Johannes W. Dietrich

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• The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

  Authors: Giebelstein J, Poschmann G, Højlund K, Schechinger W, Dietrich JW, Levin K, Beck-Nielsen H, Podwojski K, Stühler K, Meyer HE, Klein HH

  Diabetologia. 55.

  Aims/hypothesis The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance inAims/hypothesis The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. Methods Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic–euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification. Results Forty-four protein spots displayed significant (p < 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. Conclusions/interpretation Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fast-twitch pattern in the absence of marked changes in fibre-type distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.

• The parathyroid as a target for radiation damage.

  Authors: Bernhard O Boehm, Silke Rosinger, David Belyi, Johannes W Dietrich

  The New England journal of medicine. 365(7):676-8.

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• Protection from diabetes development by single-chain antibody-mediated delivery of a NF-{kappa}{kappa}B inhibitor specifically to {beta}{beta}-cells in vivo.

  Authors: Sandra Ueberberg, Timo Deutschbein, Harald H Klein, Johannes W Dietrich, Sara Akinturk, Nora Prochnow, Ralph Schirrmacher, Stephan Schneider

  American journal of physiology. Endocrinology and metabolism.

  Recently, we reported the generation of single-chain antibodies (SCAs) highly specific for rodent and human β-cells. Our current report describes the generation of a fusion protein of one of theseRecently, we reported the generation of single-chain antibodies (SCAs) highly specific for rodent and human β-cells. Our current report describes the generation of a fusion protein of one of these SCAs (SCA B1) with a NF-κB essential modifier (NEMO)-Binding Domain (NBD) peptide thereby creating a selective inhibitor of NF-κB activation in β-cells. The SCA B1-NBD fusion protein was cloned in the pIRES-EGFP, expressed in bacteria and purified by metal affinity chromatography; the newly generated complex was then intravenously administered to rodents and evaluated for its ability to protect β-cells against cytokines in vitro and diabetogenic agents in vivo. Firstly, it was clearly shown that our SCA B1-NBD fusion protein binds highly selective to CD rat β-cells in vivo. Secondly, we observed that SCA B1-mediated in vivo delivery of the NBD peptide completely blocked IL-1β + IFN-γ- and TNF-α + IFN-γ-mediated induction of NF-κB as well as islet dysfunction in culture. Finally, repeated intravenous injection of SCA B1-NBD prior to multiple low-dose administration of streptozotocin did not only induce a striking resistance to diabetes development but also preserved β-cell mass in CD mice. In conclusion, our data show for the first time that a SCA B1-NBD fusion peptide reliably protects β-cells against cytokines in vitro and allows protection from diabetes development in CD mice in vivo.

• Normal values for longitudinal function of the right ventricle in healthy women >70 years of age.

  Authors: Alfried Germing, Michael Gotzmann, Ricarda Rauße, Turgut Brodherr, Stephan Holt, Michael Lindstaedt, Johannes Dietrich, Ulrich Ranft, Ursula Krämer, Andreas Mügge

  European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

  AIMS: The application of tricuspid annular plane systolic excursion (TAPSE) as an additional echocardiographic tool to analyse right ventricular (RV) systolic function has been recently establishedAIMS: The application of tricuspid annular plane systolic excursion (TAPSE) as an additional echocardiographic tool to analyse right ventricular (RV) systolic function has been recently established and two-dimensional-guided M-mode measurements of systolic long axis function of the RV are simple, repeatable, and highly reproducible. However, rare data are available on normal values. We aimed to analyse normal values in healthy women >70 years of age. METHODS AND RESULTS: In a cross-sectional survey, we investigated a cohort of randomly selected, non-hospitalized women >70 years of age. History of myocardial infarction, valvular heart disease, and diastolic dysfunction were exclusion criteria. In order to rule out left ventricular or RV dysfunction, a normal left ventricular ejection fraction and normal values of B-type natriuretic peptide (BNP) were necessary prior to study inclusion. A detailed echocardiographic examination was performed. A total of 80 participants were included (mean age 75 +/- 2.6 years). Mean left ventricular ejection fraction was 63.8 +/- 5.7%. Tissue Doppler derived mean E/E' ratio was 10 +/- 2.3. Mean right atrial diameter was 31.3 +/- 4.7 mm. Mean values for RV outflow tract and RV dimension were 27.3 +/- 3.6 and 28.8 +/- 3.7 mm, respectively. Mean TAPSE was 23.7 +/- 3.5 mm. Mean value of BNP was normal (42.5 +/- 35.7 pg/mL). CONCLUSION: In women >70 years of age without heart failure, structural heart disease, and neurohormonal activation, normal TAPSE values are approximately 24 mm.

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• In vitro phage display in a rat beta cell line: a simple approach for the generation of a single-chain antibody targeting a novel beta cell-specific epitope.

  Authors: S Ueberberg, D Ziegler, W Schechinger, J W Dietrich, S Akinturk, H H Klein, S Schneider

  Diabetologia.

  AIMS/HYPOTHESIS: The aim of the present study was to evaluate in vitro phage display in a beta cell line as a novel strategy for the isolation of beta cell-specific agents/biomarkers. METHODS: AAIMS/HYPOTHESIS: The aim of the present study was to evaluate in vitro phage display in a beta cell line as a novel strategy for the isolation of beta cell-specific agents/biomarkers. METHODS: A single-chain antibody (SCA) library was pre-incubated with AR42J cells in order to eliminate SCAs with exocrine binding properties. It was then panned against INS-1 cells to select beta cell-targeted antibodies. RESULTS: By these means, we isolated a novel antibody, SCA B5, that binds rapidly (6.0 min) and with a 450-fold higher specificity to beta cells relative to exocrine cells. We estimated for SCA B5 a binding affinity in the low mumol/l range and 858 binding sites per beta cell. Confocal microscopy showed binding to the beta cell surface and confirmed subsequent internalisation. Moreover, staining of rat and human pancreatic tissue sections with SCA B5 suggests that the target epitope is presented in pancreatic beta cells of different origins. Infrared imaging revealed that labelling of beta cells with tracer SCA B5 is strictly dependent on beta cell mass. With competition assays we excluded insulin, glutamate decarboxylase, C-peptide and islet amyloid polypeptide as SCA B5 targets. In accordance with these predictions, SCA B5 homed in vivo highly selectively to normal beta cells and dysfunctional beta cells of diabetic rats. Moreover, accumulation of radioactively labelled SCA B5 in the pancreas was reduced by 80% after pre-injection with unlabelled SCA B5, thereby confirming the specific uptake in the pancreas. CONCLUSIONS/INTERPRETATION: We report a simple strategy for the generation of an SCA targeting a novel beta cell-specific epitope.

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• Amiodarone and radiocontrast agents correlate differently with the pattern of NTIS.

  Authors: A. Urban, A. Jeyabalan, A. Ackermann, Y. Kanthasamy, T. Tharmalingam, A. Stachon, R. Köditz, R. Gärtner, E. Conrad-Opel, H.H. Klein, S. Hering, J. W. Dietrich

  ITC 2010;

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• Generation of novel single-chain antibodies by phage-display technology to direct imaging agents highly selective to pancreatic {beta}- or {alpha}-cells in vivo.

  Authors: Sandra Ueberberg, Juris J Meier, Carmen Waengler, Wolfgang Schechinger, Johannes W Dietrich, Andrea Tannapfel, Inge Schmitz, Ralf Schirrmacher, Manfred Köller, Harald H Klein, Stephan Schneider

  Diabetes.

  Objective: Non-invasive determination of pancreatic beta-cell mass in vivo has been hampered by the lack of suitable beta-cell specific imaging agents. This report outlines an approach for theObjective: Non-invasive determination of pancreatic beta-cell mass in vivo has been hampered by the lack of suitable beta-cell specific imaging agents. This report outlines an approach for the development of novel ligands homing selectively to islet-cells in vivo. Research Design and Methods: In order to generate agents specifically binding to pancreatic islets, a phage-library was screened for single-chain-antibodies (SCAs) on rat islets using two different approaches: (1) The library was injected into rats in vivo, and islets were isolated after a circulation time of 5 minutes. (2) Pancreatic islets were directly isolated, and the library was panned in the islets in vitro. Subsequently, the identified SCAs were extensively characterized in vitro and in vivo. Results: We report the generation of SCAs that bind highly selective to either beta- or alpha-cells. These SCAs are internalised by target cells, disappear rapidly from the vasculature and exert no toxicity in vivo. Specific binding to beta- or alpha-cells was detected in cell-lines in vitro, in rats in vivo, and in human tissue in situ. Electron microscopy demonstrated binding of SCAs to the endoplasmatic reticulum and the secretory granules. Finally, in a biodistribution study the labeling intensity derived from [(125)I]-labeled SCAs after i.v. administration in rats strongly predicted the beta-cell mass and was inversely related to the glucose excursions during an intraperitoneal glucose tolerance test. Conclusions: Our data provide strong evidence that the presented SCAs are highly specific for pancreatic beta-cells and enable imaging and quantification in vivo.

• Thyroid examination in highly radiation-exposed workers after the Chernobyl accident.

  Authors: Bernhard Boehm, Marianna Steinert, Johannes Dietrich, Ralf Peter, David Belyi, Gerard Wagemaker, Silke Rosinger, Theodor Fliedner, Melanie Weiss

  European journal of endocrinology / European Federation of Endocrine Societies.

  Context: Radioactive contamination from the Chernobyl nuclear accident which happened in the morning of 26 April 1986 had a major impact on thyroid health in the Belarus region. Objective:Context: Radioactive contamination from the Chernobyl nuclear accident which happened in the morning of 26 April 1986 had a major impact on thyroid health in the Belarus region. Objective: Observational study of a cohort of 99 adults, most strongly exposed to ionizing radioactivity. Design, Setting, and Patients: Observational study performed between 1998 and 2000. The cohort was comprised of 99 workers (92 male) of the Chernobly nuclear power plant. Examination including physical examination, ultrasonography of the thyroid gland and measurement of serum free thyroxin (fT4), free triiodothyronine (fT3), and thyroid stimulating hormone (TSH). Anti-TPO, anti-Tg antibodies and TSI were also determined. Main Outcome Measures: The impact of exposure to high dose radiation, including radioactive iodine, on the thyroid gland was examined. Results: Levels of fT4 in all probands were within the normal World Health Organization-defined range. Elevated levels of fT3 were found in two workers (2%), high titres of anti-TPO and anti-Tg antibodies was present in four subjects (4%). Mild hypothyroidism was present in one patient. Enlargement of the thyroid gland was observed in 17 workers (17%). There was no evidence of clinically overt thyroid cancer. Conclusions: The Chernobyl accident showed surprisingly little impact on the thyroid in a cohort of workers strongly exposed to radiation. Our data suggest an age-dependent heterogeneity in the response to short-lived radioiodine isotopes and favors long-term follow-up analysis.

• The AQUA-FONTIS Study: Protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome.

  Authors: Johannes Dietrich, Axel Stachon, Biljana Antic, Harald Klein, Steffen Hering

  BMC endocrine disorders. 8(1):13.

  ABSTRACT: BACKGROUND: Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. AlthoughABSTRACT: BACKGROUND: Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies. Objectives: Primary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis. Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication. DESIGN: The approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes. The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation. Trial Registration: ClinicalTrials.gov NCT00591032.

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• [Absorption, transport and bio-availability of iodothyronines].

  Authors: J W Dietrich, K Brisseau, B O Boehm

  Deutsche medizinische Wochenschrift (1946). 133(31-32):1644-8.

  The frequently prescribed classical thyroid hormones (iodothyronines) are critical dose drugs with a narrow therapeutic index. Nowadays the mechanisms of their absorption, which takes placeThe frequently prescribed classical thyroid hormones (iodothyronines) are critical dose drugs with a narrow therapeutic index. Nowadays the mechanisms of their absorption, which takes place predominantly in the jejunum and ileum, have only partly been elucidated. Bioavailability of iodothyronines whose kinetics is subject to enterohepatic circulation, is about 70 %. Several factors influence their absorption including nutrients, drugs and concomitant diseases. After being absorbed only a small fraction of thyroid hormones circulates freely in plasma, whereas the greater portion is bound to plasma proteins. This binding, too, may be influenced by numerous factors; alterations by certain diseases and physiological conditions may lead to ambiguities in differential diagnosis. Intracellular accumulation of iodothyronines is accomplished by at least ten different active and energy-dependent transporters with variable tissue distribution. Particularly in critical illness (non-thyroidal illness syndrome) alterations of protein binding and membrane transport are common. In therapy of hypothyroid patients different brand-name products lack bioequivalence and thus requiring subsequent monitoring of thyroid status after treatment has been changed among different brand-name versions.

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• Iodothyronine antibodies are not correlated with prevalence or prognosis of non-thyroidal illness syndrome

  Authors: Johannes W Dietrich, Antje Ackermann, Abira Jeyabalan, Yarlini Kunanayagam, Tabotnini Tharmalingam, Aline Urban, Axel Stachon, Harald H Klein, Steffen Hering

  European Congress of Endocrinology 2008;

  Patients suffering from critical illness usually exhibit a characteristic functional state of thyrotropic feedback control that is referred to as non-thyroidal illness syndrome (NTIS). Today, therePatients suffering from critical illness usually exhibit a characteristic functional state of thyrotropic feedback control that is referred to as non-thyroidal illness syndrome (NTIS). Today, there are still important questions unsolved, e.g. regarding the interdependence of immunological and endocrine functions in critical illness. Therefore, in the context of the prospective AQUA FONTIS study we investigated 164 patients that were treated in medical, surgical and heart surgical intensive care units (ICUs) of the Bergmannsheil university hospitals in Bochum, Germany. Here, we examined the titres of antibodies reacting with thyroxine (T4-ab) and triiodothyronine (T3-ab) that were determined 24 h after admission to the ICU, and investigated their correlation with parameters of thyroid homeostasis, length of stay in hospital (LOSIH) or ICU (LOSICU) and survival of patients. All patients exhibited Gaussian distributed antibody titres that were in the normal range for healthy volunteers. Moreover, the titres didn’t correlate with functional characteristics like thyrotroph thyroid hormone sensitivity index (TTSI) as a parameter for the central component of NTIS, or sum activity of 5′-deiodinase as a marker for impaired deiodination. Again, antibody titres didn’t exhibit correlation with survival, LOSIH or LOSICU, in the latter two cases even if only the subgroup of surviving patients was considered. In conclusion, despite of immunological activation, e.g. in case of sepsis, antibodies directed against T3 or T4 are not elevated among critically ill patients nor do they play a role in the prognosis of the disease. Endocrine Abstracts (2008) 16 P821

• Thyroxine in goiter, H. pylori infection, and gastritis.

  Authors: Johannes W Dietrich, Bernhard O Boehm

  The New England journal of medicine. 355(11):1177; author reply 1177.

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• Equilibrium behaviour of feedback-coupled physiological saturation kinetics

  Authors: J. W. Dietrich, B. O. Boehm

  pages 269-74.;

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• Absorption kinetics of levothyroxine is not altered by proton-pump inhibitor therapy.

  Authors: J W Dietrich, K Gieselbrecht, R W Holl, B O Boehm

  Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et métabolisme. 38(1):57-9.

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• Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis

  Authors: J. W. Dietrich, A. Tesche, C. R. Pickardt, U. Mitzdorf

  Cybernetics and Systems. 35:315-31.

  More than 70 years after the discovery of the pituitary thyroid feedback control mechanism, a classical endocrine regulation system, most of its parameters have been identified. However, theMore than 70 years after the discovery of the pituitary thyroid feedback control mechanism, a classical endocrine regulation system, most of its parameters have been identified. However, the regulation of its central component in the pituitary gland, probably responsible for pulsatile release of thyrotropin (TSH), remains obscure. In order to infer its structure from the system ’s behavior, four different pituitary models were created and compared regarding their fractal properties. Based on the simplest model showing noncompetitive inhibition of TSH release by thyroid hormones — a physiologically plausible correlation — one alternative model added stochastic stimulation by central signals and one added an additional intrapituitary feedback loop, whereas a fourth model combined both effects. This latter model combining noncompetitive inhibition with the two additional effects showed the same fractal dimensions as a real time series, whereas the simpler models yielded significantly lower time-series complexity. These results suggest that both stochastic stimulation and ultrashort loop feedback are involved in the generation of TSH pulses in the human pituitary.

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• Antagonistic Redundancy - A Theory of Error-Correcting Information Transfer in Organisms

  Authors: J. W. Dietrich, B. O. Boehm

  pages 225-30.;

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• Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.

  Authors: Roland Gärtner, Barbara C H Gasnier, Johannes W Dietrich, Bjarne Krebs, Matthias W A Angstwurm

  The Journal of clinical endocrinology and metabolism. 87(4):1687-91.

  In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells.In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. We performed a blinded, placebo-controlled, prospective study in female patients (n = 70; mean age, 47.5 +/- 0.7 yr) with autoimmune thyroiditis and thyroid peroxidase antibodies (TPOAb) and/or Tg antibodies (TgAb) above 350 IU/ml. The primary end point of the study was the change in TPOAb concentrations. Secondary end points were changes in TgAb, TSH, and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation. Patients were randomized into 2 age- and antibody (TPOAb)-matched groups; 36 patients received 200 microg (2.53 micromol) sodium selenite/d, orally, for 3 months, and 34 patients received placebo. All patients were substituted with L-T(4) to maintain TSH within the normal range. TPOAb, TgAb, TSH, and free thyroid hormones were determined by commercial assays. The echogenicity of the thyroid was monitored with high resolution ultrasound. The mean TPOAb concentration decreased significantly to 63.6% (P = 0.013) in the selenium group vs. 88% (P = 0.95) in the placebo group. A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40% reduction in the selenium-treated patients compared with a 10% increase in TPOAb in the placebo group. TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased (P = 0.018), but were unchanged in the selenium group. Nine patients in the selenium-treated group had completely normalized antibody concentrations, in contrast to two patients in the placebo group (by chi(2) test, P = 0.01). Ultrasound of the thyroid showed normalized echogenicity in these patients. The mean TSH, free T(4), and free T(3) levels were unchanged in both groups. We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity. Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated.

• Der Hypophysen-Schilddrüsen-Regelkreis. Entwicklung und klinische Anwendung eines nichtlinearen Modells

  Authors: J. W. Dietrich

  ISBN: 9783897228504

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• Fractal Properties of the Thyrotropic Feedback Control: Implications of a Nonlinear Model Compared with Empirical Data.

  Authors: J. W. Dietrich, A. Tesche, C. R. Pickardt und U. Mitzdorf

  pages 329-34.;

  ISBN: 3852061601

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• Der Hypophysen-Schilddrüsen-Regelkreis: Entwicklung und klinische Anwendung eines nichtlinearen Modells

  Authors: Johannes W. Dietrich

  Degree: Dr. med.

  Supervisor: Prof. Dr. rer. nat. Dr. med. habil. Ulla Mitzdorf