Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers.

In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another.

Salmon Milt Extract Suppresses Glucose Uptake by Downregulating SGLT1 and GLUT2 Expression in Caco-2 Cells.

Salmon milt extract (SME) is rich in nucleotides, especially deoxyribonucleoside monophosphates (dNMPs), which has the potential to exert anti-obesity effects. Sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are responsible for absorbing sugar from the small intestine. The purpose of this study was to examine the effects of SME on the functions of SGLT1 and GLUT2 and elucidate the mechanisms underlying the inhibition of glucose absorption by SME. We investigated the effect of SME on the expression and function of intestinal glucose transporters, using differentiated Caco-2 cells. SME treatment decreased the expression SGLT1 and GLUT2 mRNA and protein in Caco-2 cells. [14C]-Labelled methyl-α-D-glucopyranoside and [3H]-labelled 2-deoxy-D-glucose (DG) uptake into Caco-2 cells was significantly reduced by SME treatment. Similarly, the dNMP mixture containing the four mononucleotides 2'-deoxyadenosine 5'-monophosphate (dAMP), 2'-deoxyguanosine 5'-monophosphate (dGMP), 2'-deoxycytidine 5'-monophosphate (dCMP), and 2'-deoxythymidine 5'-monophosphate (dTMP) decreased SGLT1 and GLUT2 expression. dNMP mixture-induced reduction in the mRNA expression of these transporters was suppressed when exposed to the mixture without dTMP. Furthermore, dNMP mixture-induced alterations in the expression of hepatocyte nuclear factor (HNF)-1α and HNF1ß, which have been characterized as modulators of both transporters also showed a similar trend. dTMP treatment alone decreased GLUT2 expression, resulting in reduced [3H] DG uptake by Caco-2 cells. SME decreased the expression of HNF1α, HNF1ß, and its targets SGLT1 and GLUT2, resulting in reduced glucose uptake by Caco-2 cells. In addition, our results revealed that dTMP plays an important role in suppressing the expression of intestinal glucose transporters.

Duodenal-Jejunal Bypass Restores Sweet Taste Receptor-Mediated Glucose Sensing and Absorption in Diabetic Rats.

Aim: The aim of the study is to identify the regulatory role of intestinal sweet taste receptors (STRs) and glucose transporters (SGLT1, GLUT2) and gut peptide secretion in duodenal-jejunal bypass (DJB)-ameliorated glycemic control in Type 2 diabetes. Materials and Methods: DJB and sham surgeries were performed in streptozotocin-induced diabetic male rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The expression of STRs (T1R2, T1R3), sweet taste signaling effector (Gα-gustducin), SGLT1, and GLUT2 was detected in the intestinal alimentary limb (A limb), biliopancreatic limb (BP limb), and common limb (C limb). The effects of STR inhibition on glucose control were measured with lactisole. Results: Glucose tolerance was improved in DJB-operated rats compared with the sham group, similar to that of normal control rats, without significant differences in food intake and body weight. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels were increased after fasting. The villus height and crypt depth were significantly increased in the A limb of DJB-operated rats. In addition, GLP-1 expression was restored in enterocytes. The expression of T1R2, Gα-gustducin, and SGLT1 was elevated in the A limb after DJB, while GLUT2 was downregulated in the A, BP, and C limbs. The localization of GLUT2 was normalized in the three intestinal limbs after DJB. However, the beneficial effects of DJB on glucose control were abolished in the presence of lactisole in vivo. Conclusion: DJB ameliorates glycemic control probably by restoring STR-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to carbohydrate.

Electroacupuncture regulates glucose metabolism by inhibiting SGLT1 levels, inhibiting microglial polarization, and alleviating Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common central neurodegenerative disease in middle-aged and elderly people. The progressive degeneration and death of dopaminergic neurons leads to insufficient dopamine (DA) neurotransmitters. Acupuncture and moxibustion can alleviate the aging of neurons. Therefore, studying the neuroprotective effects of electroacupuncture (EA) in PD mice is particularly important. METHODS: Intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) was used to establish a PD mouse model, and lipopolysaccharide (LPS) was used to induce microglia polarization. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Nissl staining and immunohistochemistry were used to detect neuronal apoptosis and injury, α-syn expression and microglial accumulation in PD mice. In addition, the levels of inflammatory factors were determined using enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the Ca2+ content. The fluorescein isothiocyanate (FITC) labeling method was used to assess glucose uptake. A reagent kit was used to detect glucose and lactate levels. RESULTS: MPTP induced the selective loss of DA neurons in the SN of mice, altered Ca2+ homeostasis, and induced an inflammatory response. In addition, maintaining Ca2+ homeostasis depends on the activity of transient receptor potential channel 1 (TRPC1). EA therapy promotes TRPC1 expression, which has a negative regulatory effect on sodium-glucose cotransporter 1 (SGLT1). Under the action of EA, TRPC1 protein expression increased, Ca2+ concentrations increased, and the effect of SGLT1 was inhibited, thereby facilitating glucose metabolism, blocking the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, restraining M1 polarization of microglia, and alleviating the PD process. CONCLUSION: EA promotes TRPC1/Ca2+ pathway activation, inhibits SGLT1-mediated regulation of glucose metabolism and PI3K/AKT pathway activation, inhibits microglial M1 polarization, and alleviates PD.

SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart.

Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.

Procyanidin B1 and p-coumaric acid from whole highland barley ameliorated HFD-induced impaired glucose tolerance via small intestinal barrier and hepatic glucose metabolism.

Highland barley is a natural source for the development of phenolic compounds that exhibit potential in preventing type 2 diabetes, which is important for the agricultural and industrial utilization of highland barley. However, very few studies have focused on their effect on small intestinal absorption and barrier dysfunction, as well as the direct target for the modulation of hepatic glucose metabolism. In this study, procyanidin B1 (PB) and p-coumaric acid (CA) isolated from highland barley supplementation in impaired glucose tolerance (IGT) mice significantly increased lactase-phlorizin hydrolase (LPH), sulfotransferase 1A1 (SULT1A1), UDP glucuronosyltransferase 1A (UGT1A) families and sodium-dependent glucose transporter 1 (SGLT1) expression in the small intestine of IGT mice, indicating beneficial effects on polyphenol deglycosylation and transportation. Supplementation with PB and CA also exhibited attenuation of small intestinal barrier dysfunction by improving the mucus layer and tight junctions, which was closely related to the transportation of phenolic compounds. In addition, PB and CA supplementation were explored directly to bind to the insulin receptor and activate the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, thereby modulating hepatic glucose metabolism and ameliorating hyperglycemic in IGT mice. These results offer crucial insights into the potential development of PB and CA as non-food nutraceuticals, as well as the extensive utilization of highland barley as an industrial crop.

Quercetin slow-release system delays starch digestion via inhibiting transporters and enzymes.

This study investigates the potential of a quercetin-based emulsion system to moderate starch digestion and manage blood glucose levels, addressing the lack of in vivo research. By enhancing quercetin bioaccessibility and targeting release in the small intestine, the emulsion system demonstrates significant inhibition of starch digestion and glucose spikes through both in vitro and in vivo experiments. The system inhibits α-amylase and α-glucosidase via competitive and mixed inhibition mechanisms, primarily involving hydrogen bonds and van der Waals forces, leading to static fluorescence quenching. Additionally, this system downregulates the protein expression and gene transcription of SGLT1 and GLUT2. These findings offer a novel approach to sustaining glucose equilibrium, providing a valuable foundation for further application of quercetin emulsion in food science.

Biophysical Analysis of a Minimalistic Kidney Model Expressing SGLT1 Reveals Crosstalk between Luminal and Lateral Membranes and a Plausible Mechanism of Isosmotic Transport.

We extended our model of the S1 tubular segment to address the mechanisms by which SGLT1 interacts with lateral Na/K pumps and tight junctional complexes to generate isosmotic fluid reabsorption via tubular segment S3. The strategy applied allowed for simulation of laboratory experiments. Reproducing known experimental results constrained the range of acceptable model outputs and contributed to minimizing the free parameter space. (1) In experimental conditions, published Na and K concentrations of proximal kidney cells were found to deviate substantially from their normal physiological levels. Analysis of the mechanisms involved suggested insufficient oxygen supply as the cause and, indirectly, that a main function of the Na/H exchanger (NHE3) is to extrude protons stemming from mitochondrial energy metabolism. (2) The water path from the lumen to the peritubular space passed through aquaporins on the cell membrane and claudin-2 at paracellular tight junctions, with an additional contribution to water transport by the coupling of 1 glucose:2 Na:400 H2O in SGLT1. (3) A Na-uptake component passed through paracellular junctions via solvent drag in Na- and water-permeable claudin-2, thus bypassing the Na/K pump, in agreement with the findings of early studies. (4) Electrical crosstalk between apical rheogenic SGLT1 and lateral rheogenic Na/K pumps resulted in tight coupling of luminal glucose uptake and transepithelial water flow. (5) Isosmotic transport was achieved by Na-mediated ion recirculation at the peritubular membrane.

Nuclear Receptor Corepressors NCOR1 and SMRT Regulate Metabolism via Intestinal Regulation of Carbohydrate Transport.

Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity, and energy expenditure, representing an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). We used a postnatal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically and underwent metabolic phenotyping, body composition analysis, and glucose tolerance testing. Jejunal IECs were isolated and profiled by bulk RNA sequencing. We found that the postnatal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without altered food intake. This appeared to be mediated by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2, and GLUT5. Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.

Highly Soluble ß-Glucan Fiber Modulates Mechanisms of Blood Glucose Regulation and Intestinal Permeability.

ß-glucans found in cereal grains have been previously demonstrated to improve blood glucose control; however, current understanding points to their high viscosity as the primary mechanism of action. In this work, we present a novel, highly soluble, low-viscosity ß-glucan fiber (HS-BG fiber) and a preclinical dataset that demonstrates its impact on two mechanisms related to the prevention of hyperglycemia. Our results show that HS-BG inhibits the activity of two key proteins involved in glucose metabolism, the α-glucosidase enzyme and the SGLT1 transporter, thereby having the potential to slow starch digestion and subsequent glucose uptake. Furthermore, we demonstrate in a multi-donor fecal fermentation model that HS-BG is metabolized by several different members of the gut microbiome, producing high amounts of short-chain fatty acids (SCFAs), known agonists of GPR43 receptors in the gut related to GLP-1 secretion. The production of SCFAs was verified in the translational gut model, SHIME®. Moreover, HS-BG fiber fermentation produces compounds that restored permeability in disrupted epithelial cells, decreased inflammatory chemokines (CXCL10, MCP-1, and IL-8), and increased anti-inflammatory marker (IL-10), which could improve insulin resistance. Together, these data suggest that the novel HS-BG fiber is a promising new functional ingredient that can be used to modulate postprandial glycemic responses while the high solubility and low viscosity enable easy formulation in both beverage and solid food matrices.

Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.

INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

Development of a selective novel fluorescent substrate for sodium-dependent transporters.

AIM: To synthesize, characterize, and validate 6FGA, a fluorescent glucose modified with a Cyanine5.5 at carbon-6 position, for probing the function of sodium-dependent glucose transporters, SGLT1 and SGLT2. MAIN METHODS: The synthesis of fluorescent glucose analogue was achieved through "click chemistry" of Cyanine5.5-alkyne and 6-azido-6-deoxy-d-glucose. Cell system studies were conducted to characterize the in vivo transport properties. KEY FINDINGS: Optical analyses revealed that 6FGA displayed similar spectral profiles to Cyanine5.5 in DMSO, allowing for concentration determination, thus supporting its utility in quantitative kinetic studies within biological assays. Uptake studies in cell system SGLT models, LLC-PK1 and HEK293 cells, exhibited concentration and time-dependent behavior, indicating saturation at specific concentrations and durations which are hallmarks of transported-mediated uptake. The results of cytotoxicity assays suggested cell viability at micromolar concentrations, enabling usage in assays for at least 1 h without significant toxicity. The dependence of 6FGA uptake on sodium, the co-transported cation, was demonstrated in LLC-PK1 and HEK293 cells. Fluorescence microscopy confirmed intracellular localization of 6FGA, particularly near the nucleus. Competition studies revealed that glucose tends to weakly reduce 6FGA uptake, although the effect did not achieve statistical significance. Assessments using standard SGLT and GLUT inhibitors highlighted 6FGA's sensitivity for probing SGLT-mediated transport. SIGNIFICANCE: 6FGA is a new fluorescent glucose analog offering advantages over existing probes due to its improved photophysical properties, greater sensitivity, enabling subcellular resolution and efficient tissue penetration in near-infrared imaging. 6FGA presents practicality and cost-effectiveness, making it a promising tool for nonradioactive, microplate-based assays at investigating SGLT-mediated glucose transport mechanisms.

Comparative evaluation of the antihyperglycemic effects of three extracts of sea mustard (Undaria pinnatifida): In vitro and in vivo studies.

Undaria pinnatifida (UP) contains multiple bioactive substances, such as polyphenols, polysaccharides, and amino acids, which are associated with various biological properties. This study aimed to evaluate the antihyperglycemic effects of three extracts obtained from UP. UP was extracted under three different conditions: a low-temperature water extract at 50 °C (UPLW), a high-temperature water extract at 90 °C (UPHW), and a 70 % ethanol extract (UPE). Nontargeted chemical profiling using high-performance liquid chromatography-triple/time-of-flight mass spectrometry (HPLC-Triple TOF-MS/MS) was conducted on the three UP extracts. Subsequently, α-glucosidase inhibitory (AGI) activity, glucose uptake, and the mRNA expression of sodium/glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) were evaluated in Caco-2 cell monolayers. Furthermore, an oral carbohydrate tolerance test was performed on C57BL/6 mice. The mice were orally administered UP at 300 mg/kg body weight (B.W.), and the blood glucose level and area under the curve (AUC) were measured. Compared with glucose, UPLW, UPHW and UPE significantly inhibited both glucose uptake and the mRNA expression of SGLT1 and GLUT2 in Caco-2 cell monolayers. After glucose, maltose, and sucrose loading, the blood glucose levels and AUC of the UPLW group were significantly lower than those of the control group. These findings suggest that UPLW has antihyperglycemic effects by regulating glucose uptake through glucose transporters and can be expected to alleviate postprandial hyperglycemia. Therefore, UPLW may have potential as a functional food ingredient for alleviating postprandial hyperglycemia.

Effects of Three Kinds of Carbohydrate Pharmaceutical Excipients-Fructose, Lactose and Arabic Gum on Intestinal Absorption of Gastrodin through Glucose Transport Pathway in Rats.

BACKGROUND: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. METHODS: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. RESULTS: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. CONCLUSION: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates artery remodeling in MCT-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH.

Sodium-glucose cotransporter 1 promotes the biofunctions of perivascular preadipocytes mediated by Akt/mTOR/p70S6K signaling pathway.

The influence of SGLT-1 on perivascular preadipocytes (PVPACs) and vascular remodeling is not well understood. This study aimed to elucidate the role and mechanism of SGLT-1-mediated PVPACs bioactivity. PVPACs were cultured in vitro and applied ex vivo to the carotid arteries of mice using a lentivirus-based thermosensitive in situ gel (TISG). The groups were treated with Lv-SGLT1 (lentiviral vector, overexpression), Lv-siSGLT1 (RNA interference, knockdown), or specific signaling pathway inhibitors. Assays were conducted to assess changes in cell proliferation, apoptosis, glucose uptake, adipogenic differentiation, and vascular remodeling in the PVPACs. Protein expression was analyzed by Western blotting, immunocytochemistry, and/or immunohistochemistry. The methyl thiazolyl tetrazolium (MTT) assay and Hoechst 33342 staining indicated that SGLT-1 overexpression significantly promoted PVPACs proliferation and inhibited apoptosis in vitro. Conversely, SGLT-1 knockdown exerted the opposite effect. Oil Red O staining revealed that SGLT-1 overexpression facilitated adipogenic differentiation, while its inhibition mitigated these effects. 3H-labeled glucose uptake experiments demonstrated that SGLT-1 overexpression enhanced glucose uptake by PVPACs, whereas RNA interference-mediated SGLT-1 inhibition had no significant effect on glucose uptake. Moreover, RT-qPCR, Western blotting, and immunofluorescence analyses revealed that SGLT-1 overexpression upregulated FABP4 and VEGF-A levels and activated the Akt/mTOR/p70S6K signaling pathway, whereas SGLT-1 knockdown produced the opposite effects. In vivo studies corroborated these findings and indicated that SGLT-1 overexpression facilitated carotid artery remodeling. Our study demonstrates that SGLT-1 activation of the Akt/mTOR/p70S6K signaling pathway promotes PVPACs proliferation, adipogenesis, glucose uptake, glucolipid metabolism, and vascular remodeling.NEW & NOTEWORTHY SGLT-1 is expressed in PVPACs and can affect preadipocyte glucolipid metabolism and vascular remodeling. SGLT-1 promotes the biofunctions of PVPACs mediated by Akt/mTOR/p70S6K signaling pathway. Compared with caudal vein or intraperitoneal injection, the external application of lentivirus-based thermal gel around the carotid artery is an innovative attempt at vascular remodeling model, it may effectively avoid the transfection of lentiviral vector into the whole body of mice and the adverse effect on experimental results.

The inflammatory injury of porcine small intestinal epithelial cells induced by deoxynivalenol is related to the decrease in glucose transport.

The present study aimed to investigate the effects of deoxynivalenol (DON) stimulation on inflammatory injury and the expression of the glucose transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter protein 2 (GLU2) in porcine small intestinal epithelial cells (IPEC-J2). Additionally, the study aimed to provide initial insights into the connection between the expression of glucose transporters and the inflammatory injury of IPEC-J2 cells. DON concentration and DON treatment time were determined using the CCK­8 assay. Accordingly, 1.0 µg/mL DON and treatment for 24 h were chosen for subsequent experiments. Then IPEC-J2 cells were treated without DON (CON, N = 6) or with 1 µg/mL DON (DON, N = 6). Lactate dehydrogenase (LDH) content, apoptosis rate, and proinflammatory cytokines including interleukin (IL)-1ß, Il-6, and tumor necrosis factor α (TNF-α) were measured. Additionally, the expression of AMP-activated protein kinase α1 (AMPK-α1), the content of glucose, intestinal alkaline phosphatase (AKP), and sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) activity, and the expression of SGLT1 and GLU2 of IPEC-J2 cells were also analyzed. The results showed that DON exposure significantly increased LDH release and apoptosis rate of IPEC-J2 cells. Stimulation with DON resulted in significant cellular inflammatory damage, as evidenced by a significant increase in proinflammatory cytokines (IL-1ß, IL-6, and TNF-α). Additionally, DON caused damage to the glucose absorption capacity of IPEC-J2 cells, indicated by decreased levels of glucose content, AKP activity, Na+/K+-ATPase activity, AMPK-α1 protein expression, and SGLT1 expression. Correlation analysis revealed that glucose absorption capacity was negatively correlated with cell inflammatory cytokines. Based on the findings of this study, it can be preliminarily concluded that the cell inflammatory damage caused by DON may be associated with decreased glucose absorption.

Glucose is one of the most basic nutrients necessary to sustain animal life and plays a crucial role in animal body composition and energy metabolism. Previous studies suggested a link between glucose absorption and inflammatory injury. In the present study, deoxynivalenol (DON) stimulation caused severe inflammatory injury and reduced the glucose absorption capacity of IPEC-J2 cells. Pearson's correlation analysis revealed a negative correlation between glucose absorption capacity and cell inflammatory cytokines. Ultimately, it can be speculated that the cellular inflammatory response triggered by DON may be related to the altered expression of glucose transporters.

Exploring Bariatric Surgery's Impact on Weight Loss and Diabetes: Sodium and Glucose Receptor Modulation.

Sodium-glucose cotransporters (SGLT) and glucose transporters (GLUT) have been shown to influence diabetes management by modulating glucose uptake by the intestine. Therefore, alterations in gastrointestinal anatomy during bariatric surgery can change SGLT and GLUT receptor activity. These changes offer an additional mechanism for weight loss and may explain the differential impact of the various bariatric surgical procedures. This review examines the current literature on SGLT and GLUT receptors and their effects on weight loss through genetic studies, pharmacologic inhibition, and how SGLT/GLUT receptors impact surgical physiologic modulation. A better understanding of Type I sodium-glucose cotransport receptors (SGLT-1), GLUT-2, and GLUT-5 could provide insight for improved procedures and allow us to determine the best method to tailor operations to a patient's individual needs.

A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type 1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.