ABSTRACT
To investigate the role of glucose transporter 1 (GLUT1) and sodium-glucose cotransporter 1 (SGLT1) in high glucose dialysate-induced peritoneal fibrosis.Thirty six male SD rats were randomly divided into 6 groups (6 in each):normal control group, sham operation group, peritoneal dialysis group (PD group), PD+phloretin group (PD+T group), PD+phlorizin group (PD+Z group), PD+phloretin+phlorizin group (PD+T+Z group). Rat model of uraemia was established using 5/6 nephrotomy, and 2.5% dextrose peritoneal dialysis solution was used in peritoneal dialysis. Peritoneal equilibration test was performed 24 h after dialysis to evaluate transport function of peritoneum in rats; HE staining was used to observe the morphology of peritoneal tissue; and immunohistochemistry was used to detect the expression of GLUT1, SGLT1, TGF-β1 and connective tissue growth factor (CTGF) in peritoneum. Human peritoneal microvascular endothelial cells (HPECs) were divided into 5 groups:normal control group, peritoneal dialysis group (PD group), PD+phloretin group (PD+T group), PD+phlorezin group (PD+Z group), and PD+phloretin+phlorezin group (PD+T+Z group). Real time PCR and Western blotting were used to detect mRNA and protein expressions of GLUT1, SGLT1, TGF-β1, CTGF in peritoneal membrane and HPECs., compared with sham operation group, rats in PD group had thickened peritoneum, higher ultrafiltration volume, and the mRNA and protein expressions of GLUT1, SGLT1, CTGF, TGF-β1 were significantly increased (all<0.05); compared with PD group, thickened peritoneum was attenuated, and the mRNA and protein expressions of GLUT1, SGLT1, CTGF, TGF-β1 were significantly decreased in PD+T, PD+Z and PD+T+Z groups (all<0.05). Pearson's correlation analysis showed that the expressions of GLUT1, SGLT1 in peritoneum were positively correlated with the expressions of TGF-β1 and CTGF (all<0.05)., the mRNA and protein expressions of GLUT1, SGLT1, TGF-β1, CTGF were significantly increased in HPECs of peritoneal dialysis group (all<0.05), and those in PD+T, PD+Z, and PD+T+Z groups were decreased (all<0.05). Pearson's correlation analysis showed that the expressions of GLUT1, SGLT1 in HPECs were positively correlated with the expressions of TGF-β1 and CTGF (all<0.05).High glucose peritoneal dialysis fluid may promote peritoneal fibrosis by upregulating the expressions of GLUT1 and SGLT1.
Subject(s)
Animals , Humans , Male , Rats , Cells, Cultured , Connective Tissue Growth Factor , Dialysis Solutions , Chemistry , Pharmacology , Gene Expression Regulation , Glucose , Pharmacology , Glucose Transporter Type 1 , Physiology , Hemodiafiltration , Methods , Peritoneal Dialysis , Methods , Peritoneal Fibrosis , Genetics , Peritoneum , Chemistry , Pathology , Phloretin , Phlorhizin , RNA, Messenger , Rats, Sprague-Dawley , Sodium-Glucose Transporter 1 , Physiology , Transforming Growth Factor beta1 , UremiaABSTRACT
<p><b>OBJECTIVE</b>To reveal the effects and related mechanisms of chlorogenic acid (CGA) on intestinal glucose homeostasis.</p><p><b>METHODS</b>Forty male Sprague-Dawley rats were randomly and equally divided into four groups: normal chow (NC), high-fat diet (HFD), HFD with low-dose CGA (20 mg/kg, HFD-LC), and HFD with high-dose CGA (90 mg/kg, HFD-HC). The oral glucose tolerance test was performed, and fast serum insulin (FSI) was detected using an enzyme-linked immunosorbent assay. The mRNA expression levels of glucose transporters (Sglt-1 and Glut-2) and proglucagon (Plg) in different intestinal segments (the duodenum, jejunum, ileum, and colon) were analyzed using quantitative real-time polymerase chain reaction. SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.</p><p><b>RESULTS</b>At both doses, CGA ameliorated the HFD-induced body weight gain, maintained FSI, and increased postprandial 30-min glucagon-like peptide 1 secretion. High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression. Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.</p><p><b>CONCLUSION</b>An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis. CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg, thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.</p>
Subject(s)
Animals , Male , Chlorogenic Acid , Pharmacology , Diet, High-Fat , Glucagon-Like Peptide 1 , Metabolism , Glucose , Metabolism , Glucose Tolerance Test , Glucose Transporter Type 2 , Metabolism , Homeostasis , Insulin , Blood , Intestines , Metabolism , Proglucagon , Metabolism , Random Allocation , Rats, Sprague-Dawley , Sodium-Glucose Transporter 1 , Metabolism , Weight GainABSTRACT
The aim of the study is to investigate the effects of concentration, intestinal segments, pH, inhibitors of proteins (P-gp), Na(+)-dependent glucose transporter (SGLT1) on the intestinal absorption of berberine, and to compare intestinal absorption of berberine in combinations. With phenol red as the indicator, in situ single pass intestinal perfusion (SPIP) model was used and intestinal absorption of pure berberine at concentrations of 36.70, 46.17 and 92.33 microg x mL(-1), simulated system of HLJDT (mixture of berberine, baicalin and geniposide), HLJDT with the concentration of berberine 92.33 microg x mL(-1) in perfusion solution of different intestinal segments (duodenum, jejunum, ileum, and colon) were determined by HPLC in combination with diode array detection (DAD). The results indicated that Ka values ofberberine at different concentrations had little significant difference among that obtained after perfusing via duodenum, jejunum, ileum and colon indicating that the absorption of berberine was mainly the passive diffusion. It was also suggested that SGLT1 and P-gp might exert some effects on the absorption of berberine. Ka and Peff values of berberine in a mixture of pure compounds and HLJDT for different intestine segments of rat showed an increasing tendency and was significantly different (P < 0.05) indicating that berberine in a mixture of pure compounds and HLJDT was assimilated better in small intestine. These results indicate that the intestinal absorption of berberine may be affected by compatibility of compounds. Additionally, berberine has wide absorption window and better absorption in colon.
Subject(s)
Animals , Male , Rats , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Physiology , Berberine , Pharmacokinetics , Colon , Metabolism , Drugs, Chinese Herbal , Pharmacokinetics , Duodenum , Metabolism , Ileum , Metabolism , Intestinal Absorption , Intestine, Small , Metabolism , Jejunum , Metabolism , Mannitol , Pharmacology , Perfusion , Rats, Sprague-Dawley , Sodium-Glucose Transporter 1 , Physiology , Verapamil , PharmacologyABSTRACT
Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1 and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about 90%) is reabsorbed by SGLT-2 located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2 is an innovative therapeutic strategy for treatment of type 2 diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2 inhibitors are considered to be potential antidiabetic drugs with an unique mechanism. This review will highlight some recent advances and structure-activity relationships in the discovery and development of SGLT-2 inhibitors including O-glycoside, C-glycoside, C, O-spiro glycoside and non glycosides.
Subject(s)
Animals , Humans , Benzhydryl Compounds , Chemistry , Pharmacology , Diabetes Mellitus, Type 2 , Drug Therapy , Glucosides , Chemistry , Pharmacology , Hypoglycemic Agents , Chemistry , Pharmacology , Molecular Structure , Monosaccharides , Chemistry , Pharmacology , Sodium-Glucose Transporter 1 , Metabolism , Sodium-Glucose Transporter 2 , Metabolism , Structure-Activity RelationshipABSTRACT
Glucose enters eukaryotic cells via two types of membrane-associated carrier proteins, the Na+/glucose cotransporters (SGLT) and the facilitative glucose transporters (GLUT). The SGLT family consists of six members. Among them, the SGLT1 and SGLT2 proteins, encoded by the solute carrier genes SLC5A1 and SLC5A2, respectively, are believed to be the most important ones and have been extensively explored in studies focusing on glucose fluxes under both physiological and pathological conditions. This review considers the regulation of the expression of the SGLT promoted by protein kinases and transcription factors, as well as the alterations determined by diets of different compositions and by pathologies such as diabetes. It also considers congenital defects of sugar metabolism caused by aberrant expression of the SGLT1 in glucose-galactose malabsorption and the SGLT2 in familial renal glycosuria. Finally, it covers some pharmacological compounds that are being currently studied focusing on the interest of controlling glycemia by antagonizing SGLT in renal and intestinal tissues.
Subject(s)
Animals , Humans , Gene Expression Regulation/genetics , Signal Transduction/genetics , Sodium-Glucose Transporter 1/genetics , /genetics , Transcription, Genetic/genetics , Diabetes Mellitus/genetics , Diabetes Mellitus/physiopathology , Gene Expression Regulation/physiology , Signal Transduction/physiology , Sodium-Glucose Transporter 1/physiology , /physiology , Transcription, Genetic/physiologyABSTRACT
Thiazide is known to decrease urinary calcium excretion. We hypothesized that thiazide shows different hypocalciuric effects depending on the stimuli causing hypercalciuria. The hypocalciuric effect of hydrochlorothiazide (HCTZ) and the expression of transient receptor potential vanilloid 5 (TRPV5), calbindin-D(28K), and several sodium transporters were assessed in hypercalciuric rats induced by high calcium diet and vitamin D3. Urine calcium excretion and the expression of transporters were measured from 4 groups of Sprague-Dawley rats; control, HCTZ, high calcium-vitamin D, and high calcium-vitamin D with HCTZ groups. HCTZ decreased urinary calcium excretion by 51.4% in the HCTZ group and only 15% in the high calcium-vitamin D with HCTZ group. TRPV5 protein abundance was not changed by HCTZ in the high calcium-vitamin D with HCTZ group compared to the high calcium-vitamin D group. Protein abundance of NHE3, SGLT1, and NKCC2 decreased in the hypercalciuric rats, and only SGLT1 protein abundance was increased by HCTZ in the hypercalciuric rats. The hypocalciuric effect of HCTZ is attenuated in high calcium and vitamin D-induced hypercalciuric rats. This attenuation seems to have resulted from the lack of HCTZ's effect on protein abundance of TRPV5 in severe hypercalciuric condition induced by high calcium and vitamin D.
Subject(s)
Animals , Rats , Calcium/therapeutic use , Calcium Channels/genetics , Cholecalciferol/toxicity , Hydrochlorothiazide/therapeutic use , Hypercalciuria/chemically induced , Rats, Sprague-Dawley , Sodium Chloride Symporter Inhibitors/therapeutic use , Sodium-Glucose Transporter 1/genetics , Sodium-Hydrogen Exchangers/genetics , Sodium-Potassium-Chloride Symporters/genetics , TRPV Cation Channels/geneticsABSTRACT
Hexosas como la glucosa, galactosa y fructosa cumplen funciones importantes en las células eucarióticas. Estas moléculas son incapaces de difundir directamente a través de las membranas celulares por lo que requieren proteínas transportadoras especializadas para entrar al interior celular. Dichas biomoléculas pertenecen a un grupo de transportadores constituida por 2 familias de proteínas: la familia de los Glut´s (del inglés Glucose Transporters) y la familia de los co-transportadores de sodio y glucosa. Según la información obtenida de la secuencia de aminoácidos por medio de librerías de cADN todos poseen una estructura básica similar: 12 (Gluts) o 14 (SGLT) dominios trasmembrana. Igualmente todos parecen estar glicosilados en alguna de sus asas extracelulares. En los últimos siete años ha habido un explosivo incremento en la información sobre estos transportadores, de hecho, hasta hace diez años solo se conocían 6 transportadores pero esta familia ha crecido rápidamente hasta llegar a 14 miembros para los Gluts y 6 miembros para los SGLT´s. El impacto de estos descubrimientos se hace notar cuando se analizan los procesos en los que se involucran estas proteínas: Control de la glicemia basal y post-prandial; mecanismos de absorción de la glucosa y fructosa en el intestino delgado; absorción de fructosa en los espermatozoides; reabsorción de glucosa a nivel tubular renal y yeyuno; maduración de la expresión de Glut´s en la mama en lactación; incorporación de glucosa al músculo durante el ejercicio; mecanismo sensor en la secreción de insulina y respuestas adaptativa del metabolismo energético durante estados de estrés, etc.
Subject(s)
Humans , Glucose/metabolism , Glucose Transport Proteins, Facilitative/metabolism , Biological Transport , Molecular Biology , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 1/chemistry , /metabolism , /chemistryABSTRACT
BACKGROUND & OBJECTIVES: Infection by Salmonella Typhimurium is one of the leading causes of intestinal dysfunction, however the underlying mechanism of this effect is largely unknown. Hence the effect of enterotoxin secreted by Salmonella Typhimurium-(S-LT) was studied on D-glucose absorption and brush border enzymes in rabbit ileum. mRNA levels encoding these proteins were also analysed. METHODS: Adult male New Zealand white rabbits were used. The polymyxine B extract of enterotoxin obtained from Salmonella Typhimurium was tested for the presence of enterotoxicity by rabbit ileal loop test. D-glucose uptake by ileal tissue was measured by the tissue accumulation method. Intestinal brush border membranes were isolated and the effect of S-LT on various brush border enzymes studied. RESULTS: S-LT significantly inhibited (P < 0.01) the absorption of Na+ dependent D-glucose uptake but had no effect on Na+ independent sugar uptake in rabbit ileum. The activities of brush border sucrase (72% P < 0.001) and lactase (47% P < 0.01) and alkaline phosphatase (43% P < 0.01) were also significantly reduced in infected animals as compared to the controls. Northern blot analysis revealed that mRNA levels encoding Na+ glucose co-transporter (SGLT1), brush border lactase and sucrase activities were unaffected in Salmonella infected rabbit ileal loops. INTERPRETATION & CONCLUSION: The findings suggest that the intestinal dysfunctions observed in Salmonella infection are unrelated to mRNA expression encoding Na+ glucose co-transporter and brush border enzyme proteins in rabbit ileum.