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The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing
PLOS One
Abstract and Figures
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. ...
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. ...
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]. ...
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]. ...
Inflammation is associated with the pathophysiology of type 2 diabetes and COVID-19. Phytochemicals have the potential to modulate inflammation, expression of SARS-CoV-2 viral entry receptors (angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) and glucose transport in the gut. This study assessed the impact of phytochemicals on these processes. We screened 12 phytochemicals alongside 10 pharmaceuticals and three plant extracts, selected for known or hypothesised effects on the SARS-CoV-2 receptors and COVID-19 risk, for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising ones, as assessed by the downregulation of TMPRSS2, and thus they were used in subsequent experiments. The cells were then co-stimulated with pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) for ≤168 h to induce inflammation, which are known to induce multiple pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Target gene expression (ACE2, TMPRSS2, SGLT1 (sodium-dependent glucose transporter 1) and GLUT2 (glucose transporter 2)) was measured by droplet digital PCR, while interleukin-1 (IL-6), interleukin-1 (IL-8) and ACE2 proteins were assessed using ELISA in both normal and inflamed cells. IL-1β and TNF-α treatment upregulated ACE2, TMPRSS2 and SGLT1 gene expression. ACE2 increased with the duration of cytokine exposure, coupled with a significant decrease in IL-8, SGLT1 and TMPRSS2 over time. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with a decrease in IL-8 (r = −0.77, p < 0.01). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 and TMPRSS2. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway. Genistein downregulated the inflammation-induced increase in SGLT1 and TMPRSS2, which may help lower the postprandial glycaemic response and COVID-19 risk or severity in healthy individuals and those with metabolic disorders.
The enteroendocrine system of the gut acts both locally and peripherally, regulating gastrointestinal function as well as metabolism, energy expenditure, and central appetite control through the release of a variety of hormones. The chemosensing ability of enteroendocrine cells is integral to their role in eliciting physiological changes in response to fluctuations in the composition of the intestinal lumen. Regulation of enteroendocrine cell activity is complex, and requires that these cells can integrate signals deriving from dietary sources as well as the nervous and endocrine systems. Here, we provide an overview of enteroendocrine cell form and function, with a focus on new insights into their distribution throughout the intestine and the stimulus secretion coupling mechanisms underlying the activity of these important members of the gut‐brain axis. © 2018 American Physiological Society. Compr Physiol 8:1603‐1638, 2018.
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.
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.
The focus of this article is on the analysis of the release and postrelease fate of the incretin hormones, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. Their actions are dealt with to the extent that they are linked to their secretion. For both hormones, their posttranslational processing is analyzed in detail, because of its importance for the understanding of the molecular heterogeneity of the hormones. Methods of analysis, in particular regarding measurements in plasma from in vivo experiments, are discussed in detail in relation to the molecular heterogeneity of the hormones, and the importance of the designations “total” versus “intact hormones” is explained. Both hormones are substrates for the ubiquitous enzyme, dipeptidyl peptidase‐4, which inactivates the peptides with dramatic consequences for their physiological spectrum of activities. The role of endogenous and exogenous antagonists of the receptors is discussed in detail because of their importance for the elucidation of the physiology and pathophysiology of the hormones. Regarding the actual secretion, the most important factors are discussed, including gastric emptying rate and the influence of the different macronutrients. Additional factors discussed are the role of bile, paracrine regulation, the role of the microbiota, pharmaceuticals, and exercise. Finally, the secretion during pathological conditions is discussed. © 2019 American Physiological Society. Compr Physiol 9:1339‐1381, 2019.
Diabetes mellitus (DM) is a metabolic syndrome that is currently being managed using different brands of prescribed medications; however, these medications are associated with different side effects. As such, medical plants are considered an alternative in traditional medicines for treating DM as they have no side effects. The present study was conceived with the aim of studying generally medicinal plants extracts in terms of their a-amylase and a-glucosidase inhibitory activities; to study the renal, hepatic, and pancreatic protective effects of these EIE: OsC (2:1) and ElE:PgC (2:1) plant extracts on streptozotocin (STZ)-induced diabetic rats after 30 days of treatment. Sprague-Dawley rats were intraperitoneally injected with STZ (60 mg/kg) to induce DM. The rats were randomly grouped into 7 groups of 5 rats each based on the intended treatment for the groups; the seven groups of rats are as follows: NC = normal control rats; NEIE:PgC (2:1) normal rats treated with combined E. longifolia and P. granatum extracts at a combination ratio of 2:1 (200 mg/kg); NEIE:OsC (2:1) = normal rats treated with combined extracts of E. longifolia and O. stamineus at 2:1 combination ratio; DC = diabetic control rats; DG = glibenclamide (0.6 mg/kg)-treated diabetic rats; DEIE:PgC (2:1) diabetic rats treated with combined extracts of E. longifolia and P. granatum at a ratio of 2:1 (200 mg/kg); DEIE: OsC (2:1) = diabetic rats treated with combined extracts of E. longifolia and O. stamineus at the same ratio. All the animal groups were treated for 4 weeks and after the treatment period, the blood glucose level, body weight, liver and renal functions, and histopathological changes of the endocrine pancreas, liver and kidneys were examined in all the experimental rats. The extracts with ≥ 50% enzyme inhibition activity were reported in A. bilimbi, A. paniculata, O. stamineus, E. longifolia and P. granatum. The outcome of the study showed that a 2:1 combination of ethanolic extract of E. longifolia and chloroform extract of P. granatum showed gave the maximum rate of a-glucosidase inhibition (148.06%), while a similar combination of ethanol extract of E. longifolia and chloroform extract of O. stamineus offered the greatest a-glucosidase inhibition (137.43%). GC-MS-based phytochemical analysis of the extracts showed the presence of fatty acids in the extracts, with palmitic acid being the highest occurring fatty acid in the extracts of O. stamineus. Results showed a significantly increase (p<0.05) in fasting blood glucose level, body weight, AST, ALT, ALP and GGT levels, total protein, albumin, globulin, blood urea level and serum creatinine level in the DC group compared to the NC group. However, changes in these parameters were ameliorated in the DEIE: OSC (2:1), DEIE:PgC (2:1) and DG groups; the ameliorative effect was significant in the DG and DEIE:PgC (2:1) groups only (p<0.05). Examination of the liver sections showed mild vacuolation in the cytoplasm of the hepatocytes, congestion in the central vein, portal vein and sinusoid, as well as mild hepatic cord disarrangement in the DC group. These pathological changes were ameliorated in the ElE:OsC (2:1), EIE:PgC (2:1) and glibenclamide-treated rats. Histological observation of the pancreas sections of the rats in the DC group showed scanty number of small sized islets of Langerhans which were scattered within the acini. The islets cells have pyknotic nuclei and scanty eosinophilic cytoplasm. Fibrosis was noted in some areas while sections of the kidneys showed normal histological structure (glomeruli, renal tubules, blood vessels and interstitium) of the kidneys the NC, DM, and treated rats. In conclusion, the outcome of this study showed that ElE:OsC (2:1) and EIE:PgC (2:1) plant extracts could serve as potential alternatives for the treatment and control of diabetes mellitus and its related complications in diabetes mellitus rats.
We have investigated the role of the extracellular signal-regulated kinase (ERK), p38 and phosphatidylinositol 3-kinase (PI 3-kinase) pathways in the regulation of intestinal fructose transport. Different combinations of anisomycin, PD98059 and wortmannin had very different effects on fructose transport in perfused isolated loops of rat jejunum. Transport was stimulated maximally by anisomycin (2µM) and blocked by SB203580 (20µM), confirming involvement of the p38 pathway. PD98059 (50µM) alone had little effect on fructose transport. However, it had a dramatic effect on stimulation by anisomycin, diminishing the Ka 50-fold from 1µM to 20nM to show that the ERK pathway restrains the p38 pathway. The Ka for diabetic jejunum was 30nM and PD98059 had no effect. Transport in the presence of anisomycin was 3.4-fold that for anisomycin plus PD98059 plus wortmannin. Transport was mediated by both GLUT5 and GLUT2. In general, GLUT2 levels increased up to 4-fold within minutes and with only minimal changes in GLUT5 or SGLT1 levels, demonstrating that GLUT2 trafficks by a rapid trafficking pathway distinct from that of GLUT5 and SGLT1. GLUT2 intrinsic activity was regulated over a 9-fold range. It is concluded that there is extensive cross-talk between the ERK, p38 and PI 3-kinase pathways in their control of brush-border fructose transport by modulation of both the levels and intrinsic activities of GLUT5 and GLUT2. The potential of the intracellular signalling pathways to regulate short-term nutrient transport during the assimilation of a meal and longer-term adaptation to diabetes and hyperglycaemia is discussed.
To clarify the physiological role of Na(+)-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1(-/-) mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1(-/-) mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ∼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2.
In healthy rodents, intestinal sugar absorption in response to sugar-rich meals and insulin is regulated by GLUT2 in enterocyte plasma membranes. Loss of insulin action maintains apical GLUT2 location. In human enterocytes, apical GLUT2 location has not been reported but may be revealed under conditions of insulin resistance.
Subcellular location of GLUT2 in jejunal enterocytes was analyzed by confocal and electron microscopy imaging and Western blot in 62 well-phenotyped morbidly obese subjects and 7 lean human subjects. GLUT2 locations were assayed in ob/ob and ob/+ mice receiving oral metformin or in high-fat low-carbohydrate diet-fed C57Bl/6 mice. Glucose absorption and secretion were respectively estimated by oral glucose tolerance test and secretion of [U-(14)C]-3-O-methyl glucose into lumen.
In human enterocytes, GLUT2 was consistently located in basolateral membranes. Apical GLUT2 location was absent in lean subjects but was observed in 76% of obese subjects and correlated with insulin resistance and glycemia. In addition, intracellular accumulation of GLUT2 with early endosome antigen 1 (EEA1) was associated with reduced MGAT4a activity (glycosylation) in 39% of obese subjects on a low-carbohydrate/high-fat diet. Mice on a low-carbohydrate/high-fat diet for 12 months also exhibited endosomal GLUT2 accumulation and reduced glucose absorption. In ob/ob mice, metformin promoted apical GLUT2 and improved glucose homeostasis. Apical GLUT2 in fasting hyperglycemic ob/ob mice tripled glucose release into intestinal lumen.
In morbidly obese insulin-resistant subjects, GLUT2 was accumulated in apical and/or endosomal membranes of enterocytes. Functionally, apical GLUT2 favored and endosomal GLUT2 reduced glucose transepithelial exchanges. Thus, altered GLUT2 locations in enterocytes are a sign of intestinal adaptations to human metabolic pathology.
Facilitative glucose transport is mediated by members of the Glut protein family that belong to a much larger superfamily of 12 transmembrane segment transporters. Six members of the Glut family have been described thus far. These proteins are expressed in a tissue- and cell-specific manner and exhibit distinct kinetic and regulatory properties that reflect their specific functional roles. Glut1 is a widely expressed isoform that provides many cells with their basal glucose requirement. It also plays a special role in transporting glucose across epithelial and endothelial barrier tissues. Glut2 is a high-K
m isoform expressed in hepatocytes, pancreatic β cells, and the basolateral membranes of intestinal and renal epithelial cells. It acts as a high-capacity transport system to allow the uninhibited (non-rate-limiting) flux of glucose into or out of these cell types. Glut3 is a low-K
m isoform responsible for glucose uptake into neurons. Glut4 is expressed exclusively in the insulin-sensitive tissues, fat and muscle. It is responsible for increased glucose disposal in these tissues in the postprandial state and is important in whole-body glucose homeostasis. Glut5 is a fructose transporter that is abundant in spermatozoa and the apical membrane of intestinal cells. Glut7 is the transporter present in the endoplasmic reticulum membrane that allows the flux of free glucose out of the lumen of this organelle after the action of glucose-6-phosphatase on glucose 6-phosphate. This review summarizes recent advances concerning the structure, function, and regulation of the Glut proteins.
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.
Background & aims:
Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption.
Methods:
We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice.
Results:
Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane.
Conclusions:
Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.
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.
Glucose absorption postprandially increases markedly to levels far greater than possible by the classic glucose transporter sodium-glucose cotransporter 1 (SGLT1).
Luminal concentrations of glucose >50 mM lead to rapid, phenotypic, non-genomic adaptations by the enterocyte to recruit another transporter, glucose transporter 2 (GLUT2), to the apical membrane to increase glucose absorption.
Isolated segments of jejunum were perfused in vivo with glucose-containing solutions in anesthetized rats. Carrier-mediated glucose uptake was measured in 10 and 100 mM glucose solutions (n = 6 rats each) with and without selective inhibitors of SGLT1 and GLUT2.
The mean rate of carrier-mediated glucose uptake increased in rats perfused with 100 mM versus 10 mM glucose to 13.9 ± 2.9 μmol from 2.1 ± 0.1 μmol, respectively (p < 0.0001). Using selective inhibitors, the relative contribution of GLUT2 to glucose absorption was 56% in the 100 mM concentration of glucose compared to the 10 mM concentration (27%; p < 0.01). Passive absorption accounted for 6% of total glucose absorption at 100 mM glucose.
A small amount of GLUT2 is active at the lesser luminal concentrations of glucose, but when exposed to concentrations of 100 mM, the enterocyte presumably changes its phenotype by recruiting GLUT2 apically to markedly augment glucose absorption.