• Altered phenotype of NK cells from obses rats can be normalized by transfer into lean animals.

      Lautenbach, Anne; Wrann, Christiane D; Jacob, Roland; Muller, Guenter; Brabant, Georg E; Nave, Heike; Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. (2009)
    • Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample.

      Völzke, Henry; Nauck, Matthias; Rettig, Rainer; Dörr, Marcus; Higham, Claire E; Brabant, Georg E; Wallaschofski, Henri; Institute of Community Medicine Institute of Clinical Chemistry and Laboratory Medicine Institute of Physiology Department of Internal Medicine B, University of Greifswald, Greifswald D-17487, Germany. voelzke@uni-greifswald.de (2009-11)
      CONTEXT: It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations. OBJECTIVES: The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context. DESIGN: We analyzed data from the population-based Study of Health in Pomerania. METHODS: We used data from 3863 subjects (1971 women) aged 20-79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays. RESULTS: Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption. CONCLUSIONS: Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.
    • Central insulin action regulates peripheral glucose and fat metabolism in mice.

      Koch, Linda; Wunderlich, F Thomas; Seibler, Jost; Könner, A Christine; Hampel, Brigitte; Irlenbusch, Sigrid; Brabant, Georg E; Kahn, C Ronald; Schwenk, Frieder; Brüning, Jens C; et al. (2008-06)
      Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.
    • Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone.

      Monaghan, Phillip J; Owen, L J; Trainer, Peter J; Brabant, Georg E; Keevil, B G; Darby, Denise; Biochemistry Department, The Christie NHS Foundation Trust, Withington, Manchester M20 4BX, UK. phillip.monaghan@nhs.net (2011-09)
      The accurate measurement of cortisol by immunoassay is compromised by the potential for cross-reactivity of reagent antibodies with structurally related steroids present in serum. This susceptibility is potentiated when normal steroid metabolism is altered pharmaceutically by antisteroidogenic drugs utilized in the management of Cushing's syndrome to moderate cortisol production. The clinical implications of falsely elevated cortisol results include over-treatment and unrecognized hypoadrenalism. To investigate the effect of the 11β-hydroxylase inhibitor metyrapone on serum cortisol assay, a comparison of measurement by immunoassay versus liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted.
    • Diet-induced obesity alters behavior as well as serum levels of corticosterone in F344 rats.

      Buchenauer, T; Behrendt, P; Bode, F J; Horn, R; Brabant, Georg E; Stephan, M; Nave, H; Institute for Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany. (2009-12-07)
      Obesity is an increasing socio-economic health problem. Diet-induced obese (DIO) rodents are widely used as a model of obesity in humans. However, there is no comprehensive data about the behavioral phenotype of DIO rodents. Therefore, the aim of the present study was to determine whether a high-fat-diet changes behavioral patterns of DIO Fischer 344 (F344) rats in comparison with lean littermates. The behavioral tests (homecage, holeboard, social interaction, and hotplate) were performed in 28 normal-weight and 28 male DIO F344 rats (mean age: 16 weeks) and revealed a significantly higher level of anxiety- and aggression-related parameters in obese rats, whereas their pain threshold was significantly lower. Fitting to a different behavioral response, basal corticosterone levels (measured by RIA) of obese animals were significantly elevated (16.0ng/ml vs. 12.5ng/ml; p<0.01). We conclude that obese rats differ in various aspects from their lean littermates. The altered behavioral characteristics displayed by DIO F344 rats have to be considered in further experiments involving DIO rodents.
    • Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats

      Behrendt, Patrick; Buchenauer, Tobias; Horn, Rüdiger; Brabant, Georg E; Jacobs, Roland; Bode, Felix; Stephan, Michael; Nave, Heike (2010)
    • Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells.

      Zheng, Xuqin; Cui, Dai; Xu, Shuhang; Brabant, Georg E; Derwahl, Michael; Division of Endocrinology, Department of Medicine, St Hedwig Hospital and Humboldt University, D-10115 Berlin, Berlin, Germany. (2010-08)
      Current chemotherapy with doxorubicin fails to eradicate anaplastic thyroid cancer or even to stop tumor progress which may be due to the failure of these drugs to effectively target putative cancer stem cells. To test this hypothesis, anaplastic thyroid cell lines were characterized by FACS for their content of cancer stem cells, their in vitro sphere-forming capacity and their expression of multidrug resistance transporters of the ABC gene family which may confer drug resistance to the cells. Cells were treated with doxorubicin in short-term and long-term culture up to 6 months to establish a resistant cell line. The survival of cancer and cancer stem cells and the differential expression of transporters were analyzed. Anaplastic thyroid cancer cell lines that consisted of 0.4-0.8% side population cells, expressed ABCG2 and multi-drug-resistant 1 (MDR1) transporters. Treatment with doxorubicin gradually killed the non-side population of cancer cells derived from anaplastic thyroid carcinoma cells. This conferred a growth advantage to cancer stem cells which in turn overgrew the culture. Resistant cell line consisted of a 70% side population fraction enriched with Oct4-positive cancer stem cells. Inhibition of ABCG2 and/or MDR1 revealed that resistance of cancer stem cells to doxorubicin may be mainly due to the expression of these ABC transporters that were highly up-regulated in the resistant subline. The poor outcome of chemotherapy with doxorubicin in anaplastic thyroid carcinoma may be partly explained by up-regulation of ABCG2 and MDR1 transporters that confers resistance to cancer stem cells. Thus an effective treatment of anaplastic thyroid cancer has not only to destroy cancer cells that represent the bulk of tumor cell population but also cancer stem cells that may drive tumor progression.
    • Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy.

      Nettekoven, Sina; Ströhle, Alexander; Trunz, Birgit; Wolters, Maike; Hoffmann, Susanne; Horn, R; Steinert, Martin; Brabant, Georg E; Lichtinghagen, Ralf; Welkoborsky, Hans-Jürgen; et al. (2008-12)
      Reports of decreased serum 25-hydroxyvitamin D (25-OHD) and altered bone metabolism associated with antiepileptic drug (AED) treatment are inconsistent and predominantly restricted to adults. In this cross-sectional observational study, the aim was to evaluate the influence of AED treatment on vitamin D status and markers of bone turnover in children with epilepsy. In 38 children taking AEDs and 44 healthy control subjects, blood samples were collected to determine the levels of serum 25-OHD, intact parathyroid hormone (iPTH), calcium (Ca), phosphate (P), bone alkaline phosphatase (BAP), osteocalcin (OC) and C terminal telopeptide of type I collagen (ICTP). More than 75% of the patients were vitamin D deficient (serum 25-OHD<20 ng/mL) and 21% of the patients had an insufficient vitamin D status (serum 25-OHD=20-30 ng/mL). In the patients, the serum levels of OC (p = 0.002) and BAP (p < 0.001) were significantly increased, but ICTP (p = 0.002) concentrations were significantly decreased compared with the control group. When patients where divided into two groups according to their medication (mono- or polytherapy), significantly lower 25-OHD (p = 0.038) and ICTP (p = 0.005) levels and elevated BAP (p = 0.023) concentrations were found in patients under polytherapy. An association between 25-OHD and the measured bone markers could not be determined. Our results indicate that the prevalence of vitamin D deficiency in epilepsy patients under AED treatment is high, especially under polytherapy, and alteration markers of bone formation and resorption suggests an accelerated skeletal turnover. The routine monitoring of serum 25-OHD and vitamin D supplementation on an individual basis should be considered.
    • Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?

      Brabant, Georg E; Poll, E M; Jonsson, P; Polydorou, D; Kreitschmann-Andermahr, Ilonka; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX. (2009)
    • Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay.

      Hoefig, C S; Köhrle, J; Brabant, Georg E; Dixit, Kashinath C S; Yap, Beng K; Strasburger, C J; Wu, Z; Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. (2011-06)
      Thyronamines are thyronergic metabolites of thyroid hormones. Lack of reliable and sensitive detection methods for endogenous 3-iodothyronamine (3-T(1)AM) has so far hampered progress in understanding their physiological action and role in endocrine homeostasis or pathophysiology of diseases.
    • Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas.

      Burrows, N; Resch, J; Cowen, R L; Von Wasielewski, R; Hoang-Vu, C; West, Catharine M L; Williams, K J; Brabant, Georg E; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2010-03)
      Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1 alpha and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 alpha was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 alpha staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1 alpha pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O(2), anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 alpha in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1 alpha and HIF-1 alpha targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1 alpha with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
    • Five commercially available insulin-like growth factor I (IGF-I) assays in comparison to the former Nichols Advantage IGF-I in a growth hormone treated population.

      Krebs, Alexander; Wallaschofski, Henri; Spilcke-Liss, Elisabeth; Kohlmann, Thomas; Brabant, Georg E; Völzke, Henry; Nauck, Matthias; Institute of Clinical Chemistry and Laboratory Medicine, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany. alexander.krebs@uni-greifswald.de (2008)
      BACKGROUND: The serum insulin-like growth factor I (IGF-I) level is accepted to diagnose the growth hormone (GH) status. Here, we evaluated the DRG IGF-I 600 ELISA, DSL IGF-I ELISA, IDS OCTEIA IGF-I, Mediagnost IGF-I-ELISA, and the Siemens Immulite 2500 IGF-I in comparison to the former Nichols Advantage IGF-I assay. METHODS: Imprecision was determined by use of a serum pool and commercial control materials. Accuracy was evaluated by means of a method comparison to Nichols in 173 serum samples of GH deficient patients. RESULTS: The Siemens and the IDS IGF-I assays showed the lowest imprecision with coefficients of variation up to 3.6% and 6.9%, respectively. Both correlated best to Nichols (Siemens: y=0.667X+8.8 microg/L, r=0.950; IDS: y=0.527 X+4.6 microg/L, r=0.927) with the lowest dispersion of residuals from a linear equation. The DSL assay had the highest comparability to Nichols (y=1.000 X+35.5 microg/L, r=0.864), but with a considerable scattering. CONCLUSIONS: To yield IGF-I determination comparable to the former Nichols IGF-I, either the Siemens or the IDS assay should be applied, and the results should be converted by a linear method transformation. Where a conversion factor is not desired, the DSL assay should be selected.
    • GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways.

      Burrows, N; Babur, M; Resch, Julia; Ridsdale, S; Mejin, M; Rowling, E; Brabant, Georg E; Williams, K; Hypoxia and Therapeutics Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. (2011-12)
      Phosphoinositide 3-kinase (PI3K) regulates the transcription factor hypoxia-inducible factor-1 (HIF-1) in thyroid carcinoma cells. Both pathways are associated with aggressive phenotype in thyroid carcinomas.
    • High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (SIADH).

      Kenz, Sami; Haas, C S; Werth, S C; Bohnet, S; Brabant, Georg E; The Christie Hospital NHS Foundation Trust, Manchester (2011-12)
    • Human growth hormone-related iatrogenic Creutzfeldt-Jakob disease--being aware of diagnostic features 25 years later.

      Dixit, Kashinath C S; Kreitschmann-Andermahr, Ilonka; Basu, Ambar; Dick, Jeremy P R; Manoharan, Prakash; Shalet, Stephen M; Brabant, Georg E; Department of Endocrinology, The Christie, Manchester, United Kingdom. kashinath.dixit@yahoo.com (2009-08)
    • Hypothyroidism following childhood cancer therapy-an under diagnosed complication.

      Brabant, Georg E; Toogood, Andy; Shalet, Stephen M; Frobisher, Clare; Lancashire, Emma R; Reulen, Raoul C; Winter, David L; Hawkins, Michael M; Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, United Kingdom. georg.brabant@manchester.ac.uk. (2011-03-28)
      To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis (n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD (p = 0.0001) or a CNS neoplasm (p < 0.00005) but not leukaemia (p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care (p = 0.004) and hospital follow-up (p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings.
    • The Interface between thyroid and diabetes mellitus.

      Duntas, L H; Orgiazzi, J; Brabant, Georg E; Endocrine Unit, Evgenidion Hospital, University of Athens Medical School, Athens, Greece (2011-02-24)
      Thyroid disease and type 1 but also type 2 diabetes mellitus are strongly associated and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with diabetes mellitus and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH.
    • Long-term safety of growth hormone replacement after CNS irradiation.

      Mackenzie, S; Craven, T; Gattamaneni, Rao; Swindell, Ric; Shalet, Stephen M; Brabant, Georg E; Department of Endocrinology, The Christie, Manchester Academic Health Science Centre, Wilmslow Road, Manchester M20 4BX, United Kingdom. (2011-09)
      Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk.
    • Measurement of salivary cortisol with liquid chromatography-tandem mass spectrometry in patients undergoing dynamic endocrine testing.

      Perogamvros, Ilias; Owen, Laura J; Keevil, Brian G; Brabant, Georg E; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-03-19)
      Objective: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) eliminates cross-reactivity, which is a major limitation of immunoassays used for the measurement of salivary cortisol (SalC). We aimed to evaluate the potential of SalC measured by LC-MS/MS in patients undergoing assessment of the HPA axis. Design and patients: Cross-sectional study of 78 patients admitted for routine testing in a specialized endocrine unit. Measurements: Matched serum and saliva samples were collected from 68 patients who had a Short Synacthen Test (SST, 250 mcg IM) and 10 patients who had an Insulin Tolerance Test (ITT, insulin 0.15 U/kg IV). Serum cortisol (SerC) was measured with an automated immunoassay and SalC with LC-MS/MS. Adequate SerC responses were >500 nmol/l. Results: In all patients with adequate responses the relative increase in SalC was significantly higher than in SerC [6.4(0.3-26.1) vs 1.0(0.3-4.9), P<0.0001)]. The SerC-SalC relationship was better explained by an exponential rather than a linear model (R(2)=0.83 vs R(2)=0.65, both P<0.0001). Based on 59 patients with adequate SerC responses to an SST, an adequate SalC response was defined as 8.3 nmol/l. 7 patients following an SST and 3 patients following an ITT showed inadequate responses in both SerC and SalC, but two patients with CBG deficiency showed a low SerC with normal SalC. Conclusions: We have shown an excellent diagnostic sensitivity and specificity of LC-MS/MS SalC in the assessment of the HPA axis and superiority over SerC when CBG levels are altered. The exponential relationship between SerC and SalC supports the concept of CBG binding capacity saturation.
    • More than a prolactinoma.

      Basu, Ambar; Brabant, Georg E; Gnanalingham, K K; Department of Endocrinology, Christie Hospital, Manchester, UK. (2008-05-07)