4955
1994
eng
article
1
2011-08-10
--
--
Drug excretion mediated by a new prototype of polyspecific transporter
CATIO~IC drugs of different types and structures (antihistaminics, antiarrhythmics, sedatives, opiates, cytostatics and antibiotics, for example) are excreted in mammals by epithelial cells of the renal proximal tubules and by hepatocytes in the liver<sup>1-4</sup>. In the proximal tubules, two functionally disparate transport systems are involved which are localized in the basolateral and luminal plasma membrane and are different from the previously identified neuronal monoamine transporters and A TP-dependent multidrug exporting proteins<sup>1-3,5-12</sup>. Here we report the isolation of a complementary DNA from rat kidney that encodes a 556-amino-acid membrane protein, OCT1, which has the functional characteristics of organic cation uptake over the basolateral membrane of renal proximal tubules and of organic cation uptake into hepatocytes. OCTl is not homologous to any other known protein and is found in kidney, liver and intestine. As OCTl translocates hydrophobic and hydrophilic organic cations of different structures, it is considered to be a new prolotype of polyspecific transporters that are important for drug elimination.
urn:nbn:de:bvb:20-opus-59327
5932
In: Nature (1994) 372, S. 549 - 552.
Deutsches Urheberrecht
Dirk Gründemann
Valentin Gorboulev
Stepan Gambaryan
Maike Veyhl
Hermann Koepsell
deu
swd
Biologie
Biowissenschaften; Biologie
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/4955/Gorboulev27.pdf
5704
2010
eng
article
1
2012-03-18
--
--
Sucrose- and H+-Dependent Charge Movements Associated with the Gating of Sucrose Transporter ZmSUT1
Background: In contrast to man the majority of higher plants use sucrose as mobile carbohydrate. Accordingly protondriven sucrose transporters are crucial for cell-to-cell and long-distance distribution within the plant body. Generally very negative plant membrane potentials and the ability to accumulate sucrose quantities of more than 1 M document that plants must have evolved transporters with unique structural and functional features. Methodology/Principal Findings: To unravel the functional properties of one specific high capacity plasma membrane sucrose transporter in detail, we expressed the sucrose/H+ co-transporter from maize ZmSUT1 in Xenopus oocytes. Application of sucrose in an acidic pH environment elicited inward proton currents. Interestingly the sucrose-dependent H+ transport was associated with a decrease in membrane capacitance (Cm). In addition to sucrose Cm was modulated by the membrane potential and external protons. In order to explore the molecular mechanism underlying these Cm changes, presteady-state currents (Ipre) of ZmSUT1 transport were analyzed. Decay of Ipre could be best fitted by double exponentials. When plotted against the voltage the charge Q, associated to Ipre, was dependent on sucrose and protons. The mathematical derivative of the charge Q versus voltage was well in line with the observed Cm changes. Based on these parameters a turnover rate of 500 molecules sucrose/s was calculated. In contrast to gating currents of voltage dependentpotassium channels the analysis of ZmSUT1-derived presteady-state currents in the absence of sucrose (I =Q/t) was sufficient to predict ZmSUT1 transport-associated currents. Conclusions: Taken together our results indicate that in the absence of sucrose, ‘trapped’ protons move back and forth between an outer and an inner site within the transmembrane domains of ZmSUT1. This movement of protons in the electric field of the membrane gives rise to the presteady-state currents and in turn to Cm changes. Upon application of external sucrose, protons can pass the membrane turning presteady-state into transport currents.
urn:nbn:de:bvb:20-opus-68538
6853
PLOS ONE (2010) 5, 9, DOI: 10.1371/journal.pone.0012605
Armando Carpaneto
Hermann Koepsell
Ernst Bamberg
Rainer Hedrich
Dietmar Geiger
deu
uncontrolled
Sucrose
Pflanzen (Botanik)
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5704/Geiger_journal.pone.0012605.pdf
5459
2012
eng
article
1
2012-01-30
--
--
Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells
During stroke the blood–brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907% after 6 h OGD and was still higher (210%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells.
urn:nbn:de:bvb:20-opus-67241
6724
Neuroscience Letters (2012) 506, 44– 49; http://dx.doi.org/10.1016/j.neulet.2011.10.045
241778
Deutsches Urheberrecht
Winfried Neuhaus
Malgorzata Burek
Cholpon C Djuzenova
Serge C Thal
Hermann Koepsell
Norbert Roewer
Carola Y Förster
deu
swd
Blut-Hirn-Schranke
deu
swd
Schlaganfall
deu
swd
Glucosetransportproteine
deu
swd
NMDA-Antagonist
deu
swd
NMDA-Rezeptor
eng
uncontrolled
blood-brain barrier
eng
uncontrolled
MK801
eng
uncontrolled
NMDAR
eng
uncontrolled
stroke
eng
uncontrolled
glut1
eng
uncontrolled
sglt1
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5459/Foerster_Neuhaus_NeuroscienceLetters506.pdf
12565
2012
eng
3128-3142
14
21
article
1
2016-01-27
--
--
The GTPase ARFRP1 controls the lipidation of chylomicrons in the Golgi of the intestinal epithelium
The uptake and processing of dietary lipids by the small intestine is a multistep process that involves several steps including vesicular and protein transport. The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) controls the ARF-like 1 (ARL1)-mediated Golgi recruitment of GRIP domain proteins which in turn bind several Rab-GTPases. Here, we describe the essential role of ARFRP1 and its interaction with Rab2 in the assembly and lipidation of chylomicrons in the intestinal epithelium. Mice lacking Arfrp1 specifically in the intestine \((Arfrp1^{vil−/−})\) exhibit an early post-natal growth retardation with reduced plasma triacylglycerol and free fatty acid concentrations. \(Arfrp1^{vil−/−}\) enterocytes as well as Arfrp1 mRNA depleted Caco-2 cells absorbed fatty acids normally but secreted chylomicrons with a markedly reduced triacylglycerol content. In addition, the release of apolipoprotein A-I (ApoA-I) was dramatically decreased, and ApoA-I accumulated in the \(Arfrp1^{vil−/−}\) epithelium, where it predominantly co-localized with Rab2. The release of chylomicrons from Caco-2 was markedly reduced after the suppression of Rab2, ARL1 and Golgin-245. Thus, the GTPase ARFRP1 and its downstream proteins are required for the lipidation of chylomicrons and the assembly of ApoA-I to these particles in the Golgi of intestinal epithelial cells.
Human Molecular Genetics
10.1093/hmg/dds140
urn:nbn:de:bvb:20-opus-125658
Human Molecular Genetics, 2012, Vol. 21, No. 14 3128–3142. doi:10.1093/hmg/dds140
Alexander Jaschke
Bomee Chung
Deike Hesse
Reinhart Kluge
Claudia Zahn
Markus Moser
Klaus-Jürgen Petzke
Regina Brigelius-Flohé
Dmytro Puchkov
Hermann Koepsell
Joerg Heeren
Hans-Georg Joost
Annette Schürmann
eng
uncontrolled
ARF
Menschliche Anatomie, Zytologie, Histologie
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12565/dds140.pdf
11735
2014
eng
23
13
article
1
2015-08-05
--
--
Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis
Background: Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis.
Methods: Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student's t-test (paired two-tailed) and X-2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05.
Results: BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR.
Conclusions: BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.
Molecular Cancer
10.1186/1476-4598-13-23
1476-4598
24495286
urn:nbn:de:bvb:20-opus-117352
Molecular Cancer 2014 13:23. doi:10.1186/1476-4598-13-23
Diego Cardani
Claudia Sardi
Barbara La Ferla
Guiseppe D'Orazio
Michele Sommariva
Fabrizio Marcucci
Daniela Olivero
Elda Tagliabue
Hermann Koepsell
Francesco Nicotra
Andrea Balsari
Christiano Rumio
eng
uncontrolled
apoptosis
eng
uncontrolled
prevention
eng
uncontrolled
doxorubicin
eng
uncontrolled
cancer
eng
uncontrolled
gastrointestinal mucositis
eng
uncontrolled
SGLT-1
eng
uncontrolled
synthetic D-glucose analogy
eng
uncontrolled
chemotherapy
eng
uncontrolled
inflammation
eng
uncontrolled
clinical practice guidelines
eng
uncontrolled
intestinal mucositis
eng
uncontrolled
epithelial cells
eng
uncontrolled
oral mucositis
eng
uncontrolled
gene-expression
Biowissenschaften; Biologie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11735/121_Cardani_Molecular_Cancer.pdf
11726
2014
eng
e89977
2
9
article
1
2015-08-04
--
--
The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing
Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels. In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion.
PLOS ONE
10.1371/journal.pone.0089977
24587162
urn:nbn:de:bvb:20-opus-117262
PLoS ONE 9(2): e89977. doi:10.1371/journal.pone.0089977
Pia V. Röder
Kerstin E. Geillinger
Tamara S. Zietek
Bernard Thorens
Hermann Koepsell
Hannelore Daniel
eng
uncontrolled
rat small-intestine
eng
uncontrolled
brush border membrane
eng
uncontrolled
apical GLUT2
eng
uncontrolled
incretin secretion
eng
uncontrolled
diffusive component
eng
uncontrolled
sugar absorption
eng
uncontrolled
mice
eng
uncontrolled
calcium absorption
eng
uncontrolled
phosphorylation
eng
uncontrolled
cotransporter
Biowissenschaften; Biologie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11726/115_Roeder_PLOS_ONE.pdf
14916
2015
eng
490365
2015
article
1
2017-05-24
--
--
Ileal interposition in rats with experimental type 2 like diabetes improves glycemic control independently of glucose absorption
Bariatric operations in obese patients with type 2 diabetes often improve diabetes before weight loss is observed. In patients mainly Roux-en-Y-gastric bypass with partial stomach resection is performed. Duodenojejunal bypass (DJB) and ileal interposition (IIP) are employed in animal experiments. Due to increased glucose exposition of L-cells located in distal ileum, all bariatric surgery procedures lead to higher secretion of antidiabetic glucagon like peptide-1 (GLP-1) after glucose gavage. After DJB also downregulation of Na\(^{+}\)-D-glucose cotransporter SGLT1 was observed. This suggested a direct contribution of decreased glucose absorption to the antidiabetic effect of bariatric surgery. To investigate whether glucose absorption is also decreased after IIP, we induced diabetes with decreased glucose tolerance and insulin sensitivity in male rats and investigated effects of IIP on diabetes and SGLT1. After IIP, we observed weight-independent improvement of glucose tolerance, increased insulin sensitivity, and increased plasma GLP-1 after glucose gavage. The interposed ileum was increased in diameter and showed increased length of villi, hyperplasia of the epithelial layer, and increased number of L-cells. The amount of SGLT1-mediated glucose uptake in interposed ileum was increased 2-fold reaching the same level as in jejunum. Thus, improvement of glycemic control by bariatric surgery does not require decreased glucose absorption.
Journal of Diabetes Research
10.1155/2015/490365
urn:nbn:de:bvb:20-opus-149166
Journal of Diabetes Research Volume 2015, Article ID 490365 (2015). DOI: 10.1155/2015/490365
Christian Ferdinand Jurowich
Christoph Otto
Prashanth Reddy Rikkala
Nicole Wagner
Ivana Vrhovac
Ivan Sabolić
Christoph-Thomas Germer
Hermann Koepsell
eng
uncontrolled
glucagon like peptide-1
eng
uncontrolled
food intake
eng
uncontrolled
body weight
eng
uncontrolled
cotransporter SGLT1
eng
uncontrolled
bariatric surgery
eng
uncontrolled
biliopancreatic diversion
eng
uncontrolled
intestinal glucose
eng
uncontrolled
gut hormones
eng
uncontrolled
duodenal jejunal bypass
eng
uncontrolled
Y-gastric bypass
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Institut für Anatomie und Zellbiologie
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14916/061_Jurowich_Journal_of_Diabetes_Research.pdf
16523
2016
eng
175
7
article
1
2018-07-20
--
--
Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions
Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.
Frontiers in Pharmacology
10.3389/fphar.2016.00175
urn:nbn:de:bvb:20-opus-165236
Front. Pharmacol. 7:175. DOI:10.3389/fphar.2016.00175
Cristina Arimany-Nardi
Gerard Minuesa
Marçal Pastor-Anglada
Thorsten Keller
Itziar Erkizia
Hermann Koepsell
Javier Martinez-Picado
eng
uncontrolled
hOCT1
eng
uncontrolled
pharmacogenetics
eng
uncontrolled
lamivudine
eng
uncontrolled
HIV infection
eng
uncontrolled
therapy
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16523/059_Arimany-Nardi_FRONTIERS IN PHARMACOLOGY.pdf
16490
2016
eng
1209-1228
3
39
article
1
2018-07-19
--
--
Expression of JAK3 Sensitive Na\(^+\) Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes
Background:
Similar to tumor cells, activated T-lymphocytes generate ATP mainly by glycolytic degradation of glucose. Lymphocyte glucose uptake involves non-concentrative glucose carriers of the GLUT family. In contrast to GLUT isoforms, Na+-coupled glucose-carrier SGLT1 accumulates glucose against glucose gradients and is effective at low extracellular glucose concentrations. The present study explored expression and regulation of SGLT1 in activated murine splenic cytotoxic T cells (CTLs) and human Jurkat T cells.
Methods:
FACS analysis, immunofluorescence, confocal microscopy, chemiluminescence and Western blotting were employed to estimate SGLT1 expression, function and regulation in lymphocytes, as well as dual electrode voltage clamp in SGLT1 ± JAK3 expressing Xenopus oocytes to quantify the effect of janus kinase3 (JAK3) on SGLT1 function.
Results:
SGLT1 is expressed in murine CTLs and also in human Jurkat T cells. 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake was significantly decreased by SGLT1-blocker phloridzin (0.2 mM) and by pharmacological inhibition of JAK3 with WHI-P131 (156 µM), WHI-P154 (11.2 µM) and JAK3 inhibitor VI (0.5 µM). Electrogenic glucose transport (Iglucose) in Xenopus oocytes expressing human SGLT1 was increased by additional expression of human wild type JAK3, active A568VJAK3 but not inactive K851AJAK3. Coexpression of JAK3 enhanced the maximal transport rate without significantly modifying affinity of the carrier. Iglucose in SGLT1+JAK3 expressing oocytes was significantly decreased by WHI-P154 (11.2 µM). JAK3 increased the SGLT1 protein abundance in the cell membrane. Inhibition of carrier insertion by brefeldin A (5 µM) in SGLT1+JAK3 expressing oocytes resulted in a decline of Iglucose, which was similar in presence and absence of JAK3.
Conclusions:
SGLT1 is expressed in murine cytotoxic T cells and human Jurkat T cells and significantly contributes to glucose uptake in those cells post activation. JAK3 up-regulates SGLT1 activity by increasing the carrier protein abundance in the cell membrane, an effect enforcing cellular glucose uptake into activated lymphocytes and thus contributing to the immune response.
Cellular Physiology and Biochemistry
10.1159/000447827
urn:nbn:de:bvb:20-opus-164900
Cell Physiol Biochem 2016;39:1209-1228
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Shefalee K. Bhavsar
Yogesh Singh
Piyush Sharma
Vishal Khairnar
Zohreh Hosseinzadeh
Shaqiu Zhang
Monica Palmada
Ivan Sabolic
Hermann Koepsell
Karl S. Lang
Philipp A. Lang
Florian Lang
eng
uncontrolled
tumor cell
eng
uncontrolled
Cytotoxic T lymphocytes
eng
uncontrolled
Glucose uptake
eng
uncontrolled
Jurkat T cells
eng
uncontrolled
Energy depletion
eng
uncontrolled
Janus kinase
Medizin und Gesundheit
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16490/033_Bhavsar_CELLULAR PHYSIOLOGY AND BIOCHEMISTRY.pdf
16760
2016
eng
35215
6
article
1
2018-08-29
--
--
A Renal Olfactory Receptor Aids in Kidney Glucose Handling
Olfactory receptors (ORs) are G protein-coupled receptors which serve important sensory functions beyond their role as odorant detectors in the olfactory epithelium. Here we describe a novel role for one of these ORs, Olfr1393, as a regulator of renal glucose handling. Olfr1393 is specifically expressed in the kidney proximal tubule, which is the site of renal glucose reabsorption. Olfr1393 knockout mice exhibit urinary glucose wasting and improved glucose tolerance, despite euglycemia and normal insulin levels. Consistent with this phenotype, Olfr1393 knockout mice have a significant decrease in luminal expression of Sglt1, a key renal glucose transporter, uncovering a novel regulatory pathway involving Olfr1393 and Sglt1. In addition, by utilizing a large scale screen of over 1400 chemicals we reveal the ligand profile of Olfr1393 for the first time, offering new insight into potential pathways of physiological regulation for this novel signaling pathway.
Scientific Reports
10.1038/srep35215
urn:nbn:de:bvb:20-opus-167605
Scientific Reports 6:35215 (2016). DOI: 10.1038/srep35215
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Blythe D. Shepard
Lydie Cheval
Zita Peterlin
Stuart Firestein
Hermann Koepsell
Alain Doucet
Jennifer L. Pluznick
eng
uncontrolled
olfactory receptor
eng
uncontrolled
Olfr1393
eng
uncontrolled
kidney
eng
uncontrolled
glucose handling
Biowissenschaften; Biologie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16760/Shepard_Scientific_Reports.pdf
16767
2016
eng
26428
6
article
1
2018-08-29
--
--
Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice
Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.
Scientific Reports
10.1038/srep26428
urn:nbn:de:bvb:20-opus-167678
Scientific Reports 6:26428 (2016). DOI: 10.1038/srep26428
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Linda A. Gallo
Micheal S. Ward
Amelia K. Fotheringham
Aowen Zhuang
Danielle J. Borg
Nicole B. Flemming
Ben M. Harvie
Toni L. Kinneally
Shang-Ming Yeh
Domenica A. McCarthy
Hermann Koepsell
Volker Vallon
Carol Pollock
Usha Panchapakesan
Josephine M. Forbes
eng
uncontrolled
SGLT2 inhibitor
eng
uncontrolled
empagliflozin
eng
uncontrolled
glucose lowering agent
eng
uncontrolled
kidney disease
eng
uncontrolled
type 2 diabetes
Medizin und Gesundheit
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16767/Gallo_Scientific_Reports.pdf
17381
2017
eng
7
article
1
2018-12-07
--
--
Loss of endometrial sodium glucose cotransporter SGLT1 is detrimental to embryo survival and fetal growth in pregnancy
Embryo implantation requires a hospitable uterine environment. A key metabolic change that occurs during the peri-implantation period, and throughout early pregnancy, is the rise in endometrial glycogen content. Glycogen accumulation requires prior cellular uptake of glucose. Here we show that both human and murine endometrial epithelial cells express the high affinity Na\(^+\)-coupled glucose carrier SGLT1. Ussing chamber experiments revealed electrogenic glucose transport across the endometrium in wild type (\(Slc5a1^{+/+}\)) but not in SGLT1 defcient (\(Slc5a1^{−/−}\)) mice. Endometrial glycogen content, litter size and weight of offspring at birth were signifcantly lower in \(Slc5a1^{−/−}\) mice. In humans, \(SLC5A1\) expression was upregulated upon decidualization of primary endometrial stromal cells. Endometrial \(SLC5A1\) expression during the implantation window was attenuated in patients with recurrent pregnancy loss when compared with control subjects. Our fndings reveal a novel mechanism establishing adequate endometrial glycogen stores for pregnancy. Disruption of this histiotrophic pathway leads to adverse pregnancy outcome.
Scientific Reports
10.1038/s41598-017-11674-3
28974690
urn:nbn:de:bvb:20-opus-173814
Scientific Reports (2017) 7:12612. https://doi.org/10.1038/s41598-017-11674-3
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Madhuri S. Salker
Yogesh Singh
Ni Zeng
Hong Chen
Shaqiu Zhang
Anja T. Umbach
Hajar Fakhri
Ursula Kohlhofer
Leticia Quintanilla-Martinez
Ruban R. Peter Durairaj
Flavio S. V. Barros
Pavle Vrljicak
Sascha Ott
Sara Y. Brucker
Diethelm Wallwiener
Ivana Vrhovac Madunić
Davorka Breljak
Ivan Sabolić
Hermann Koepsell
Jan J. Brosens
Florian Lang
eng
uncontrolled
biology
eng
uncontrolled
embryology
eng
uncontrolled
intrauterine growth
eng
uncontrolled
paediatric research
Biowissenschaften; Biologie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17381/Salker_s41598-017-11674-3.pdf
18089
2017
eng
14
7
article
1
2019-05-20
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Sodium-myoinositol cotransporter-1, SMIT1, mediates the production of reactive oxygen species induced by hyperglycemia in the heart
Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy.
Scientific Reports
10.1038/srep41166
urn:nbn:de:bvb:20-opus-180891
Scientific Reports (2017) 7:41166. https://doi.org/10.1038/srep41166
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Anne Van Steenbergen
Magali Balteau
Audrey Ginion
Laura Ferté
Sylvain Battault
Christophe de Meester de Ravenstein
Jean-Luc Balligand
Evangelos-Panagiotis Daskalopoulos
Patrick Gilon
Florin Despa
Sanda Despa
Jean-Louis Vanoverschelde
Sandrine Horman
Hermann Koepsell
Gerard Berry
Louis Hue
Luc Bertrand
Christophe Beauloye
eng
uncontrolled
hyperglycemia
eng
uncontrolled
Sodium-myoinositol cotransporter-1 (SMIT1)
eng
uncontrolled
glucose metabolism
eng
uncontrolled
heart
eng
uncontrolled
NADPH oxidase 2 (NOX2)
eng
uncontrolled
sodium/glucose cotransporters (SGLT)
eng
uncontrolled
cardiomyocytes
Pflanzen (Botanik)
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18089/Steenbergen_ScientificReports_2017.pdf
17649
2018
eng
e0205109
10
13
article
1
2019-02-12
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--
Functional analysis of a triplet deletion in the gene encoding the sodium glucose transporter 3, a potential risk factor for ADHD
Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na\(^{+}\) currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes.
The cation conductance of hSGLT3[wt] was activated by application of glucose or the specific agonist 1-desoxynojirimycin (DNJ) as revealed by inward currents in the voltage clamp configuration and cell depolarization in the current clamp mode. Almost no currents and changes in membrane potential were observed when glucose or DNJ were applied to hSGLT3[ΔM500]-injected oocytes, demonstrating a loss of function by this amino acid deletion in hSGLT3. To monitor membrane targeting of wt and mutant hSGLT3, fusion constructs with YFP were generated, heterologously expressed in Xenopus laevis oocytes and analyzed for membrane fluorescence by confocal microscopy. In comparison to hSGLT3[wt] the fluorescent signal of mutant [ΔM500] was reduced by 43% indicating that the mutant phenotype might mainly result from inaccurate membrane targeting. As revealed by homology modeling, residue M500 is located in TM11 suggesting that in addition to the core structure (TM1-TM10) of the transporter, the surrounding TMs are equally crucial for transport/sensor function.
In conclusion, our findings indicate that the deletion [ΔM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance, which may, in interaction with other ADHD risk-related gene variants, influence the risk for ADHD in deletion carriers.
PLoS ONE
10.1371/journal.pone.0205109
urn:nbn:de:bvb:20-opus-176495
PLoS ONE 2018, 13(10):e0205109. DOI: 10.1371/journal.pone.0205109
602805
728018
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Nadine Schäfer
Maximilian Friedrich
Morten Egevang Jørgensen
Sina Kollert
Hermann Koepsell
Erhard Wischmeyer
Klaus-Peter Lesch
Dietmar Geiger
Frank Döring
eng
uncontrolled
Xenopus laevis oocytes
eng
uncontrolled
ADHD
eng
uncontrolled
glucose
eng
uncontrolled
cell membranes
eng
uncontrolled
membrane proteins
eng
uncontrolled
membrane potential
eng
uncontrolled
crystal structure
eng
uncontrolled
amino acid analysis
Biowissenschaften; Biologie
open_access
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Julius-von-Sachs-Institut für Biowissenschaften
Lehrstuhl für Molekulare Psychiatrie
OpenAIRE
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17649/Schaefer_PLoS_ONE.pdf
23065
2020
eng
29127-29139
45
5
article
1
2021-03-11
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Antidiabetic Effects of a Tripeptide That Decreases Abundance of Na\(^+\)-D-glucose Cotransporter SGLT1 in the Brush-Border Membrane of the Small Intestine
In enterocytes, protein RS1 (RSC1A1) mediates an increase of glucose absorption after ingestion of glucose-rich food via upregulation of Na+-D-glucose cotransporter SGLT1 in the brush-border membrane (BBM). Whereas RS1 decelerates the exocytotic pathway of vesicles containing SGLT1 at low glucose levels between meals, RS1-mediated deceleration is relieved after ingestion of glucose-rich food. Regulation of SGLT1 is mediated by RS1 domain RS1-Reg, in which Gln-Ser-Pro (QSP) is effective. In contrast to QSP and RS1-Reg, Gln-Glu-Pro (QEP) and RS1-Reg with a serine to glutamate exchange in the QSP motif downregulate the abundance of SGLT1 in the BBM at high intracellular glucose concentrations by about 50%. We investigated whether oral application of QEP improves diabetes in db/db mice and affects the induction of diabetes in New Zealand obese (NZO) mice under glucolipotoxic conditions. After 6-day administration of drinking water containing 5 mM QEP to db/db mice, fasting glucose was decreased, increase of blood glucose in the oral glucose tolerance test was blunted, and insulin sensitivity was increased. When QEP was added for several days to a high fat/high carbohydrate diet that induced diabetes in NZO mice, the increase of random plasma glucose was prevented, accompanied by lower plasma insulin levels. QEP is considered a lead compound for development of new antidiabetic drugs with more rapid cellular uptake. In contrast to SGLT1 inhibitors, QEP-based drugs may be applied in combination with insulin for the treatment of type 1 and type 2 diabetes, decreasing the required insulin amount, and thereby may reduce the risk of hypoglycemia.
ACS Omega
10.1021/acsomega.0c03844
urn:nbn:de:bvb:20-opus-230654
Lizenz: https://pubs.acs.org/page/policy/authorchoice_termsofuse.html
publish
ACS Omega 2020, 5, 29127−29139. DOI:10.1021/acsomega.0c03844
true
true
Christoph Otto
Alexandra Friedrich
Ivana Vrhovac Madunić
Christian Baumeier
Robert W. Schwenk
Dean Karaica
Christoph-Thomas Germer
Annette Schürmann
Ivan Sabolić
Hermann Koepsell, Hermann
eng
uncontrolled
chemistry
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Institut für Anatomie und Zellbiologie
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23065/acsomega.0c03844.pdf
23255
2020
eng
1207–1248
472
article
1
2021-03-31
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Glucose transporters in the small intestine in health and disease
Absorption of monosaccharides is mainly mediated by Na\(^+\)-d-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of d-glucose and d-galactose while GLUT5 is relevant for d-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal d-glucose concentrations, respectively. At high luminal d-glucose, the abundance SGLT1 in the BBM is increased. Hence, d-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity d-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease d-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between d-fructose transport and metabolism, are discussed.
Pflügers Archiv - European Journal of Physiology
0031-6768
10.1007/s00424-020-02439-5
urn:nbn:de:bvb:20-opus-232552
publish
Pflügers Archiv - European Journal of Physiology 472, 1207–1248 (2020). https://doi.org/10.1007/s00424-020-02439-5
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Hermann Koepsell
eng
uncontrolled
glucose transporter
eng
uncontrolled
small intestine
eng
uncontrolled
regulation
eng
uncontrolled
SGLT1
eng
uncontrolled
GLUT2
eng
uncontrolled
GLUT5
eng
uncontrolled
glucose-galactose malabsorption
eng
uncontrolled
fructose intolerance
eng
uncontrolled
diabetes
eng
uncontrolled
bariatric surgery
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23255/424_2020_Article_2439.pdf
23274
2020
eng
1299–1343
472
article
1
2021-04-01
--
--
Glucose transporters in brain in health and disease
Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters incapillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-D-glucosecotransporters SGLT1 are expressed. The glucose transporters mediate uptake of D-glucose across the blood-brain barrier anddelivery of D-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demandsin response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified andproposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based onexperiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and theircerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, andSGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functionalchanges of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy defi-ciency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome
Pflügers Archiv - European Journal of Physiology
0031-6768
10.1007/s00424-020-02441-x
urn:nbn:de:bvb:20-opus-232746
publish
Pflügers Archiv - European Journal of Physiology (2020) 472:1299–1343. https://doi.org/10.1007/s00424-020-02441-x
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Hermann Koepsell
eng
uncontrolled
glucosetransporter
eng
uncontrolled
brain
eng
uncontrolled
GLUT1
eng
uncontrolled
GLUT2
eng
uncontrolled
GLUT3
eng
uncontrolled
GLUT4
eng
uncontrolled
SGLT1
eng
uncontrolled
diabetes
eng
uncontrolled
Parkinson’s disease
eng
uncontrolled
stroke
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23274/424_2020_Article_2441.pdf