Search Results (21)

Background/Objectives: Dietary glucose is transported across the intestinal absorptive cell into the systemic circulation by the apically located Na⁺-dependent glucose transporter 1 (SGLT1, SLC5A1) and basally residing Na⁺-independent glucose transporter 2 (GLUT2, SLC2A2). Whilst recent experimental evidence has shown that sensing of sweet compounds by the gut-expressed sweet taste receptor T1R2–T1R3 and glucagon-like peptide-2 receptor signalling are components of the pathway controlling SGLT1 expression, little is known about the mechanisms involved in the regulation of GLUT2. In this study, we tested the hypothesis that T1R2–T1R3 and its downstream signalling pathway participate in the regulation of intestinal GLUT2. Methods: We used in vivo and in vitro approaches employing a weaning pig model, a heterologous expression assay, and knockout mice for elucidating the regulation of GLUT2 by luminal sugars. Results: A plant-based sweetener formulation included in piglets’ diet led to a marked increase in GLUT2 expression in piglets’ intestine, compared to controls. The sweeteners that do not activate pig T1R2–T1R3 failed to upregulate GLUT2. There was a significant increase in GLUT2 expression when the sweetener sucralose, which activates T1R2–T1R3, was included in the drinking water of wild-type mice. However, in knockout mice, in which the genes for the sweet receptor subunit T1R3 and the associated G-protein gustducin were deleted, there was no upregulation of GLUT2 expression in response to sucralose supplementation. There was a notable increase in GLUT2 expression in wild-type mice fed a high-carbohydrate diet compared to when maintained on a low-carbohydrate diet. However, in GLP-2 receptor knockout mice kept on the high-carbohydrate diet, there was no enhancement in GLUT2 expression. Conclusions: The experimental evidence suggests that luminal sweet sensing via T1R2–T1R3 and the enteroendocrine-derived GLP-2 are constituents of the regulatory pathway controlling GLUT2 expression. Full article

Molecular differences exist between birds with high residual water intake (HRWI) compared to those with low residual water intake (LRWI). Residual water intake (RWI) is defined as the difference between the water intake of a bird and the expected water intake corrected for metabolic body weight, feed intake, and body weight gain. Tissue metabolomic analysis revealed significantly increased kidney glucose, fructose, and arabitol in the LRWI group compared to the HRWI group. mRNA expression analysis of apical sodium glucose cotransporters SGLT1, SGLT4, SGLT5, and SGLT6 showed decreased expression of SGLTs 1, 5, and 6 in LRWI birds (p < 0.05), whereas SGLT4 expression was increased compared with HRWI birds (p < 0.01). An analysis of basal glucose transporters GLUT1, GLUT2, GLUT5, and GLUT9 showed significantly increased GLUT2 expression in LRWI birds compared with HRWI birds (p < 0.01). We postulate that SGLT4 is the main apical transporter in chicken kidneys and that its increased expression reduces these birds’ need for water, resulting in less drinking. This is balanced by the increased expression of the basal transporter GLUT2, indicating better glucose retention, which may partly explain the physiological mechanism behind why these birds drink less water. Innately driven broiler water intake could therefore be influenced by the expression of kidney solute transporters. Full article

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. Full article

Heart failure (HF) is a complex clinical syndrome caused by structural or functional dysfunction of the ventricular filling or blood supply. Diabetes mellitus (DM) is an independent predictor of mortality for HF. The increase in prevalence, co-morbidity and hospitalization rates of both DM and HF has further fueled the possibility of overlapping disease pathology between the two. For decades, antidiabetic drugs that are known to definitively increase the risk of HF are the thiazolidinediones (TZDs) and saxagliptin in the dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin, which causes sodium and water retention, and whether metformin is effective or safe for HF is not clear. Notably, sodium-glucose transporter 2 (SGLT2) inhibitors and partial glucagon-like peptide-1 receptor agonists (GLP-1 RA) all achieved positive results for HF endpoints, with SGLT2 inhibitors in particular significantly reducing the composite endpoint of cardiovascular mortality and hospitalization for heart failure (HHF). Further understanding of the mutual pathophysiological mechanisms between HF and DM may facilitate the detection of novel therapeutic targets to improve the clinical outcome. This review focuses on the association between HF and DM, emphasizing the efficacy and safety of antidiabetic drugs and HF treatment. In addition, recent therapeutic advances in HF and the important mechanisms by which SGLT2 inhibitors/mineralocorticoid receptor antagonist (MRA)/vericiguat contribute to the benefits of HF are summarized. Full article

Type 2 diabetes mellitus is a multifactorial disorder whose primary manifestation usually initiates with elevated blood sugar levels. Several antidiabetic agents are used to manage type 2 diabetes mellitus, of which empagliflozin is an oral sodium-glucose co-transporter (SGLT-2) inhibitor in the kidney. This research aims to develop and validate a simple analytical method for determining empagliflozin levels in biological fluid and to further evaluate grapefruit juice’s impact on empagliflozin pharmacokinetics in rats. High-Performance Liquid Chromatography (HPLC) was used to establish a simple, rapid, and accurate method for determining empagliflozin levels in rat plasma, in the presence of grapefruit juice. Four groups of rats (n = 10 rats in each) were used in the preclinical study. Group A (healthy rats) received empagliflozin alone; Group B (healthy rats) received empagliflozin with grapefruit; Group C (diabetic rats) received empagliflozin with grapefruit; and Group D (healthy, negative control) received no medication. The rats (n = 10) were given grapefruit juice instead of water for seven days before receiving the empagliflozin dose (0.16 mg/kg). Some pharmacokinetic parameters for each group were determined. The maximum plasma concentration (C_max) and area under the curve (AUC) of empagliflozin in Group A without grapefruit intake were 730 ng/mL and 9264.6 ng × h/mL, respectively, with T_max (2 h). In Group B, C_max was 1907 ng/mL and AUC was 10,290.75 ng × h/mL in the presence of grapefruit, with T_max (1 h); whereas, in Group C, the C_max was 2936 ng/mL and AUC was 18657 ng × h/mL, with T_max (2 h). In conclusion, our results showed that the co-administration of grapefruit with empagliflozin should be cautiously monitored and avoided, in which grapefruit elevates the plasma level of empagliflozin. This may be attributed to the inhibition of the uridine enzyme in the grapefruit by hesperidin, naringin, and flavonoid. Full article

Glucose level in birds’ tissue decreases due to heat stress (HS)-induced reduction in feed intake (FI); impairing metabolism and growth. The effect of glucose supplementation on the performance of broiler chickens was evaluated under thermoneutral (TN) and HS conditions. Glucose was supplemented at 0 and 6% under TN-(25 °C) and HS-(25 °C–35 °C–25 °C) conditions. The treatments were TN + 0%-glucose (TN0); TN + 6%-glucose (TN6), HS + 0%-glucose (HS0) and HS + 6%-glucose (HS6). There were 6 replicates (19 birds each)/treatment. Heat and glucose supplementation were applied from d28–35. At d35, Pectoralis (P.) major was sampled from one bird/replicate to determine glucose transporters’ mRNA expression. Heat application lowered (p < 0.05) FI, body weight gain, and increased feed and water conversion ratios. Glucose supplementation increased total energy intake by 4.9 and 3.2% in TN and HS groups, respectively but reduced FI under TN and HS conditions. The P. major- and drumstick-yield reduced (p < 0.05) in HS0 compared to TN0, TN6 and HS6. Under HS, glucose supplementation improved eviscerated carcass weight by 9% and P. major yield by 14%. Glucose supplementation increased SGLT1 expression with/without heat treatment while HS independently increased the expression of GLUT 1, 5 and 10. Glucose supplementation under HS could improve performance of broilers. Full article

Sodium glucose cotransporters (SGLTs) are cotransporters located in the cell membrane of various epithelia that uptake glucose or galactose and sodium into the cell. Its founding member, SGLT1, represents a major pharmaceutically relevant target protein for development of new antidiabetic drugs, in addition to being the target protein of the oral rehydration therapy. Previous studies focused primarily on the transport of substrates and ions, while our study focuses on the effect of water transport. SGLT1 is implicated in the absorption of water, yet the exact mechanism of how the water absorption occurs or how inhibitors of SGLT1, such as phlorizin, are able to inhibit it is still unclear. Here we present a comprehensive study based on molecular dynamics simulations with the aim of determining the influence of the energetic and dynamic properties of SGLT1, which are influenced by selected sugar uptake inhibitors on water permeation. Full article

The human sodium–glucose cotransporter protein (SGLT1) is an important representative of the sodium solute symporters belonging to the secondary active transporters that are critical to the homeostasis of sugar, sodium, and water in the cell. The underlying transport mechanism of SGLT1 is based on switching between inward- and outward-facing conformations, known as the alternating access model, which is crucial for substrate transport, and has also been postulated for water permeation. However, the nature of water transport remains unclear and is disputed along the passive and active transport, with the latter postulating the presence of the pumping effect. To better examine the water transport in SGLT1, we performed a series of equilibrium all-atom molecular dynamics simulations, totaling over 6 $\mathsf{\mu }$s of sample representative conformational states of SGLT1 and its complexes, with the natural substrates, ions, and inhibitors. In addition to elucidating the basic physical factors influencing water permeation, such as channel openings and energetics, we focus on dynamic flexibility and its relationship with domain motion. Our results clearly demonstrate a dependence of instantaneous water flux on the channel opening and local water diffusion in the channel, strongly supporting the existence of a passive water transport in SGLT1. In addition, a strong correlation found between the local water diffusion and protein domain motion, resembling the “rocking-bundle” motion, reveals its facilitating role in the water transport. Full article

Background: adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium–glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic HF through the modulation of adropin levels. Methods: we prospectively enrolled 417 patients with T2DM and HF from an entire cohort of 612 T2DM patients. All eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including SGLT2 inhibitor dapagliflozin 10 mg, daily, orally. Anthropometry, clinical data, echocardiography/Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration. Results: in the entire group, dapagliflozin led to an increase in adropin levels by up to 26.6% over 6 months. In the female subgroup, the relative growth (Δ%) of adropin concentrations was sufficiently higher (Δ% = 35.6%) than that in the male subgroup (Δ% = 22.7%). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e’ were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e’ (p = 0.001) were independent predictive values for adropin changes. Conclusion: the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent ofN-terminal brain natriuretic pro-peptide levels. Full article

Tryptophan (Trp) has been shown to improve the growth and gut function of weaned piglets. Whether the growth-promoting effect of Trp is due to the improvement in nutrient transport and absorption during weaning or under conditions of inflammation has not been fully characterized. The objective of this study was to determine the effects of Trp on lipopolysaccharide (LPS)-induced changes in glucose and amino acid (AA) transport in the rat jejunum. Twenty-four 7-week-old Sprague Dawley rats were randomly divided into one of three groups: control, LPS, and Trp + LPS. Rats were supplemented with 0 or 0.1 mg Trp per gram body weight/d in drinking water for 7 days and were intraperitoneally injected with LPS (5 mg/kg BW) on day 8. After 24 h, rats were sacrificed, and jejunum samples were isolated for the analysis of glucose and AA transport using an Ussing chamber and the expression of glucose and AA transporters. The results showed that Trp alleviated the LPS-induced increase in jejunal permeability (p < 0.05) and decrease in changes in the short-circuit current of glucose, arginine, glutamine, glutamate, glycine, histidine, leucine, lysine, taurine, threonine, and Trp (p < 0.05). Trp reversed (p < 0.05) the LPS-induced downregulation of expression of the glucose transporter SGLT1 and AA transporters solute carrier family 38 member 2 (SNAT2) and solute carrier family 7 member 8 (LAT2), as well as ATPase Na⁺/K⁺ transporting subunit alpha 2 (ATP1A2). However, Trp increased (p < 0.01) the LPS-induced upregulation of acidic AA transporter solute carrier family 1 member 1 (EAAT3) expression. The above findings may help to develop nutritional interventions for the differential targeting of gut nutrient transporters, aiming to improve gut function and health in the presence of inflammation in both humans and animals. Full article

Besides structural alterations in the myocardium, heart failure with preserved ejection fraction (HFpEF) is also associated with molecular and physiological alterations of the peripheral skeletal muscles (SKM) contributing to exercise intolerance often seen in HFpEF patients. Recently, the use of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) in clinical studies provided evidence for a significant reduction in the combined risk of cardiovascular death or hospitalization for HFpEF. The present study aimed to further elucidate the impact of Empagliflozin (Empa) on: (1) SKM function and metabolism and (2) mitochondrial function in an established HFpEF rat model. At the age of 24 weeks, obese ZSF1 rats were randomized either receiving standard care or Empa in the drinking water. ZSF1 lean animals served as healthy controls. After 8 weeks of treatment, echocardiography and SKM contractility were performed. Mitochondrial function was assessed in saponin skinned fibers and SKM tissue was snap frozen for molecular analyses. HFpEF was evident in the obese animals when compared to lean—increased E/é and preserved left ventricular ejection fraction. Empa treatment significantly improved E/é and resulted in improved SKM contractility with reduced intramuscular lipid content. Better mitochondrial function (mainly in complex IV) with only minor modulation of atrophy-related proteins was seen after Empa treatment. The results clearly documented a beneficial effect of Empa on SKM function in the present HFpEF model. These effects were accompanied by positive effects on mitochondrial function possibly modulating SKM function. Full article

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67⁺glucagon⁺ and Ki67⁺insulin⁺) while apoptosis was reduced (caspase3⁺glucagon⁺ and caspase3⁺insulin⁺). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism. Full article

The reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms. Full article

The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases. Full article

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells. Full article