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The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing
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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... These dipeptides may be absorbed more promptly than protein-bound amino acids, since they do not have to go through any further digestion [11]. It is identified that transporters of cationic amino acid (CAT1 and CAT2) and peptide (PepT1 and PepT2) in the intestinal epithelium are associated with the capacity of nutrient absorption [2,[12][13][14]. Moreover, estimating phytase activity in fermented SBM, which reflects the efficiency of phosphorus ileal digestibility in broiler chickens, necessitates more exploring. ...
... During the 1st week of age, the room temperature was primarily adjusted to 33 • C and then gradually declined until reaching 21 ± 1 • C, and humidity was kept around 60% during the whole experimental period; also the stocking density was 10 birds/M 2 . The experimental diets were formulated as three stages: starter (d 1-10), grower (d [11][12][13][14][15][16][17][18][19][20][21][22][23][24] and finisher (d [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], with nutrients that cover the requirements of Ross broiler nutritional specification of ROSS [25]. Clean water and feed were allowed all the time. ...
... These dipeptides may be absorbed more promptly than protein-bound amino acids, since they do not have to go through any further digestion [11]. It is identified that transporters of cationic amino acid (CAT1 and CAT2) and peptide (PepT1 and PepT2) in the intestinal epithelium are associated with the capacity of nutrient absorption [2,[12][13][14]. Moreover, estimating phytase activity in fermented SBM, which reflects the efficiency of phosphorus ileal digestibility in broiler chickens, necessitates more exploring. ...
... During the 1st week of age, the room temperature was primarily adjusted to 33 • C and then gradually declined until reaching 21 ± 1 • C, and humidity was kept around 60% during the whole experimental period; also the stocking density was 10 birds/M 2 . The experimental diets were formulated as three stages: starter (d 1-10), grower (d [11][12][13][14][15][16][17][18][19][20][21][22][23][24] and finisher (d [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], with nutrients that cover the requirements of Ross broiler nutritional specification of ROSS [25]. Clean water and feed were allowed all the time. ...
Inclusion of microbial fermented soybean meal in broiler feed has induced advantageous outcomes for their performance and gastrointestinal health via exhibiting probiotic effects. In this study, soybean meal (SBM) was subjected to double-stage microbial fermentation utilizing functional metabolites of fungi and bacteria. In broiler diet, DFSBM replaced SBM by 0, 25, 50 and 100%. DFSBM was reported to have higher protein content and total essential, nonessential and free amino acids (increased by 3.67%, 12.81%, 10.10% and 5.88-fold, respectively, compared to SBM). Notably, phytase activity and lactic acid bacteria increased, while fiber, lipid and trypsin inhibitor contents were decreased by 14.05%, 38.24% and 72.80%, respectively, in a diet containing 100% DFSBM, compared to SBM. Improved growth performance and apparent nutrient digestibility, including phosphorus and calcium, and pancreatic digestive enzyme activities were observed in groups fed higher DFSBM levels. In addition, higher inclusion levels of DFSBM increased blood immune response (IgG, IgM, nitric oxide and lysozyme levels) and liver antioxidant status. Jejunal amino acids- and peptide transporter-encoding genes (LAT1, CAT-1, CAT-2, PepT-1 and PepT-2) were upregulated with increasing levels of DFSBM in the ration. Breast muscle crude protein, calcium and phosphorus retention were increased, especially at higher inclusion levels of DFSBM. Coliform bacteria load was significantly reduced, while lactic acid bacteria count in broiler intestines was increased with higher dietary levels of DFSBM. In conclusion, replacement of SBM with DFSBM positively impacted broiler chicken feed utilization and boosted chickens’ amino acid transportation, in addition to improving the nutritional value of their breast meat.
... Follow absorption, it proceeds through phase-II metabolism before being ultimate by the liver into bile or via the kidneys into urine. Quercetin and its glycosid transported by sodium-dependent glucose co-transporters (SGLTs), which the apical membrane of intestinal epithelial cells [38]. Additionally, querc the intestinal microbiota and protects the intestinal barrier [39]. ...
... Following intestinal absorption, it proceeds through phase-II metabolism before being ultimately eliminated by the liver into bile or via the kidneys into urine. Quercetin and its glycosides are mostly transported by sodium-dependent glucose co-transporters (SGLTs), which are found on the apical membrane of intestinal epithelial cells [38]. Additionally, quercetin modifies the intestinal microbiota and protects the intestinal barrier [39]. ...
Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and is regarded as an excellent free-radical scavenger. Apoptotic cell death of cancer cells caused by quercetin has been demonstrated by many prior studies. It is present in many fruits, vegetables, and herbs. Quercetin targets apoptosis, by upregulating Bax, caspase-3, and p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, and Bcl-2. Additionally, it has been reported to increase STAT3 protein degradation in liver cancer cells while decreasing STAT3 activation. Quercetin has a potential future in chemoprevention, based on substantial research on its anticancer effects. The current review discusses quercetin’s mechanisms of action, nanodelivery strategies, and other potential cellular effects in liver cancer.
... In this process, the glucose in the blood is transported by glucose transporters, such as GLUT4. In this way, blood glucose content is gradually reduced to the normal level [172]. Inhibition of transporters responsible for glucose moved from the intestinal tract could substantially impact postprandial hyperglycemia [173]. ...
... To address this question, we analyzed gene expression in the jejunum of mice after six weeks on snacking. Glucose transporter 2 (GLUT2) and sodium/glucose cotransporter 1 (SGLT1), encoded by Slc2a2 and Slc5a1, are responsible for intestinal glucose absorption whereby SGLT1 is located on the apical and GLUT2 on the basolateral side of the enterocyte [32]. ...
Objective:
Snacking, i.e., the intake of small amounts of palatable food items, is a common behavior in modern societies, promoting overeating and obesity. Shifting food intake into the daily rest phase disrupts circadian rhythms and is also known to stimulate weight gain. We therefore hypothesized that chronic snacking in the inactive phase may promote body weight gain and that this effect is based on disruption of circadian clocks.
Methods:
Male mice were fed a daily chocolate snack either during their rest or their active phase and body weight development and metabolic parameters were investigated. Snacking experiments were repeated in constant darkness and in clock-deficient mutant mice to examine the role of external and internal time cues in mediating the metabolic effects of snacking.
Results:
Chronic snacking in the rest phase increased body weight gain and disrupted metabolic circadian rhythms in energy expenditure, body temperature, and locomotor activity. Additionally, these rest phase snacking mice assimilated more energy during the inactive phase. Body weight remained increased in rest phase snacking wildtype mice in constant darkness as well as in clock-deficient mutant mice under a regular light-dark cycle compared to mice snacking in the active phase. Weight gain effects were abolished in clock-deficient mice in constant darkness.
Conclusions:
Our data suggest that mistimed snacking increases energy resorption and promotes body weight gain. This effect requires a functional circadian clock at least under constant darkness conditions.
... Digested nutrients, such as glucose, lipid, and amino acids in the small intestine are absorbed by various nutrient transporters located at the enterocyte brush borders [33]. The GLUT1, GLUT2 (mediated glucose), and GLUT5 (mediated fructose) play important roles in the transport process of monosaccharides in the mammalian intestine, and SGLT1 mediates the absorption of D-glucose and D-galactose in the intestine [34]. The PEPT1, SLC1A1, SLC7A7, and SLC6A19 have been identified as the major intestinal transporters for peptides, acidic, basic, and neutral amino acids, respectively [35], while FABP1, FABP2, and FABP4 are the major intestinal transporters for lipids [36]. ...
The small intestine is the main site for digestion and absorption of nutrients, and the development of the small intestine can be affected by several factors, such as diet composition, age, and genotype. Thus, this study aimed to compare the small intestinal morphology and digestive function differences at different ages of three pig breeds. Thirty litters of newborn Taoyuan black (TB), Xiangcun black (XB), and Duroc (DR) piglets (ten litters per breed) were selected for this study. Ten piglets from each breed were selected and sampled at 1, 10, 21, and 24 d old. The results showed that the TB and XB piglets had lower growth but had higher lactase and maltase activities in the jejunum compared with the DR piglets, while most of the digestive enzyme activities in the ileum were higher in the DR piglets at different ages. The expression levels of nutrient transporters, mainly including amino acids, glucose, and fatty acids transporters, differed in the jejunum at different ages among three pig breeds and were higher in the DR piglets at 1 d old and XB piglets at 24 d old. Collectively, these findings suggest that the phenotypic differences in the growth, intestinal morphology, and digestive function among the three pig breeds mainly resulted from the differences in digestive enzymes and nutrient transporters in the intestine.
Objective:
Gastric bypass surgery has been shown to improve metabolic profiles via GLP1, which may also have cognitive benefits for Alzheimer's disease (AD) patients. However, the exact mechanism requires further investigation.
Methods:
Roux-en-Y gastric bypass or sham surgery was performed on APP/PS1/Tau triple transgenic mice (an AD mice model) or wild type C57BL/6 mice. Morris Water Maze (MWM) test was used to evaluate the cognitive function of mice and animal tissue samples were obtained for measurements two months after the surgery. Additionally, STC-1 intestine cells were treated with siTAS1R2 and siSGLT1, and HT22 nerve cells were treated with Aβ, siGLP1R, GLP1 and siSGLT1 in vitro to explore the role of GLP1-SGLT1 related signaling pathway in cognitive function.
Results:
The MWM test showed that bypass surgery significantly improved cognitive function in AD mice as measured by navigation and spatial probe tests. Moreover, bypass surgery reversed neurodegeneration, down-regulated hyperphosphorylation of Tau protein and Aβ deposition, improved glucose metabolism, and up-regulated the expression of GLP1, SGLT1, and TAS1R2/3 in the hippocampus. Furthermore, GLP1R silencing down-regulated SGLT1 expression, whereas SGLT1 silencing increased Tau protein deposition and exacerbated dysregulated of glucose metabolism in HT22 cells. However, RYGB did not alter the level of GLP1 secretion in the brainstem (where central GLP1 is mainly produced). Additionally, GLP1 expression was upregulated by RYGB via TAS1R2/3-SGLT1 activation sequentially in the small intestine.
Conclusion:
RYGB surgery could improve cognition function in AD mice through facilitating glucose metabolism and reducing tau phosphorylation and Aβ deposition in the hippocampus, mediated by peripheral serum GLP1 activation of SGLT1 in the brain. Furthermore, RYGB increased GLP1 expression through sequential activation of TAS1R2/TAS1R3 and SGLT1 in the small intestine.
Equine insulin dysregulation (ID) comprises amplified insulin responses to oral carbohydrates or insulin resistance, or both, which leads to sustained or periodic hyperinsulinaemia. Hyperinsulinaemia is important in horses because of its clear association with laminitis risk, and the gravity of this common sequela justifies the need for a better understanding of insulin and glucose homeostasis in this species. Post-prandial hyperinsulinaemia is the more commonly identified component of ID and is diagnosed using tests that include an assessment of the gastrointestinal tract (GIT). There are several factors present in the GIT that either directly, or indirectly, enhance insulin secretion from the endocrine pancreas, and these factors are collectively referred to as the enteroinsular axis (EIA). A role for key components of the EIA, such as the incretin peptides glucagon-like peptide-1 and 2, in the pathophysiology of ID has been investigated in horses. By comparison, the function (and even existence) of many EIA peptides of potential importance, such as glicentin and oxyntomodulin, remains unexplored. The incretins that have been examined all increase insulin responses to oral carbohydrate through one or more mechanisms. This review presents what is known about the EIA in horses, and discusses how it might contribute to ID, then compares this to current understanding derived from the extensive studies undertaken in other species. Future directions for research are discussed and knowledge gaps that should be prioritised are suggested.
The availability of glucose transporter in the small intestine critically determines the capacity for glucose uptake and consequently systemic glucose homeostasis. Hence a better understanding of the physiological regulation of intestinal glucose transporter is pertinent. However, the molecular mechanisms that regulate sodium-glucose linked transporter 1 (SGLT1), the primary glucose transporter in the small intestine, remain incompletely understood. Recently, the Drosophila SLC5A5 (dSLC5A5) has been found to exhibit properties consistent with a dietary glucose transporter in the Drosophila midgut, the equivalence of the mammalian small intestine. Hence, the fly midgut could serve as a suitable model system for the study of the in vivo molecular underpinnings of SGLT1 function. Here, we report the identification, through a genetic screen, of Drosophila transmembrane protein 214 (dTMEM214) that acts in the midgut enterocytes to regulate systemic glucose homeostasis and glucose uptake. We show that dTMEM214 resides in the apical membrane and cytoplasm of the midgut enterocytes, and that the proper subcellular distribution of dTMEM214 in the enterocytes is regulated by the Rab4 GTPase. As a corollary, Rab4 loss-of-function phenocopies dTMEM214 loss-of-function in the midgut as shown by a decrease in enterocyte glucose uptake and an alteration in systemic glucose homeostasis. We further show that dTMEM214 regulates the apical membrane localization of dSLC5A5 in the enterocytes, thereby revealing dTMEM214 as a molecular regulator of glucose transporter in the midgut.
Context: Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) (Fabaceae) has traditionally been used to treat diabetes mellitus.
Objective: This study demonstrates the antidiabetic and antioxidant effects of aqueous extract of LS leaves in vivo and in vitro.
Materials and methods: The effects of aqueous LS leaf extract on glucose uptake, sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) mRNA expression in Caco-2 cells, α-glucosidase, and lipid peroxidation were evaluated in vitro. The antidiabetic effects were evaluated using an oral glucose tolerance test (OGTT) and a 28-day consecutive administration to streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic mice.
Results: The extract significantly inhibited glucose uptake (IC50: 236.2 ± 36.05 µg/mL) and downregulated SGLT1 and GLUT2 mRNA expression by approximately 90% in Caco-2 cells. Furthermore, it non-competitively inhibited α-glucosidase in a concentration-dependent manner with the IC50 and Ki of 6.52 ± 0.42 and 1.32 µg/mL, respectively. The extract at 1000 mg/kg significantly reduced fasting blood glucose levels in both the OGTT and 28-day consecutive administration models as compared with untreated STZ-NA-induced diabetic mice (p < 0.05). Significant improvements of serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and GLUT4 levels were observed. Furthermore, the extract markedly decreased oxidative stress markers by 37–53% reduction of superoxide dismutase 1 (SOD1) in muscle and malondialdehyde (MDA) in muscle and pancreas, which correlated with the reduction of MDA production in vitro (IC50: 24.80 ± 7.24 µg/mL).
Conclusion: The LS extract has potent antihyperglycemic activity to be used as alternative medicine to treat diabetes mellitus.
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.
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.