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Aims/hypothesis: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels. Methods: CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca2+ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes GPR142 and CASR were knocked out to evaluate roles in amino acid sensing. Results: RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including FFAR1, GPBAR1, GPR119, CASR and GPR142. Glucose induced action potential firing and cytosolic Ca2+ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While CASR knockout blunted intracellular Ca2+ responses, a CASR/GPR142 double knockout was needed to reduce GIP secretory responses to aromatic amino acids. Conclusions/interpretation: The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity. [ABSTRACT FROM AUTHOR]

It has been shown that the jejunum represents the most important site for the nutrient’s absorption in several species. However, in pigs, this information seems to be controversial and limited information are available about differences in intestinal physiology between female and castrated male pigs. The trans-epithelial electrical resistance (TEER) and the active uptake of L-glutamate (L-Glu), L-arginine (L-Arg), L-methionine (L-Met) and D-glucose (D-Glu) in the jejunum and ileum of female (n = 5) and castrated male (n = 7) pigs fed a protein-restricted grower and finisher diet (128 and 112 g of crude protein/kg dry matter) were investigated. The intestine segments were collected at slaughter and mounted in Ussing chambers. Results were further investigated by protein expression analysis of the D-Glu transporter Sodium-dependent Glucose Transporter 1 (SGLT1) and using serum creatinine, non-esterified fatty acids (NEFAs) and serum glucose concentrations measurements as indicators of muscle mass deposition and metabolic status of the animals. A linear mixed-effects regression (Lme4) model was used for data analysis. Independent of sex, the uptake of both L-Met and D-Glu was higher (p

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To describe the pharmacology, clinical efficacy, and safety evidence of sotagliflozin, the first approved dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in heart failure (HF) management. Data sources: A literature search of studies published between January 2012 and September 2023 were identified using PubMed, MEDLINE, and clinicaltrials.gov with search terms of "sotagliflozin," "Inpefa," or "LX4211." Study selection and data extraction: All available studies in English were considered. Studies were included if they investigated drug pharmacology, efficacy, or safety information. Data synthesis: Two phase 3 trials of sotagliflozin, SOLOIST-WHF and SCORED, evaluated sotagliflozin compared with placebo in patients with type 2 diabetes mellitus (T2DM). SOLOIST-WHF reported a statistically decreased rate of cardiovascular and HF events with sotagliflozin (hazard ratio [HR] = 0.67, 95% CI = 0.52-0.85), while SCORED found a statistically significant decrease in incidence of cardiovascular events in patients with T2DM, chronic kidney disease (CKD), and risk factors for cardiovascular disease in patients in the sotagliflozin group (HR = 0.74, 95% CI = 0.63-0.88). Relevance to patient care and clinical practice in comparison to existing agents: While approval of sotagliflozin expands treatment options for patients with HF, the SGLT2 inhibitors, dapagliflozin and empagliflozin, have more data supporting their use in HF, additional risk reduction benefits in patients with CKD, and approval for use in T2DM. Landmark trials of sotagliflozin required a previous diagnosis of T2DM, despite the broader approved indication. Where sotagliflozin will be adopted into the treatment of HF is unclear due to the evidence and benefits of already established SGLT2 inhibitors and the need for comparison with SGLT2 inhibitors. Conclusion: Given the limitations of currently available evidence, including difficulty in fully interpreting the trial results due to changes in primary endpoints, not adjudicating the events, and not reaching the original power calculations, more investigation is warranted to determine the benefit of sotagliflozin compared with SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.

Objective: To examine the hepatoprotective effects of gedunin in streptozotocin (STZ)-induced diabetic rats. Methods: Rats were divided into 4 groups: control, STZ, gedunin, and STZ+gedunin. Biochemical parameters for liver function and liver histology were studied. The molecular interaction of gedunin with the liver glucose transporters GLUT2 and SGLT1 was examined using AutoDock Vina. Results: Gedunin attenuated STZ-induced increase in the levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma-glutamyl transferase in the serum and liver tissue, reduced lipid peroxidation, and enhanced antioxidant activity. Histopathological studies showed considerable restoration of liver architecture in gedunin-treated diabetic rats. In silico studies revealed stable binding of gedunin with GLUT2 and SGLT1. Conclusions: Gedunin exerts hepatoprotective effects in STZ-induced diabetic rats by reducing liver enzymatic activities and oxidative stress. Further studies are warranted to verify the mechanism of its hepatoprotective action.

Abstract Background Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating “Liushen Pill” and “Shenfu Decoction,” has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism. Methods In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague–Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated. Results In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism. Conclusions XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.

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. [ABSTRACT FROM AUTHOR]

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPK α was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1 iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPK α and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity. This study verified the role of Piezo1 in enterocytes inhibits intestinal sugar and lipid absorption, and revealed a previously unexplored mechano-regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity and diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To examine the hepatoprotective effects of gedunin in streptozotocin (STZ)-induced diabetic rats. Methods: Rats were divided into 4 groups: control, STZ, gedunin, and STZ+gedunin. Biochemical parameters for liver function and liver histology were studied. The molecular interaction of gedunin with the liver glucose transporters GLUT2 and SGLT1 was examined using AutoDock Vina. Results: Gedunin attenuated STZ-induced increase in the levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma-glutamyl transferase in the serum and liver tissue, reduced lipid peroxidation, and enhanced antioxidant activity. Histopathological studies showed considerable restoration of liver architecture in gedunin-treated diabetic rats. In silico studies revealed stable binding of gedunin with GLUT2 and SGLT1. Conclusions: Gedunin exerts hepatoprotective effects in STZ-induced diabetic rats by reducing liver enzymatic activities and oxidative stress. Further studies are warranted to verify the mechanism of its hepatoprotective action. [ABSTRACT FROM AUTHOR]

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity. [ABSTRACT FROM AUTHOR]

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.

Congenital glucose-galactose malabsorption (CGGM) is a rare metabolic disorder caused by a deficient intestinal sodium-dependent glucose cotransporter (SGLT1) protein. Its failure leads to a lack of absorption of galactose, glucose, and sodium, which remains inside the intestinal lumen. The consequence of that involves, among other things, dehydration and diarrhea on neonatal onset. The basic treatment consists of diet management. A 6-month-old Brazilian infant with CGGM caused by a one base pair deletion on SLC5A1gene, in both alleles, causing a frameshift mutation and, consequently, a deleterious impact on the terminal protein portion is, for the first time, characterized here. Besides the common disease aspects, the child presented Necrotizing Enterocolitis (NEC), a new outcome for his condition. The fact that a non-consanguineous couple could produce a child with a recessive disease is puzzling. However, we were able to correlate all symptoms, including NEC, to the disruption of the protein terminal portion, based on literature review. This article brings a new point of view on disease report; putting together the social aspects, clinical examination, laboratory trials, genetic diagnostic, protein assemble and literature research in order to fulfill the patient history. This process allows us to improve the understanding of the disease mechanism, perform targeted genetic counseling and institute appropriate treatment using an adequate diet through nutritional guidance and surveillance.

A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted. [ABSTRACT FROM AUTHOR]

Background: The hypoglycemic effects of Chinese bayberry leaves proanthocyanidins (BLPs) have been demonstrated. It is unclear, nevertheless, whether BLPs reduced postprandial blood glucose levels by regulating glucose uptake and glucose transport. Method: This study investigated the effect of BLPs (25, 50, and 100 µg/mL) on glucose uptake and glucose transport in human intestinal epithelial cells (Caco-2 cells). The uptake of 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]- D-glucose (2-NBDG) and disaccharidases activity in Caco-2 cells were measured. The glucose transport ability across the cell membrane was determined using the established Caco-2 monolayer model. The transcript and protein levels of key glucose transporters were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Results: The results showed that BLPs significantly decreased glucose uptake and disaccharidases activity (p < 0.05). Otherwise, BLPs treatment obviously inhibited glucose transport across the Caco-2 monolayer in both simulated-fast (5 mM glucose) and simulated-fed (25 mM glucose) conditions. It was attributed to the suppression of glucose transporter2 (GLUT2) and sodium-dependent glucose cotransporter 1 (SGLT1) by BLPs. BLPs were found to significantly downregulated the transcript level and protein expression of glucose transporters (p < 0.05). Meanwhile, the mRNA expression of phospholipase C (PLC) and protein kinase C (PKC) involved in the signaling pathway associated with glucose transport were decreased by BLPs. Conclusion: These results suggested that BLPs inhibited intestinal glucose transport via inhibiting the expression of glucose transporters. It indicated that BLPs could be potentially used as a functional food in the diet to modulate postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

D-allulose, D-sorbose and D-tagatose are D-fructose isomers that are called rare sugars. These rare sugars have been studied intensively in terms of biological production and food application as well as physiological effects. There are limited papers with regard to the transporters mediating the intestinal absorption of these rare sugars. We examined whether these rare sugars are absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) as well as via GLUT type 5 (GLUT5) using rats. High-fructose diet fed rats, which express more intestinal GLUT5, exhibited significantly higher peripheral concentrations, Cmax and AUC0–180 min when D-allulose, D-sorbose and D-tagatose were orally administrated. KGA-2727, a selective SGLT1 inhibitor, did not affect the peripheral and portal vein concentrations and pharmacokinetic parameters of these rare sugars. The results suggest that D-allulose, D-sorbose and D-tagatose are likely transported via GLUT5 but not SGLT1 in rat small intestine. [ABSTRACT FROM AUTHOR]

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.

Abstract Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre‐ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8–9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short‐circuit current (∆Isc) induced by glucose. Tissue viability was confirmed by a positive ∆Isc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d‐glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum (P

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity.

Purpose: Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained remain virtually unknown. Therefore, in this study, we explored the expression status of SGLT1 and SGLT2 in breast cancer patients and examined the effects of SGLT1 inhibitors on breast carcinoma cells in vitro. Methods: SGLT1 and SGLT2 were immunolocalized and we first correlated the findings with clinicopathological factors of the patients. We then administered mizagliflozin and KGA-2727, SGLT1 specific inhibitors to MCF-7 and MDA-MB-468 breast carcinoma cell lines, and their growth-inhibitory effects were examined. Protein arrays were then used to further explore their effects on the growth factors. Results: The SGLT1 high group had significantly worse clinical outcome including both overall survival and disease-free survival than low group. SGLT2 status was not significantly correlated with clinical outcome of the patients. Both mizagliflozin and KGA-2727 inhibited the growth of breast cancer cell lines. Of particular interest, mizagliflozin inhibited the proliferation of MCF-7 cells, even under very low glucose conditions. Mizagliflozin downregulated vascular endothelial growth factor receptor 2 phosphorylation. Conclusion: High SGLT1 expression turned out as an adverse clinical prognostic factor in breast cancer patient. This is the first study demonstrating that SGLT1 inhibitors suppressed breast carcinoma cell proliferation. These results indicated that SGLT1 inhibitors could be used as therapeutic agents for breast cancer patients with aggressive biological behaviors. [ABSTRACT FROM AUTHOR]

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated. [ABSTRACT FROM AUTHOR]

The kidneys filter large amounts of glucose. To prevent the loss of this valuable fuel, the tubular system of the kidney, particularly the proximal tubule, has been programmed to reabsorb all filtered glucose. The machinery involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane and the facilitative glucose transporter GLUT2 on the basolateral membrane. The proximal tubule also generates new glucose, particularly in the post-absorptive phase but also to enhance bicarbonate formation and maintain acid-base balance. The glucose reabsorbed or formed by the proximal tubule is primarily taken up into peritubular capillaries and returned to the systemic circulation or provided as an energy source to further distal tubular segments that take up glucose by basolateral GLUT1. Recent studies provided insights on the coordination of renal glucose reabsorption, formation, and usage. Moreover, a better understanding of renal glucose transport in disease states is emerging. This includes the kidney in diabetes mellitus, when renal glucose retention becomes maladaptive and contributes to hyperglycemia. Furthermore, enhanced glucose reabsorption is coupled to sodium retention through the sodium-glucose cotransporter SGLT2, which induces secondary deleterious effects. As a consequence, SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing. Recent studies discovered unique roles for SGLT1 with implications in acute kidney injury and glucose sensing at the macula densa. This review discusses established and emerging concepts of renal glucose transport, and outlines the need for a better understanding of renal glucose handling in health and disease.

Abstract Cryptosporidiosis is one of the main causes of diarrhea in children and young livestock. The interaction of the parasite with the intestinal host cells has not been characterized thoroughly yet but may be affected by the nutritional demand of the parasite. Hence, we aimed to investigate the impact of C. parvum infection on glucose metabolism in neonatal calves. Therefore, N = 5 neonatal calves were infected with C. parvum on the first day of life, whereas a control group was not (N = 5). The calves were monitored clinically for one week, and glucose absorption, turnover and oxidation were assessed using stable isotope labelled glucose. The transepithelial transport of glucose was measured using the Ussing chamber technique. Glucose transporters were quantified on gene and protein expression level using RT-qPCR and Western blot in the jejunum epithelium and brush border membrane preparations. Plasma glucose concentration and oral glucose absorption were decreased despite an increased electrogenic phlorizin sensitive transepithelial transport of glucose in infected calves. No difference in the gene or protein abundance of glucose transporters, but an enrichment of glucose transporter 2 in the brush border was observed in the infected calves. Furthermore, the mRNA for enzymes of the glycolysis pathway was increased indicating enhanced glucose oxidation in the infected gut. In summary, C. parvum infection modulates intestinal epithelial glucose absorption and metabolism. We assume that the metabolic competition of the parasite for glucose causes the host cells to upregulate their uptake mechanisms and metabolic machinery to compensate for the energy losses.

The pathogenesis of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia is not yet fully clarified. Recent studies suggest an up-regulation of the intestinal glucose transporter SGLT-1 aimed to prevent carbohydrate malabsorption. The overexpression of SGLT-1 could therefore represents one of the mechanisms underlying the wide glycemic excursions found in patients after gastrectomy, but studies investigating the use of SGLT-1/SGLT-2 inhibitors in patients with post-gastrectomy reactive hyperinsulinemic hypoglycaemia are very scant in the literature. We report the case of a 37-year-old non diabetic man who frequently presented symptoms of hypoglycaemia in the postprandial period. In 2012, he underwent Roux en-Y gastric bypass (RYGB) and after two years, he started to experience typical symptoms of reactive hyperinsulinaemic hypoglycaemia. We suggested healthy modifications of dietary habits and periodic follow-up visits with a dietitian. After three months, the patient still presented symptoms of reactive hypoglycaemia; we provided him with Flash Glucose Monitoring (FGM) to assess trend of glucose levels in interstitial fluid during the day and we decided to introduce canagliflozin 300 mg/day before the main meal. Hypoglycaemic events previously referred by the patient and clearly recorded by FGM completely disappeared taking canagliflozin. We found a reduction of time spent in hypoglycaemia, an improvement of glycemic variability and an increase of time in target range. It was also noted a reduction of time spent in hyperglicemia with consequent improvement of average glucose values and of glucose main indicator. This is the first report with FGM supporting a role of canagliflozin in th emanagement of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia. Our preliminary results are very limited but in line with those of the literature and showed for the first time a reduction of hypoglycaemic events and an improvement of glycemic variability through a flash glucose monitoring system. Further studies are mandatory to confirm this therapeutic opportunity. [ABSTRACT FROM AUTHOR]

Background. Chronic stress promotes the development of atherosclerosis, causing disruptions in the body's hormone levels and changes in the structural function of organs. Objective. The purpose of this study was to investigate the pathological changes in the adrenal gland in a model of atherosclerosis under chronic stress and to verify the expression levels of Sodium-glucose cotransporter (SGLT) 1 and SGLT2 in the adrenal gland and their significance in the changes of adrenal gland. Methods. The model mice were constructed by chronic unpredictable stress, high-fat diet, and Apoe-/- knockout, and they were tested behaviorally at 0, 4, 8 and 12 weeks. The state of the abdominal artery was examined by ultrasound, and the pathological changes of the aorta and adrenal glands were observed by histological methods, and the expression levels and distribution of SGLT1 and SGLT2 in the adrenal gland were observed and analyzed by immunofluorescence and immunohistochemistry. The predictive value of SGLT1 and SGLT2 expression levels on intima-media thickness, internal diameter and adrenal abnormalities were verified by receiver operating characteristic (ROC) curves, support vector machine (SVM) and back-propagation (BP) neural network. Results. The results showed that chronic stress mice had elevated expression levels of SGLT1 and SGLT2. The model mice developed thickening intima-media and smaller internal diameter in the aorta, and edema, reticular fiber rupture, increased adrenal glycogen content in the adrenal glands. More importantly, analysis of ROC, SVM and BP showed that SGLT1 and SGLT2 expression levels in the adrenal glands could predict the above changes in the aorta and were also sensitive and specific predictors of adrenal abnormalities. Conclusion. SGLT1 and SGLT2 could be potential biomarkers of adrenal injury in atherosclerosis under chronic stress. [ABSTRACT FROM AUTHOR]

Simple Summary: Energy deficiency causes multiple organ dysfunctions in the lipopolysaccharide (LPS)-induced model. Quercetin is a flavonoid found in many plants including herbal medicines; nevertheless, the protective effects of quercetin in alleviating LPS-induced energy deficiency remain unclear. In the present study, an in ovo LPS-induced inflammation model was established in chicken embryos. Quercetin attenuated the increase in glycogen and lipid contents in the liver after LPS stimulation when compared with the control group. Quercetin could downregulate the mRNA expressions of AMPKα1 and AMPKα2 in the duodena, ceca, and livers when compared with the LPS group; quercetin decreased the immunoreactivity to AMPKα2 in the duodena and livers. The LPS-induced high mRNA expressions of PPARα and SGLT1 were blocked by quercetin in the duodena, ceca, and livers. Quercetin improved the APOA4 decrease in the duodena, ceca, and livers after LPS induction. Quercetin could downregulate the mRNA expression of PEPT1 in the duodena and ceca increased after LPS challenge. These data demonstrate that quercetin improves the energy deficiency induced by LPS in chicken embryos. Energy deficiency causes multiple organ dysfunctions after LPS induction. Quercetin is a phenolic compound found in herbal medicines. However, the effects of quercetin in alleviating LPS-induced energy deficiency remain unclear. In the present study, an in vivo LPS-induced inflammation model was established in chicken embryos. Specific pathogen-free chicken embryos (n = 120) were allocated to control, PBS with or without ethanol, quercetin (10, 20, or 40 nmol, respectively), and LPS (125 ng/egg) with or without quercetin groups. Fifteen day old embryonated eggs were injected with the abovementioned solutions via the allantoic cavity. On embryonic day 19, the tissues of the embryos were collected for histopathological examination using frozen oil red O staining, RNA extraction, real-time quantitative polymerase chain reaction, and immunohistochemical investigations. The glycogen and lipid contents in the liver increased after LPS stimulation as compared with the PBS group, whereas quercetin decreased the accumulation as compared with the LPS group. The mRNA expressions of AMPKα1 and AMPKα2 in the duodena, ceca, and livers were upregulated after LPS induction as compared with the PBS group, while quercetin could downregulate these expressions as compared with the LPS group. The immunopositivity of AMPKα2 in the villus, crypt, lamina propria, tunica muscularis, and myenteric plexus in the duodena and in the cytoplasms of hepatocytes significantly increased after LPS induction when compared with the PBS group (p < 0.01), whereas the immunopositivity to AMPKα2 in the quercetin treatment group significantly decreased when compared with the LPS group (p < 0.01 or p < 0.05). The LPS-induced high expressions of transcription factor PPARα and glucose transporter (SGLT1) were blocked by quercetin in the duodena, ceca, and livers. Quercetin treatment improved the LPS-induced decrease in APOA4 in the duodena, ceca, and livers. The mRNA expression of PEPT1 in the duodena and ceca increased after LPS challenge, whereas quercetin could downregulate PEPT1 gene expression. These data demonstrate that quercetin improved the energy deficiency induced by LPS in chicken embryos. The LPS-induced inflammation model was established to avoid the effect of LPS exposure from the environment and intestinal flora. The results form the basis the administration of quercetin pretreatment (in ovo infection) to improve the energy state of chicken embryos and improve the inflammation response. [ABSTRACT FROM AUTHOR]

Congenital glucose-galactose malabsorption is a rare autosomal recessive disorder caused by mutations in SLC5A1 encoding the apical sodium/glucose cotransporter SGLT1. We present clinical and molecular data from eleven affected individuals with congenital glucose-galactose malabsorption from four unrelated, consanguineous Turkish families. Early recognition and timely management by eliminating glucose and galactose from the diet are fundamental for affected individuals to survive and develop normally. We identified novel SLC5A1 missense variants, p.Gly43Arg and p.Ala92Val, which were linked to disease in two families. Stable expression in CaCo-2 cells showed that the p.Ala92Val variant did not reach the plasma membrane, but was retained in the endoplasmic reticulum. The p.Gly43Arg variant, however, displayed processing and plasma membrane localization comparable to wild-type SGLT1. Glycine-43 displays nearly invariant conservation in the relevant structural family of cotransporters and exchangers, and localizes to SGLT1 transmembrane domain TM0. p.Gly43Arg represents the first disease-associated variant in TM0; however, the role of TM0 in the SGLT1 function has not been established. In summary, we are expanding the mutational spectrum of this rare disorder. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has no approved pharmacological treatments. Sodium-glucose cotransporter (SGLT)-1 is a glucose transporter that mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344 182) to proxy SGLT-1i. Outcome genetic data comprised 1483 NAFLD cases and 17 781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; P = .023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Body mass and food intake change during the female ovarian cycle: does glucose transport by the small intestine also vary?What is the main finding and its importance?We have optimised Ussing chamber methodology to measure region‐specific active glucose transport in the small intestine of adult C57BL/6 mice. Our study provides the first evidence that jejunal active glucose transport changes during the oestrous cycle in mice, and is higher at pro‐oestrus than oestrus. These results demonstrate adaptation in active glucose uptake, concurrent with previously reported changes in food intake. Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre‐ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8–9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short‐circuit current (∆Isc) induced by glucose. Tissue viability was confirmed by a positive ∆Isc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d‐glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum (P < 0.01). Incubation with the sodium–glucose cotransporter 1 (SGLT1) inhibitor phlorizin reduced active glucose transport in a dose‐dependent manner in all regions (P < 0.01). Active glucose uptake induced by addition of 45 mM glucose to the mucosal chamber in the absence or presence of phlorizin was assessed in jejunum at each oestrous cycle stage (n = 9–10 mice per stage). Overall, active glucose uptake was lower at oestrus compared to pro‐oestrus (P = 0.025). This study establishes an ex vivo method to measure region‐specific glucose transport in the mouse small intestine. Our results provide the first direct evidence that SGLT1‐mediated glucose transport in the jejunum changes across the ovarian cycle. The mechanisms underlying these adaptations in nutrient absorption remain to be elucidated. [ABSTRACT FROM AUTHOR]

The pathogenesis of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia is not yet fully clarified. Recent studies suggest an up-regulation of the intestinal glucose transporter SGLT-1 aimed to prevent carbohydrate malabsorption. The overexpression of SGLT-1 could therefore represents one of the mechanisms underlying the wide glycemic excursions found in patients after gastrectomy, but studies investigating the use of SGLT-1/SGLT-2 inhibitors in patients with post-gastrectomy reactive hyperinsulinemic hypoglycaemia are very scant in the literature. We report the case of a 37-year-old non diabetic man who frequently presented symptoms of hypoglycaemia in the postprandial period. In 2012, he underwent Roux en-Y gastric bypass (RYGB) and after two years, he started to experience typical symptoms of reactive hyperinsulinaemic hypoglycaemia. We suggested healthy modifications of dietary habits and periodic follow-up visits with a dietitian. After three months, the patient still presented symptoms of reactive hypoglycaemia; we provided him with Flash Glucose Monitoring (FGM) to assess trend of glucose levels in interstitial fluid during the day and we decided to introduce canagliflozin 300 mg/day before the main meal. Hypoglycaemic events previously referred by the patient and clearly recorded by FGM completely disappeared taking canagliflozin. We found a reduction of time spent in hypoglycaemia, an improvement of glycemic variability and an increase of time in target range. It was also noted a reduction of time spent in hyperglicemia with consequent improvement of average glucose values and of glucose main indicator. This is the first report with FGM supporting a role of canagliflozin in the management of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia. Our preliminary results are very limited but in line with those of the literature and showed for the first time a reduction of hypoglycaemic events and an improvement of glycemic variability through a flash glucose monitoring system. Further studies are mandatory to confirm this therapeutic opportunity.

Cryptosporidiosis is one of the main causes of diarrhea in children and young livestock. The interaction of the parasite with the intestinal host cells has not been characterized thoroughly yet but may be affected by the nutritional demand of the parasite. Hence, we aimed to investigate the impact of C. parvum infection on glucose metabolism in neonatal calves. Therefore, N = 5 neonatal calves were infected with C. parvum on the first day of life, whereas a control group was not (N = 5). The calves were monitored clinically for one week, and glucose absorption, turnover and oxidation were assessed using stable isotope labelled glucose. The transepithelial transport of glucose was measured using the Ussing chamber technique. Glucose transporters were quantified on gene and protein expression level using RT-qPCR and Western blot in the jejunum epithelium and brush border membrane preparations. Plasma glucose concentration and oral glucose absorption were decreased despite an increased electrogenic phlorizin sensitive transepithelial transport of glucose in infected calves. No difference in the gene or protein abundance of glucose transporters, but an enrichment of glucose transporter 2 in the brush border was observed in the infected calves. Furthermore, the mRNA for enzymes of the glycolysis pathway was increased indicating enhanced glucose oxidation in the infected gut. In summary, C. parvum infection modulates intestinal epithelial glucose absorption and metabolism. We assume that the metabolic competition of the parasite for glucose causes the host cells to upregulate their uptake mechanisms and metabolic machinery to compensate for the energy losses. [ABSTRACT FROM AUTHOR]

Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls. However, there was a need to examine SGLT1 expression in other tissues, such as the kidneys. Whether NE may directly affect SGLT1 protein expression has not yet been investigated, although such a link has been shown for sodium glucose cotransporter 2 (SGLT2). Hence, we aimed to determine (i) whether our murine model of neurogenic hypertension displays elevated renal SGLT1 expression and (ii) whether NE may directly promote elevations of SGLT1 in human proximal tubule (HK2) cells. We did indeed demonstrate that in vivo, in our mouse model of neurogenic hypertension, hyperactivation of the SNS promotes SGLT1 expression in the kidneys. In subsequent in vitro experiments in HK2 cells, we found that NE increased SGLT1 protein expression and translocation as assessed by both specific immunohistochemistry and/or a specific SGLT1 ELISA. Additionally, NE promoted a significant elevation in interleukin-6 (IL-6) levels which resulted in the promotion of SGLT1 expression and proliferation in HK2 cells. Our findings suggest that the SNS upregulates SGLT1 protein expression levels with potential adverse consequences for cardiometabolic control. SGLT1 inhibition may therefore provide a useful therapeutic target in conditions characterized by increased SNS activity, such as chronic kidney disease. [ABSTRACT FROM AUTHOR]

In the changing internal and external conditions, maintenance of a constant internal environment – homeostasis – plays a significant role in the proper functioning of the organism. Kidneys play a key role in the homeostasis of glucose, in which the sodium-dependent glucose co-transporters contribute to renal glucose reabsorption. Although the localisation of Na+-glucose co-transporters has been extensively covered in animals’ kidneys, the localisation of the transporters in birds’ kidneys is still understudied. The purpose of this study was to immunolocalise the sodium-dependent co-transporters SGLT1 and SGLT2 in kidneys of ostrich chickens of different ages. In the study, kidney material derived from fifteen ostriches was divided equally into three age groups – 1-, 7-, and 14-days-old ostrich chickens. The polyclonal antibodies Rabbit antiSGLT1 and Rabbit anti-SGLT2 (Abcam, UK) served as primary antibodies and were used together with the IHC kit (Abcam, UK). With the AxioCam HRc camera (Germany) connected to the microscope Zeiss Axioplan-2 Imaging (Germany), the photos were taken and saved to the computer. As the result of the study on ostrich chickens of different ages, SGLT1 was noted to be localised in the renal straight proximal tubules and SGLT2 in the proximal convoluted tubules of nephron. The immunohistochemical locations of sodium-dependent glucose co-transporters revealed to be similar in ostriches’ kidneys of all age groups. The staining for SGLT2 was noted to be more intensive compared to the staining for SGLT1. As avian kidneys have unique morphological and functional features compared to animals, it is recommended that further studies would be performed on the renal tissue of different avian species

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a newer class of drugs that have primarily been used in the treatment of type 2 diabetes. However, as new findings from clinical trials have become available, their indication has been expanded to include treatment of heart failure and chronic kidney disease without the presence of diabetes. The pathophysiological mechanisms of extraglycemic effects of SGLT2i are still being unraveled, but one of the most prominent consequences is a decrease in blood pressure, which has implications for hemodynamics and arterial stiffness. Recent findings indicate that this class of drugs has a beneficial effect on lowering nocturnal blood pressure (BP), with special importance in type 2 diabetes (DMT2), since unregulated nocturnal hypertension is associated with an increased incidence of cardiovascular (CV) events. In this mini-review, we have summarized current knowledge about the effects of SGLT2i on blood pressure, including office, home, and ambulatory BP, and potential implications for treatment of hypertension in diabetic and non-diabetic individuals, with positive effects on cardiorenal outcomes.

Beside the ongoing efforts to determine structural information, detailed functional studies on transporters are essential to entirely understand the underlying transport mechanisms. We recently found that solid supported membrane-based electrophysiology (SSME) enables the measurement of both sugar binding and transport in the Na+/sugar cotransporter SGLT1 (Bazzone et al, 2022a). Here, we continued with a detailed kinetic characterization of SGLT1 using SSME, determining KM and KDapp for different sugars, kobs values for sugar-induced conformational transitions and the effects of Na+, Li+, H+ and Cl- on sugar binding and transport. We found that the sugar-induced pre-steady-state (PSS) charge translocation varies with the bound ion (Na+, Li+, H+ or Cl-), but not with the sugar species, indicating that the conformational state upon sugar binding depends on the ion. Rate constants for the sugar-induced conformational transitions upon binding to the Na+-bound carrier range from 208 s-1 for D-glucose to 95 s-1 for 3-OMG. In the absence of Na+, rate constants are decreased, but all sugars bind to the empty carrier. From the steadystate transport current, we found a sequence for sugar specificity (Vmax/KM): D-glucose > MDG > D-galactose > 3-OMG > D-xylose. While KM differs 160-fold across tested substrates and plays a major role in substrate specificity, Vmax only varies by a factor of 1.9. Interestingly, D-glucose has the lowest Vmax across all tested substrates, indicating a rate limiting step in the sugar translocation pathway following the fast sugar-induced electrogenic conformational transition. SGLT1 specificity for D-glucose is achieved by optimizing two ratios: the sugar affinity of the empty carrier for D-glucose is similarly low as for all tested sugars (KD,Kapp = 210 mM). Affinity for D-glucose increases 14-fold (KD,Naapp = 15 mM) in the presence of sodium as a result of cooperativity. Apparent affinity for D-glucose during transport increases 8-fold (KM = 1.9 mM) compared to KD,Naapp due to optimized kinetics. In contrast, KM and KDapp values for 3-OMG and D-xylose are of similar magnitude. Based on our findings we propose an 11-state kinetic model, introducing a random binding order and intermediate states corresponding to the electrogenic transitions detected via SSME upon substrate binding. [ABSTRACT FROM AUTHOR]

Glucose-galactose malabsorption is a rare inherited autosomal recessive genetic defect. A mutation in the glucose sodium-dependent transporter-1 gene will alter the transportation and absorption of glucose and galactose in the intestine. The defect in the SGLT-1 leads to unabsorbed galactose, glucose, and sodium, which stay in the intestine, leading to dehydration and hyperosmotic diarrhea. Often, glucose-galactose malabsorption patients are highly dependent on fructose, their primary source of carbohydrates. This study aims to investigate all published studies on congenital glucose-galactose malabsorption and fructose malabsorption. One hundred published studies were assessed for eligibility in this study, and thirteen studies were identified and reviewed. Studies showed that high fructose consumption has many health effects and could generate life-threatening complications. None of the published studies included in this review discussed or specified the side effects of fructose consumption as a primary source of carbohydrates in congenital glucose-galactose malabsorption patients. [ABSTRACT FROM AUTHOR]

Ascaris suum constitutes a major problem in commercial pig farming worldwide. Lower weight gains in infected pigs probably result from impaired nutrient absorption. This study investigated intestinal nutrient transport in 4 groups of 6 pigs each, which were inoculated with 30 living adult A. suum , or antigen fractions consisting of (1) total excretory–secretory (ES) antigens of adult worms, (2) ES antigens secreted exclusively from the parasites' body surface (trans-cuticular ES) and (3) cuticular somatic antigens of A. suum , compared to placebo-treated controls. Three days after inoculation into the gastrointestinal tract, glucose, alanine and glycyl-l-glutamine transport was measured in the duodenum, jejunum and ileum using Ussing chambers. Transcription of relevant genes [sodium glucose cotransporter 1 (SGLT1), glucose transporter 1 (GLUT1), GLUT2, hypoxia-inducible factor 1-alpha (Hif1 α), interleukin-4 (IL-4), IL-13, signal transducer and activator of transcription 6 (STAT6), peptide transporter 1 (PepT1)] and expression of transport proteins [SGLT1, phosphorylated SGLT1, GLUT2, Na+/K+-ATPase, amino acid transporter A (ASCT1), PepT1] were studied. Although no significant functional changes were noted after exposure to adult A. suum , a significant downregulation of jejunal GLUT1, STAT6, Hif1 α and PepT1 transcription as well as ileal GLUT2 and PepT1 expression indicates a negative impact of infection on transport physiology. Therefore, the exposure period of 3 days may have been insufficient for functional alterations to become apparent. In contrast, A. suum antigens mainly induced an upregulation of transport processes and an increase in transcription of relevant genes in the duodenum and jejunum, possibly as a compensatory reaction after a transient downregulation. In the ileum, a consistent pattern of downregulation was observed in all inoculated groups, in line with the hypothesis of impaired nutrient transport. [ABSTRACT FROM AUTHOR]

Anthocyanins are substances with multiple physiological activities widely present in red wine, but the influence of structure (methylation, hydroxylation, acylation, glycosylation) on the transport remains ill-defined. In the present study, Caco-2 monolayers were used as an in vitro model of the absorptive intestinal epithelium to transport different types of anthocyanin samples. Results showed that both methylation and acetylation promote the level of transport. Monoglycoside standard exhibited higher transport amount and rate compared to diglycoside standard while the transport level of the monoglycoside mixture was unexpectedly lower than that of the diglycoside mixture. Caco-2 monolayers appeared to be more capable of transporting the single standard than the mixed standard. Meanwhile, the transport of anthocyanins in Caco-2 cell model showed time- and concentration-dependent trends. Anthocyanin treatment had a greater effect on sodium-dependent glucose transporter 1 (SGLT1) mRNA expression than glucose transporter 2 (GLUT2), and significantly down-regulated the protein expression of SGLT1. Although the low bioavailability of anthocyanins requires much more research, further evidence of the role of structure is provided. [ABSTRACT FROM AUTHOR]

We assessed the functional role of the spiral valve in carbohydrate digestion and glucose acquisition during different feeding states in Acipenser fulvescens and Squalus suckleyi. For S. suckleyi, maltase activity was highest in the anterior and mid spiral valve, while sodium-glucose linked transporter 1 (sglt1) transcripts peaked in the mid spiral valve. Alongside these metrics, glucose tissue uptake demonstrated decreased maximal transport rates from 24 h to 7+ days post feeding, demonstrating a putative means for energy conservation. A. fulvescens showed the highest maltase activity and sglt1 abundance in regions anterior to the spiral valve (pyloric ceca and anterior intestine). Additionally, glucose transport did not reach saturation in the spiral valve and anterior intestine of A. fulvescens over the measured concentrations, suggestive of a heightened capacity in these regions for glucose uptake. Overall, the spiral valve played a primary role in glucose digestion and transport in S. suckleyi, whereas A. fulvescens utilized the anterior intestine in addition to the spiral valve. Combined, these results also suggest regional functionality of carbohydrate acquisition within the spiral intestine in S. suckleyi but not in A. fulvescens. This demonstrates that the spiral valve may not always be the primary region of nutrient absorption in all species as suggested in the literature, highlighting the importance of comparing morphological and functional studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

The series of the cardiovascular outcome trails have demonstrated the nephroprotective properties of the gliflozins. Canagliflozin in the CREDENCE, which was the first study with a primary focus on the evaluation of the nephroprotective properties of gliflozin, have demonstrated the possibility to slow the progression of the renal disease. The paper summarizes the additional data from the CREDENCE trail: assessment of the efficacy of canagliflozin by initial eGFR; efficacy in individuals with GFR

Aims Sleeve gastrectomy (SG) has been proven effective in the treatment of obesity and type 2 diabetes. We hypothesized that SGLT3 may play an important role in the mechanism of glucose control and weight loss after SG. Materials and methods Daily body weight and food intake were measured in SG and sham-operated mice. Glucose tolerance test, SGLT3 agonist (αMG), and SGLT1 inhibitor (phlorizin) perfusion experiments were used to detect changes in intestinal SGLT3 and SGLT1 activity following SG. Expression of SGLT3a and SGLT1 was assessed at 2 weeks, 1 month after surgery by quantitative PCR and fluorescence immunoassay. Hematoxylin and eosin staining was used to detect morphological changes in the villi. SGLT3 and SGLT1 expression was measured after stimulation of human intestinal epithelial cells (HIEC). Results Both the body weight and daily food intake of the SG-treated mice decreased within 30 days after surgery. Oral glucose absorption was significantly reduced at 30 days. The intestinal stimulation proved that SG can improve glucose metabolism, which can be reversed by αMG and enhanced by phlorizin. Villus height and surface area of the intestine in SG mice decreased after surgery. mRNA expression of SGLT3a and SGLT1 decreased at 2 weeks and 1 month after SG, immunofluorescence also confirmed these changes. HIEC stimulation confirmed that αMG could increase the expression of SGLT3 and SGLT1, but the expression of SGLT1 was down regulated when phlorizin was added to the medium. Conclusion The results suggest that reducing SGLT3 expression might contribute to lowering blood glucose and controlling body weight after SG.

Inhibitors of the sodium-glucose cotransporter type 2 (SGLT2i) are a modern class of antihyperglycemic drugs with an insulin-independent mechanism of action. Due to its ability to effectively lower blood glucose levels, improve a number of other cardiometabolic parameters (body weight, blood pressure, uric acid), as well as reduce cardiovascular and renal risks, SGLT2i have become drugs of choice for many of patients with type 2 diabetes mellitus (T2DM). Meanwhile, along with the generally recognized classes-effects of this group of drugs, there are intragroup features, including those associated with their different selectivity in sodium-glucose cotransporters of types 1 and 2 (SGLT1 and SGLT 2). For example, one of the most studied SGLT2i, canagliflozin, in addition to its inhibitory activity against SGLT2, can also moderately block SGLT1 in the intestine and kidneys that could give a maximum efficiency in the control glycemia and others cardiometabolic parameters. In addition, canagliflozin improves not only cardiovascular, but also renal prognosis in patients with T2DM, which is reflected in the corresponding indications in the summary of product characteristics of the drug. This document summarize the established and new data regarding the efficacy and safety of canagliflozin, as well as its place in the treatment of T2DM.

For most cells, including lymphocytes, glucose is a primary energy source, and, therefore, it is vital to understand the regulatory mechanisms that control the work of glucose transporters. Lymphocytes are pivotal for mediation of immune and inflammatory responses. A feature of lymphocytes is increasing glucose utilization during activation of the immune function, which is strongly dependent on glucose uptake. Some studies show that elevated glucose concentration in diabetes mellitus affects lymphocytes’ glucose transporters expression, whichcorrelates with impaired immune functions and may become one of the predisposing factors of contracting infectious diseases. Recent studies have focused on glucose transporters as therapeutic targets for a variety of diseases, including diabetes mellitus. This review demonstrates the effect of photobiomodulationtherapy on glucose uptake by Na+-coupled glucose carrier SGLT1 and facilitated diffusion glucose carriers of the GLUT family (GLUT1, GLUT3, GLUT4) in normal and diabetic lymphocytes.

Beside the ongoing efforts to determine structural information, detailed functional studies on transporters are essential to entirely understand the underlying transport mechanisms. We recently found that solid supported membrane-based electrophysiology (SSME) enables the measurement of both sugar binding and transport in the Na+/sugar cotransporter SGLT1 (Bazzone et al, 2022a). Here, we continued with a detailed kinetic characterization of SGLT1 using SSME, determining KM and KDapp for different sugars, kobs values for sugar-induced conformational transitions and the effects of Na+, Li+, H+ and Cl− on sugar binding and transport. We found that the sugar-induced pre-steady-state (PSS) charge translocation varies with the bound ion (Na+, Li+, H+ or Cl−), but not with the sugar species, indicating that the conformational state upon sugar binding depends on the ion. Rate constants for the sugar-induced conformational transitions upon binding to the Na+-bound carrier range from 208 s−1 for D-glucose to 95 s−1 for 3-OMG. In the absence of Na+, rate constants are decreased, but all sugars bind to the empty carrier. From the steady-state transport current, we found a sequence for sugar specificity (Vmax/KM): D-glucose > MDG > D-galactose > 3-OMG > D-xylose. While KM differs 160-fold across tested substrates and plays a major role in substrate specificity, Vmax only varies by a factor of 1.9. Interestingly, D-glucose has the lowest Vmax across all tested substrates, indicating a rate limiting step in the sugar translocation pathway following the fast sugar-induced electrogenic conformational transition. SGLT1 specificity for D-glucose is achieved by optimizing two ratios: the sugar affinity of the empty carrier for D-glucose is similarly low as for all tested sugars (KD,Kapp = 210 mM). Affinity for D-glucose increases 14-fold (KD,Naapp = 15 mM) in the presence of sodium as a result of cooperativity. Apparent affinity for D-glucose during transport increases 8-fold (KM = 1.9 mM) compared to KD,Naapp due to optimized kinetics. In contrast, KM and KDapp values for 3-OMG and D-xylose are of similar magnitude. Based on our findings we propose an 11-state kinetic model, introducing a random binding order and intermediate states corresponding to the electrogenic transitions detected via SSME upon substrate binding.

The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (β2-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the β2-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I125-cyanopindolol, a β2-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a β2-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the β2-AR. Oral administration of glucose with a non-bioavailable β2-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical β2-ARs in stimulating gut glucose uptake, and suggesting enterocyte β2-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether β2-ARs mediate glucose sensing also in other tissues.