1,721,039 research outputs found
Glucagon-like Peptide‑1 (GLP-1) Receptor Agonists—The New Super Weapons in Obesity Therapy?
No full textZusammenfassung Adipositas ist einechronische Krankheit mit hoher und immer noch steigender Prävalenz und vielen Begleiterkrankungen, was sie zu einem wachsenden globalen Problem macht. Eine effektive und nachhaltige Gewichtsreduktion war bisher oft nur durch die metabolische Chirurgie zu erreichen. Bisherige adjuvante medikamentöse Therapien waren wenig effektiv. „Glucagon-like peptide‑1“-Rezeptor-Agonisten (GLP-1-RA), die zur Behandlung von Typ-2-Diabetes eingesetzt werden, haben sich in präklinischen und klinischen Studien als wirksam bei der Förderung der Gewichtsabnahme erwiesen und ihre Weiterentwicklung ist im vollen Gang. Diese Übersicht fasst aktuelle Studien zusammen, die mit GLP-1-RA und verwandten Inkretinmimetika durchgeführt wurden. Sie gibt dabei einen Überblick über die maximal erreichbare Gewichtsabnahme durch bereits verfügbare Substanzen sowie neue Entwicklungen und skizziert aber auch noch offenstehende Fragen.Abstract Obesity is a chronic disease with a high and still increasing prevalence and many comorbidities, making it a growing global problem. Achieving effective and sustainable weight loss has often only been possible through metabolic surgery. Previous adjuvant drug therapies have been less effective. Glucagon-like peptide‑1 agonists (GLP-1-RA) used to treat type 2 diabetes have been shown to be effective in promoting weight loss in preclinical and clinical studies and their further development is ongoing. This review summarizes recent studies conducted with GLP‑1-RA and related incretin mimetics. This article provides the reader a review of the maximum achievable weight loss (in percent) with available substances as well as new developments, but also outlines questions that are still open.Zusammenfassung Adipositas ist einechronische Krankheit mit hoher und immer noch steigender Prävalenz und vielen Begleiterkrankungen, was sie zu einem wachsenden globalen Problem macht. Eine effektive und nachhaltige Gewichtsreduktion war bisher oft nur durch die metabolische Chirurgie zu erreichen. Bisherige adjuvante medikamentöse Therapien waren wenig effektiv. „Glucagon-like peptide‑1“-Rezeptor-Agonisten (GLP-1-RA), die zur Behandlung von Typ-2-Diabetes eingesetzt werden, haben sich in präklinischen und klinischen Studien als wirksam bei der Förderung der Gewichtsabnahme erwiesen und ihre Weiterentwicklung ist im vollen Gang. Diese Übersicht fasst aktuelle Studien zusammen, die mit GLP-1-RA und verwandten Inkretinmimetika durchgeführt wurden. Sie gibt dabei einen Überblick über die maximal erreichbare Gewichtsabnahme durch bereits verfügbare Substanzen sowie neue Entwicklungen und skizziert aber auch noch offenstehende Fragen.Abstract Obesity is a chronic disease with a high and still increasing prevalence and many comorbidities, making it a growing global problem. Achieving effective and sustainable weight loss has often only been possible through metabolic surgery. Previous adjuvant drug therapies have been less effective. Glucagon-like peptide‑1 agonists (GLP-1-RA) used to treat type 2 diabetes have been shown to be effective in promoting weight loss in preclinical and clinical studies and their further development is ongoing. This review summarizes recent studies conducted with GLP‑1-RA and related incretin mimetics. This article provides the reader a review of the maximum achievable weight loss (in percent) with available substances as well as new developments, but also outlines questions that are still open
Carbohydrate metabolism and the liver: Actual aspects from physiology and disease
No full textThe liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. This is achieved by a tightly regulated system of enzymes and kinases regulating either glucose breakdown or synthesis in hepatocytes. This process is under the control of glucoregulatory mediators among which insulin plays a key role. In type 2 diabetes, as well as in liver disease, alterations in hepatic glucose metabolism like an increased post-absorptive glucose production together with diminished glucose uptake following carbohydrate ingestion occur, implying insulin resistance as a central pathological principle. Knowledge of the processes involved in maintaining glucose homeostasis as well as insulin resistance is a prerequisite to develop new therapeutic approaches in diabetes as well as in liver disease. In the recent years, genetically-altered mouse models that have helped to identify enzymes, transcription factors and mediators that are essential for maintaining glucose homeostasis in the liver and provide a valuable tool to study carbohydrate metabolism in liver disease. In this current review, genetically manipulated animals either overexpressing or lacking key gluconeogenic enzymes, hepatic transcription factors, IGF-1, hepatic insulin receptors, adipokines and hepatitis C core antigen will be discussed in the context of human disease
Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome
No full textObjective The objective of this study was to quantitatively determine cytokine mRNA expression in inflammatory bowel disease under different clinical conditions including active disease, remission or an impaired response to a glucocorticoid (GC) therapy. Methods Mucosal biopsies were taken from 33 patients with ulcerative colitis (UC), 21 patients with Crohn's disease (CD) and 11 controls. Peripheral blood mononuclear cells (PBMNC) were isolated from 24 CU patients, 18 CD patients and 11 controls. Cytokine-mRNA [interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha)] expression was measured by quantitative reverse transcriptase-polymerase chain reaction in biopsies and PBMNC, and correlated to endoscopic findings, clinical activity and outcome after 6 months GC therapy. Results IL-1 beta, IL-6 and TNF-alpha were the largely dominating cytokines. In contrast to IL-1 beta and TNF-alpha-, IL-6 expression was restricted to inflamed mucosa and correlated with the clinical activity and C-reactive protein levels in cases of pancolitis ulcerosa. TNF-alpha was elevated in CD even in endoscopic normal tissue. IL-2 and IFN-gamma were down-regulated in PBMNC from CID and UC. No Th1 or Th2 specificity could be detected. Cytokine mRNA levels did not correlate with the response to a GC therapy. Conclusion IL-6 sharply distinguishes between inflamed and non-inflamed mucosa, and is therefore a suitable marker of intestinal inflammation. Its selective expression in the inflammatory site makes it an interesting target for future therapeutic strategies. TNF-alpha overexpression even in remission suggests a key role of this cytokine in CD pathogenesis and is possibly a feature that allows one to differentiate CD from UC. (c) 2005 Lippincott Williams & Wilkins
Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2: evidence of inhibition by interleukin-1 beta
No full textBackground and aims: Glucocorticoids are potent anti-inflammatory drugs widely used in the treatment of inflammatory bowel disease, but many patients do not benefit from glucocorticoid therapy (glucocorticoid resistance) or need inappropriately high doses to retain remission (glucocorticoid dependency). Because of the role of intestinal epithelial cells in inflammatory bowel disease we examined glucocorticoid receptor signaling and the effect of interleukin-1 beta as one of the main proinflammatory cytokines in the intestinal epithelial cell lines IEC-6 and Caco-2. Methods: Dexamethasone effects on transcriptional activation was measured by reporter gene assay using a construct containing glucocorticoid-responsive elements. The transrepressive effect was monitored by a nuclear factor (NF) kappaB inducible reporter construct. In addition in IEC-6 cells immuncytochemistry was used to monitor glucocorticoid receptor translocation. Results: Dexamethasone induced receptor-mediated reporter gene transcription and receptor translocation, while interleukin-1 beta significantly inhibited dexamethasone effects. Dexamethasone inhibited interleukin-1 beta induced, NF-kappaB driven gene transcription only in IEC-6 and not in Caco-2 cells. However, in Caco-2 cells glucocorticoid receptor overexpression resulted in a marked decrease in NF-kappaB activity even in absence of dexamethasone. Conclusions: These studies demonstrate that glucocorticoid receptor driven gene regulation in intestinal epithelial cells may contribute to the anti-inflammatory effects of glucocorticoids in inflammatory bowel disease. Our data are consistent with the notion that interleukin-1 beta produced during inflammatory response induces steroid resistance, which is a common clinical problem in treating patients with inflammatory bowel disease
EndoBarrier Gastrointestinal Liner in Type 2 Diabetic Patients Improves Liver Fibrosis as Assessed by Liver Elastography
No full textMany obese people with type 2 diabetes develop non-alcoholic fatty liver disease, which may progress to liver fibrosis. EndoBarrier gastrointestinal liner is an innovative interventional treatment option for type 2 diabetic patients, which could affect diabetes associated liver disease. The aim of this retrospective study was to analyze the effect of 1-year EndoBarrier therapy on liver fibrosis and steatosis. As an indicator of fibrosis, liver stiffness was assessed by liver elastography at baseline, 2 weeks after EndoBarrier implantation and then every 3 months until explantation. 13/19 patients had elevated liver stiffness at baseline, corresponding to liver fibrosis grade 2 to 4. In these patients, liver stiffness reduced significantly during EndoBarrier therapy from 10.4kPa (IQR 6.0-14.3) at baseline to 5.3kPa (IQR 4.3-7.7, p < 0.01) by the time of EndoBarrier explantation, corresponding to a normalization of the initially pathologic findings in most patients. Liver steatosis was also assessed by elastographic measurements in terms of the controlled attenuation parameter. In all patients, baseline measurements showed high grade steatosis. Improvements were seen from initially 343 dB/m (IQR 326-384) to 317 dB/m (IQR 269-375, p < 0.05) by the time of explantation. However, most patients were still classified high grade steatosis after completion of EndoBarrier treatment. In this observational study, we show that liver fibrosis is a common condition in obese patients suffering from type 2 diabetes, and that EndoBarrier gastrointestinal liner substantially improves liver fibrosis in these patients
Influence of NFκB inhibitors on IL-1β-induced chemokine CXCL8 and -10 expression levels in intestinal epithelial cell lines: glucocorticoid ineffectiveness and paradoxical effect of PDTC
Full text linkActivation of intestinal epithelial cell (IEC) nuclear factor kappa B (NF kappa B) and the consequent chemokine upregulation are crucial events in inflammatory bowel disease (IBD) pathogenesis. Not much is known about the consequences of NF kappa B inhibition in terms of chemokine expression in intestinal cells. Therefore, we aimed to evaluate the efficacy of compounds known to disrupt the NF kappa B pathway on NF kappa B transcriptional activity and CXCL8 and CXCL10 gene expression in intestinal cell lines. The influence of NF kappa B inhibitors (dexamethasone, pyrrolidine dithiocarbamate (PDTC) and BAY 11-7082) on IL-1 beta-induced NF kappa B transcriptional activity was investigated by transient transfection of Caco-2 cells with an NF kappa B-secreted alkaline phosphatase reporter plasmid. Il-1 beta stimulated CXCL8 and CXCL10 mRNA and protein expression and was studied in Caco-2 and HT29 cells in the presence and absence of the NF kappa B inhibitors by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent serologic assay, respectively. To reveal alternative signalling cascades, experiments were also performed in the presence of the p38MAPK inhibitor SB 203580 and the ERK inhibitor PD 98059. Dexamethasone did not downregulate chemokine expression sufficiently, probably due to a lack of glucocorticoid receptors in these cells. While BAY11-7082 inhibited chemokine expression, PDTC led to a paradoxical upregulation of CXCL8 in Caco-2 cells, which could be prevented by inhibition of p38MAPK. These data explain the frequent unresponsiveness of IBD to glucocorticoid treatment and suggest that alternative NF kappa B inhibition in IECs might be of use in IBD therapy. Drug development based on measuring anti-NF kappa B activity might be misleading and should therefore also include studies on relevant gene products
NF-κB-dependent synergistic regulation of CXCL10 gene expression by IL-1β and IFN-γ in human intestinal epithelial cell lines
No full textBackground and aims Little is known about the intestinal epithelial expression and secretion of CXCL10 (IP-10), a chemokine involved in recruiting T cells and monocytes. We aimed to study CXCL10 gene expression and regulation by the pro-inflammatory cytokines interleukin (IL)-1 beta, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in intestinal epithelial cell lines. Materials and methods CXCL10 expression and secretion kinetics were assessed in Caco-2, HT-29 and DLD1 human colon epithelial cells, treated with IL-1 beta, TNF-alpha, IFN-gamma alone or in combination with each other by real-time polymerase chain reaction (PCR), Northern blotting and enzyme-linked immunoabsorbent assay (ELISA). Transient transfections with TGL-IP10 (CXCL10 promoter) and TGL-IP10-kappa B2 mutant promoter and gelshifts and supershifts for nuclear factor (NF)-kappa B were also performed. Results Real-time PCRs and ELISA experiments revealed that IL-1 beta was the strongest and earliest inducer of CXCL10 messenger ribonucleic acid (mRNA) expression and protein secretion in Caco-2 cell line, whereas INF-gamma had a delayed kinetics. There was a strong synergistic effect of either TNF-alpha or IL-1 beta with IFN-gamma both on CXCL10 mRNA expression and protein secretion in all three cell lines. Real-time PCR and ELISA experiments using a specific NF-kappa B inhibitor and transfection experiments with a NF-kappa B-binding defective CXCL10 promoter construct revealed that the induction of CXCL10 by IL-1 beta and its synergism with IFN-gamma is NF-kappa B dependent. Conclusion These data demonstrate that in colonic epithelial cells, depending on the cellular context and utilizing the NF-kappa B pathway, IL-1 beta alone and/or in synergism with IFN-gamma may play a major role in the induction of CXCL10
Gelenkbeteiligung bei Akromegalie
No full textZusammenfassungDie Akromegalie ist eine seltene Erkrankung, welche in den meisten Fällen aus einer hypophysären Überproduktion von Wachstumshormon (GH – Growth Hormone) resultiert. Der in der Folge anhaltende IGF-1(Insulin like Growth Factor-1)-Exzess bewirkt zahlreiche morphologische und metabolische Veränderungen des Organismus inklusive Organomegalie, arterieller Hypertonie und Diabetes mellitus. Insbesondere die kardiovaskuläre Morbidität nimmt zu, diese ist auch hauptverantwortlich für vermehrte Sterblichkeit der Betroffenen. Wiewohl nicht prognoseentscheidend, manifestiert sich die Erkrankung gleichfalls am Bewegungsapparat. Drei Komplikationen sind relevant: eine Arthropathie größerer Gelenke, lumbale Wirbelsäulenveränderungen sowie das Karpaltunnelsyndrom. Die Behandlung dieser Komplikationen unterscheidet sich nicht von der Therapie anderer Krankheitsmanifestationen: entscheidend ist die Beseitigung des GH-/IGF-1-Exzesses. Je früher die Diagnose gestellt und die Behandlung eingeleitet wird, desto besser ist die Prognose, sind doch ossäre/artikuläre Veränderungen in vielen Fällen irreversibel.</jats:p
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