Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion.

To clarify the physiological role of Na(+)-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1(-/-) mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1(-/-) mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ∼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2

Risk governance in organizations

Dieses Buch dokumentiert 10 Jahre Risk-Governance-Forschung an der Universität Siegen. In 50 Beiträgen reflektieren Forscher und Praktiker Risk Governance vor dem Hintergrund ihrer eigenen Forschungen und/oder Erfahrungen und geben jeweils einen Entwicklungsimpuls für die Zukunft der Risk Governance. Das Buch zeigt die große Bandbreite und Tiefe des Forschungsgebietes auf und diskutiert Grundannahmen, Implementierungsfragen, die Rolle der Risk Governance als Transformationsmotor, ihre Wirkung in den verschiedenen betrieblichen Funktionen, Entwicklungsperspektiven und den Beitrag der Risk Governance zu einer nachhaltigen Ausrichtung von Unternehmen.This book documents 10 years of risk governance research at the University of Siegen. In 50 contributions, researchers and practitioners reflect on risk governance against the background of their own research and/or experience and provide a development impetus for the future of risk governance. The book shows the wide range and depth of the research field and discusses basic assumptions, implementation issues, the role of risk governance as transformation engine, its impact in the various operational functions, development perspectives, and the contribution of risk governance to a sustainable orientation of companies

Acute- and long-term effects of Na+/H+ exchanger isoform 1 inhibitors on acid secretion and survival in cultured gastric rabbit parietal cells

Na+/H+-Austauscher (NHE) sind ubiquitär exprimierte Proteine mit wichtigen zellulären Aufgaben bei der Regulation von pHi-, Volumen-, Salz- und Wasserhaushalt. Im Magenepithel ist Na+/H+ Austausch mitverantwortlich für die Aufrechterhaltung des Schutzes der Mukosa vor der hohen luminalen Säurekonzentration, wird aber auch bei der Säuresekretion aktiviert und ist bei der Volumenregulation der Parietalzellen wesentlich beteiligt. Im Magenepithel werden vier verschiedenen NHE Isoformen exprimiert. In dieser Arbeit wurde untersucht, ob NHE Hemmstoffe unterschiedlicher Substanzklassen Einfluss auf die Säuresekretion haben. Keine Substanz inhibierte akut die als 14C-Aminopyrin-Aufnahme gemessene, Forskolin-stimulierte Säuresekretion. Eine NHE Hemmung über den Zeitraum von 3 Tagen konnte jedoch eine Reduktion der maximalen Säuresekretion bewirken. Dieser Effekt war bei NHE1 und NHE2 Hemmung stärker ausgeprägt als bei alleiniger NHE1 Hemmung. Um zu klären, ob die Abnahme der Säuresekretion auf Zytotoxizität der Hemmstoffe und ein daraus resultierendes Absterben der Parietalzellen zurückzuführen ist, wurde die Zellzahl bei 3 tägiger NHE Hemmung untersucht. Hierbei zeigte sich, dass die Apoptoserate der Parietalzellen nicht gesteigert war. Parietalzellen zeigen nach Forskolin-Stimulation eine rasche Zellschrumpfung, gefolgt von anschließender Volumenerholung. Da die Volumenregulation durch Na+/H+ Austausch mediiert wird, wurde die Wirkung der Inhibitoren auf die Volumenregulation untersucht. Dabei fand sich, dass alle Substanzen die Volumenregulation hemmen. Die hierbei verwendeten Konzentrationen lassen die Aussage zu, dass nach Forskolin-Stimulation der Parietalzellen entweder NHE1, NHE2 oder beide Isoformen an der Volumenregulation beteiligt sind. Die durchgeführten Experimente zeigen, dass eine Hemmung der Na+/H+ Austauscher Isoformen NHE1/NHE2 keinen akuten Effekt auf die Säurebildung von kultivierten Parietalzellen hat, aber die Fähigkeit zur Volumenregulation einschränkt. Dies könnte eine Erklärung für die Langzeiteffekte der NHE Inhibitoren auf die maximale Säuresekretionskapazität von kultivierten Parietalzellen sein, sowie für die Veränderungen der Magenepithelstruktur in NHE1 und NHE2 defizienten Mäusen.Na+/H+ exchanger (NHE) are ubiquitously expressed proteins with important cellular functions on intracellular pH, volume, ion and water homeostasis. In the gastric epithelium Na+/H+ exchange is responsible for the maintenance of mucosa protection to the high luminal proton concentration, is activated during acid secretion and also involved in parietal cell volume regulation. The gastric epithelium expresses 4 different NHE isoforms. Aim of this study was to investigate the effect of different NHE inhibitors on acid secretion. No substance inhibited forskolin-stimulated acid formation, measured as 14C-aminopyrine uptake ratio. However, incubation for three days prior to stimulation decreased maximal acid secretory capacity in concentrations that were fully inhibitory for NHE1, and even more so when NHE2 was also inhibited. To test if there was a direct toxic effect of the NHE inhibitors on parietal cells in culture, cell survival after a three day incubation period was determined. The cell number of the inhibitor treated cells was not significantly different from the control cells. In parietal cells NHE are also involved in volume regulation, therefore the effect of NHE inhibitors on volume regulation was investigated. After forskolin-stimulation parietal cells show an initial cytoplasmatic shrinkage followed by rapid volume recovery. All inhibitors showed a marked inhibition of the forskolin induced shrinkage and the regulatory volume increase. The used concentrations indicate that NHE1, NHE2 or both isoforms are involved in parietal cell volume regulation. In conclusion, this data indicate that acute NHE1 and NHE2 inhibition in cultured parietal cells had no effect on forskolin-stimulated acid secretion but reduce the capability to regulate their cell volume. This maybe one explanation for the long-term inhibitory effects of NHE inhibitors on maximal acid secretory capacity in cultured rabbit parietal cells and could also explain the histological changes in the gastric mucosa of NHE1 and NHE2 knockout mice

Development of SGLT1 and SGLT2 inhibitors

Sodium-glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism

ATP and adenosine in the local regulation of water transport and homeostasis by the kidney

Regulation of body water homeostasis is critically dependent on the kidney and under the control of AVP, which is released from the neurohypophysis. In the collecting duct (CD) of the kidney, AVP activates adenylyl cyclase via vasopressin V2 receptors. cAMP-dependent activation of protein kinase A phosphorylates the water channel aquaporin-2 and increases water permeability by insertion of aquaporin-2 into the apical cell membrane. However, local factors modulate the effects of AVP to fine tune its effects, accelerate responses, and potentially protect the integrity of CD cells. Nucleotides like ATP belong to these local factors and act in an autocrine and paracrine way to activate P2Y2 receptors on CD cells. Extracellular breakdown of ATP and cAMP forms adenosine, the latter also induces specific effects on the CD by activation of adenosine A1 receptors. Activation of both receptor types can inhibit the cAMP-triggered activation of protein kinase A and reduce water permeability and transport. This review focuses on the role and potential interactions of the ATP and adenosine system with regard to the regulation of water transport in the CD. We address the potential stimuli and mechanisms involved in nucleotide release and adenosine formation, and discuss the corresponding signaling cascades that are activated. Potential interactions between the ATP and adenosine system, as well as other factors involved in the regulation of CD function, are outlined. Data from pharmacological studies and gene-targeted mouse models are presented to demonstrate the in vivo relevance to water transport and homeostasis