion in GLUT2 knockout mice following an oral glucose gavage. This suggests that GLUT2 plays a limited role in K and L cell-mediated incretin secretion. ...
... This suggests that GLUT2 plays a limited role in K and L cell-mediated incretin secretion. Our findings aligned with those of Roder et al. [40], as the downregulation of GLUT2 by AE appeared to have minimal or no effect on incretin hormone secretion. Overall, the inhibition of SGLT1 contributes to the sustain release of incretin by AE. ...
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Nipa palm vinegar has been traditionally used to lower blood glucose levels by diabetic patients. This study aims to analyse the effect of aqueous extract (AE) of nipa palm vinegar on glycemic parameters and glucose transporter-incretin hormonal system in type 2 diabetic rat. The model was established using a combination of high-fat diet (p.o.) and low dose streptozotocin (i.p.). AE (250, 500, and 1000 mg/kg) was administered orally once daily for 28 days. Biochemical parameters related to type 2 diabetes including fasting glucose, serum insulin, lipid profiles, incretin hormone, liver, and pancreatic histology were evaluated. Relative expression of jejunal glucose transporters was also determined. Induction of diabetes caused significant (p = 0.026) weight loss, hyperlgycemia, hypoinsulinemia, dyslipidemia and reduced incretin hormones. Diabetes onset also disturbed HOMA-IR and HOMA-ß cell function indices, altered the morphological features of hepatocytes and pancreatic islet and overexpressed intestinal glucose transporters, SGLT1 and GLUT2. Repetitive oral administration of AE (1000 mg/kg) for 28 days ameliorated the biochemical abnormalities and improved HOMA-β cell function of diabetic rats. Histological studies revealed AE treatment preserved the integrity of pancreatic islet and protected hepatocytes from degeneration and atrophic effects of streptozotocin. Further analysis suggested the effect of AE in stimulating incretin hormones secretion via the action of DPP4 inhibitor and by modulating jejunal SGLT1 expression. In conclusion, the study suggested AE exerted its antidiabetic effect partially by stimulating insulin secretion via incretin hormone and intestinal glucose transporter pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-025-04933-8.
... Thus, at these concentrations of glucose, blocking SGLT1 and thereby secondary active transport of glucose, 30%-40% of total glucose absorption was not mediated by SGLT1, justifying the search for additional routes of absorption. SGLT1 is not expressed at the basolateral membrane, 22 we did not expect to see changes in glucose absorption during intra-arterial administration of phlorizin ( Figure 2E). Total glucose absorption in the first stimulation period was 488.5 and 453.8 μmol/15 min in the second ( Figure 2F, p = 0.09). ...
... 12 That same study showed complete inhibition of glucose absorption by co-administration of phlorizin and cytochalasin B, which block the passive intracellular transport, leaving no room for a paracellular component of absorption. 34 However, a more recent study 22 found GLUT2 to be located only at the basolateral membrane, confirmed by intestinal immuno-staining. Röder et al. 22 detected apical GLUT2 by Western blot but also detected considerable amounts of other basolateral markers in the apical membrane preparations and thus assumed that detectable GLUT2 was due to basolateral contamination. ...
... 34 However, a more recent study 22 found GLUT2 to be located only at the basolateral membrane, confirmed by intestinal immuno-staining. Röder et al. 22 detected apical GLUT2 by Western blot but also detected considerable amounts of other basolateral markers in the apical membrane preparations and thus assumed that detectable GLUT2 was due to basolateral contamination. In addition to this, there was no increase in GLUT2 protein density after a glucose gavage, which would be expected with proposed models of GLUT2 trafficking. ...
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Aim Intestinal glucose transport involves SGLT1 in the apical membrane of enterocytes and GLUT2 in the basolateral membrane. In vivo studies have shown that absorption rates appear to exceed the theoretical capacity of these transporters, suggesting that glucose transport may occur via additional pathways, which could include passive mechanisms. The aim of the study was to investigate glucose absorption in an in vitro model, which has proven useful for endocrine studies. Methods We studied both transcellular and paracellular glucose absorption in the isolated vascularly perfused rat small intestine. Glucose absorbed from the lumen was traced with ¹⁴ C‐ d ‐glucose, allowing sensitive and accurate quantification. SGLT1 and GLUT2 activities were blocked with phlorizin and phloretin. ¹⁴ C‐ d ‐mannitol was used as an indicator of paracellular absorption. Results Our results indicate that glucose absorption in this model involves two transport mechanisms: transport mediated by SGLT1/GLUT2 and a paracellular transport mechanism. Glucose absorption was reduced by 60% when SGLT1 transport was blocked and by 80% when GLUT2 was blocked. After combined luminal SGLT1 and GLUT2 blockade, ~30% of glucose absorption remained. d ‐mannitol absorption was greater in the proximal small intestine compared to the distal small intestine. Unexpectedly, mannitol absorption increased markedly when SGLT1 transport was blocked. Conclusion In this model, glucose absorption occurs via both active transcellular and passive paracellular transport, particularly in the proximal intestine, which is important for the understanding of, for example, hormone secretion related to glucose absorption. Interference with SGLT1 activity may lead to enhanced paracellular transport, pointing to a role in the regulation of the latter.
... The dysregulation of fatty acid sensing reduces GLP-1 and CCK-8 [145,146], which can alter the gut-brain communication pathways, impairing satiety signals and leading to overeating. It has also been shown that heightened expression of nutrient transporters like SGLT1 and GLUT2 in the small intestine has been implicated in the exacerbation of hyperglycemia and insulin resistance [147]. ...
... However, the degree of its implications in hyperglycemia has yet to be determined. It is now well known that the increased expression and activity of SGLT1 in the small intestine is a pathophysiological factor in hyperglycemia [147]. When SGLT1 was inhibited in humans, postprandial GIP decreased, and GLP-1 increased [157]. ...
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The role of the gut‐to‐brain axis in the regulation of nutrient sensing has been studied extensively for decades. Research has mainly centered on vagal afferent and efferent neurotransmission along the gastrointestinal tract, followed by the integration of luminal information in the nodose ganglia and transmission to vagal integral sites in the brain. The physiological and cellular mechanisms of nutrient sensing by enterocytes and enteroendocrine cells have been well established; however, the roles of the enteric nervous system (ENS) remain elusive. Recent advances in targeting specific neuronal subpopulations and imaging techniques unravel the plausible roles of the ENS in nutrient sensing. In this review, we highlight physiological, cellular, and molecular insights that direct toward direct and indirect roles of the ENS in luminal nutrient sensing and vagal neurotransmission along the gut–brain axis and discuss functional maladaptations observed during metabolic insults, as observed during obesity and associated comorbidities, including type 2 diabetes.
... Intestinal glucose absorption is predominantly mediated by the active and passive glucose transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) [1]. Overexpression of these genes may increase intestinal glucose absorption, contributing to postprandial hyperglycaemia, a significant risk factor for type 2 diabetes [2,3]. ...
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As the organ with one of the largest surface areas facing the environment and responsible for nutrient uptake, the small intestine expresses numerous transport proteins in its brush‐border membrane for efficient absorption and supply of dietary macro‐ and micronutrients. The understanding of regulation and functional interplay of these nutrient transporters is of emerging interest in nutrition and medical physiology research in respect to development of diabetes, obesity, and inflammatory bowel disease worldwide. The peptide transporter 1 (PepT1, SLC15A1) is abundantly expressed particularly in the intestinal tract and provides highly effective transport of amino acids in the form of di‐ and tripeptides and features a substantial acceptance for structurally related compounds and drugs. These characteristics bring PepT1 into focus for nutritional and medical/pharmaceutical approaches, as it is the essential hub responsible for oral bioavailability of dietary protein/peptide supplements and peptide‐like drugs in eukaryotic organisms. Detailed analysis of molecular processes regulating PepT1 expression and function achieved in the last two decades has helped to define and use adjusting tools and to better integrate the transporter's role in cell and organ physiology. In this article, we provide an overview of the current knowledge on PepT1 function in health and disease, and on regulatory factors modulating its gene and protein expression as well as transport activity. © 2018 American Physiological Society. Compr Physiol 8:843‐869, 2018.
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GLP‐1 was described as an incretin over 30 years ago. GLP‐1 is encoded by the preproglucagon gene ( Gcg ), which is expressed in the intestine, the pancreas, and the central nervous system. GLP‐1 activates GLP‐1 receptors (GLP‐1r) on the β‐cell to induce insulin secretion in a glucose‐dependent manner. GLP‐1 also inhibits α‐cell secretion of glucagon. As few, if any, GLP‐1r are expressed on α‐cells, indirect regulation, via β‐ or δ‐cell products has been thought to be the primary mechanism by which GLP‐1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP‐1r on α‐cells for direct regulation as well. Although the predominant source of circulating GLP‐1 is the intestine, the α‐cell becomes a source of GLP‐1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP‐1 is also be important in regulating nutrient‐induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg ‐derived protein produced by the α‐cell, in stimulating insulin secretion by acting on GLP‐1r. Altogether, these data clearly demonstrate the important role of Gcg ‐derived peptides in regulating insulin secretion. Because of GLP‐1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577‐595, 2020.
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Chapter
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1. A method of measuring absorption from the intestinal tract of anæsthetized small laboratory animals is described in detail. 2. The jejunal absorption rates of water and of glucose and galactose have been measured in groups of rats under various common anæthetics. These produced no distinguishable effects. 3. A marked variation in the capacity of the jejunum to absorb occurred among individual rats subjected to the same treatment. 4. The rate of glucose absorption from solutions of 290 mOsM tonicity can be described in terms of two components, one a constant amount and the other proportional to the water absorption rate. 5. The rate of absorption of xylose from solutions of 290 mOsM tonicity is directly proportional to the water absorption rate. 6. The increase in sugar absorption for a given increment of water absorption depends upon the concentration of sugar in the intestinal fluid.
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Key points In intestine, nutrients including glucose and amino acids and non‐nutrients including bile acids increase secretion of anti‐diabetic gut peptides such as gluco‐insulinotropic peptide (GIP), glucagon‐like peptide‐1 (GLP‐1) and peptide tyrosine tyrosine (PYY). Facilitative glucose transporter pathways in addition to active electrogenic transporter pathways contribute to GIP, GLP‐1 and PYY secretion; in particular, the facilitative glucose transporter 2 (GLUT2) is involved. Sucralose, in the presence of glucose, can strongly and acutely upregulate GIP, GLP‐1 and PYY secretion in a time scale of minutes. Amino acid‐stimulated GIP, GLP‐1 and PYY secretion is acutely regulated by the calcium‐sensing receptor (CasR). The results establish new functions for GLUT2 and CasR as regulators of gut peptide secretion that sense nutrients and provide signalling pathways for the release of GIP, GLP‐1 and PYY.
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