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W A Scherbaum

Publications and source records attributed to W A Scherbaum.

At least 19 recordsLinked to original sources
PubMed2007

Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway.

CONTEXT: Obesity is associated with hypersecretion of cortisol and aldosterone and a high prevalence of arterial hypertension. At the cellular level, a direct effect of adipocytes on the expression of the steroidogenic acute regulatory (StAR) protein, a regulator of cortisol and aldosterone synthesis, and on aldosterone and cortisol secretion has been shown. However, the molecular mechanisms mediating this effect are not known. OBJECTIVE: Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. Therefore, we investigated whether adipocytes stimulate adrenal steroidogenesis through the activation of Wnt-signaling. RESULTS: Using immunohistochemistry, we detected the expression of frizzled and beta-catenin in the adult human adrenal cortex. Transient transfection of a Wnt-dependent reporter-gene into adrenal NCI-H295R cells showed an induction of Wnt-mediated transcription to 308% after treatment with human fat cell-conditioned medium (FCCM). This finding was paralleled by an induction of StAR promoter activity (420%) by FCCM. The induction of StAR promoter activity by FCCM was inhibited by 49% when Wnt-signaling was blocked by the soluble Wnt-antagonist secreted Frizzled-Related-Protein-1 (sFRP-1). Overexpression of a constitutively active mutant of beta-catenin induced the transcription of the StAR promoter (440%). beta-Catenin and FCCM induced SF-1-mediated transcription at a SF-1-driven reporter gene (420 and 402%, respectively). Furthermore, the secretion of aldosterone and cortisol by NCI-H295R cells induced by FCCM was significantly inhibited by the Wnt-antagonist sFRP-1. CONCLUSION: These data indicate that the Wnt-signaling pathway is one of the mechanisms mediating the effects of fat cells on adrenal StAR transcription and aldosterone and cortisol secretion.

Adipocytes↗
PubMed2007

Improved prediction of relapse of Graves' thyrotoxicosis by combined determination of TSH receptor and thyroperoxidase antibodies.

BACKGROUND: Recently, we and others have demonstrated that high levels of auto-antibodies to the human TSH-receptor (TRAb) predict relapse of hyperthyroidism in Graves' disease (GD). Our objective was to extend the outcome of the prediction by combining TRAb with thyroperoxidase antibody (TPO-Ab) measurement. PATIENTS AND METHODS: One hundred and thirty-one GD patients (118 females, 13 males) were analysed, of whom 94 patients (71.8%) had relapse, whereas 37 (28.2%) went into remission. Second generation TRAb and TPO-Ab assays were performed in GD patients with relapse and remission in mean 4.3 months after initial diagnosis. RESULTS: The mean anti-TPO-Ab levels were similar in all patients with relapse and remission. However, there was a steady decline from 4047 U/ml to 530 U/ml in the remission group that correlated positively with TRAb values (>2 to >10 IU/l). The relapse group remained at consistently high levels. The positive predictive value (PPV) for relapse in patients with TRAbs >6 IU/l and anti-TPO-Abs >5000 U/ml was 100, whereas TRAbs >6 IU/l and anti-TPO-Abs >500 U/ml were associated with a PPV of 93.7 up to 96 (p=0.008). These Ab constellations accounted for about one third of all GD patients. For patients with TRAbs between >2 and <6 IU/l the PPV was 66.7-90.0. CONCLUSION: Our follow-up analysis indicates that the prediction of relapse of GD can be improved by a combined measurement of TRAb and TPO-Ab. In patients with moderately increased Abs, determined about 6 months after initial diagnosis, an ablative therapy can be approached without delay.

Adolescent↗
PubMed2006

The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression.

Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could "prime" leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) significantly increased in peripheral blood leukocytes from "MetS" subjects (n=39) compared to "no MetS" subjects (n=35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-alpha +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-alpha +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-alpha +31%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.

Gene Expression Regulation↗
PubMed2006

[Detection of a previously unrecognized type 2 diabetes using a risk questionnaire. Efficiency for general population screening].

BACKGROUND AND OBJECTIVE: The detection of unknown cases of diabetes mellitus is of great medical and public health interest. In the present study a stepwise screening procedure was used to examine the effectiveness of a diabetes-risk questionnaire at a population level. PATIENTS AND METHODS: 58,254 insured persons (34,179 men and 24,075 women (55 years and older) enrolled in the Health Insurance "Techniker Krankenkasse" of Thuringia and the Duesseldorf area were contacted per mail to participate. 21,218 returned the questionnaire. They were contacted again and encouraged to participate in a medical check-up for early detection of diabetes. RESULTS: Data of 4,314 individuals (20.3%) who participated in the medical check-up were analysed. Their fasting blood glucose was measured (FBG, n=3,888) and, if necessary, they underwent an additional oral glucose tolerance test (OGTT, n=2,048). In 192 cases (4.5%) the general practitioner (GP) diagnosed manifest diabetes mellitus. In an additional 393 patients (9.1%) an impaired glucose tolerance was found. Analysis of documented blood glucose measurements suggested a manifest diabetes mellitus in 3.5% (by OGTT) and 10.3% (by FBG), as well as an impaired glucose tolerance in 16.1% (by OGTT) and 36.6% (by FBG). CONCLUSIONS: These results demonstrate good effectiveness of the screening procedure among the participants of a medical check-up programme for early detection of diabetes mellitus and its precursors. However, the effectiveness of population-based diabetes screening with only a mailing of a risk questionnaire was unsatisfactory.

Aged↗
PubMed2006

High prevalence of undiagnosed impaired glucose regulation and diabetes mellitus in patients scheduled for an elective coronary angiography.

BACKGROUND: Impaired glucose regulation (IGR) and diabetes mellitus (DM) are amongst the main risk factors for developing coronary heart disease (CHD). The aim of this study was to investigate previously unknown glucose metabolism disorder in patients scheduled for an elective coronary angiography. METHODS: A total of 141 patients scheduled for coronary angiography without signs of acute myocardial ischemia or previous history of a glucose metabolism disorder were prospectively included in the study. An oral glucose tolerance test (OGTT) was performed in each patient. RESULTS: IGR was diagnosed in 40.4% (95% confidence interval 32.3-49.0) and undetected DM in 22.7% (16.1-30.5) of patients undergoing an elective coronary angiography. Depending on the severity of CHD, the percentage of IGR and DM increased up to 45.3% (34.6-56.5) and 26.7% (17.8-37.4) in the subgroup with the need of percutaneous angioplasty, while the corresponding proportions in the group without CHD were 30.3% (15.6-48.7) and 12.1% (3.4-28.2). The percentage of undiagnosed DM increased with the number of epicardial vessels involved. Using the recommended fasting plasma glucose value of > or = 126 mg/dl for the diagnosis of DM, we would have missed 71.9% of the patients with undiagnosed DM. If all patients with a fasting plasma glucose of > or = 90 mg/dl had been subjected to OGTT, 93.8% of DM would have been identified. CONCLUSIONS: Prevalences of DM and IGR are higher than expected in patients with CHD. An OGTT should be considered for all patients with a fasting plasma glucose > or = 90 mg/dl undergoing a coronary angiography.

Aged↗
PubMed2006

The diabetic charcot foot: MRI discloses bone stress injury as trigger mechanism of neuroarthropathy.

It is generally accepted that traumatic bone injury contributes to the clinical picture of neuroarthropathy of the foot in diabetes, i.e., of the diabetic Charcot foot. While radiology is capable of visualizing only advanced bone injuries, like complete fractures, magnetic resonance imaging (MRI) discloses bone injuries that precede complete fractures (stress bone injuries). In diabetic polyneuropathy, stress bone injuries are silent in terms of pain, due to the lack of pain sensation. At the foot, their clinical appearance is characterized by inflammatory swelling with little or no pain. The present paper reviews the contribution of MRI to the detection of bone injuries in what is called stage 0 Charcot foot, with emphasis on the bearings for the treatment strategy.

Bone Marrow Diseases↗
PubMed2006

Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.

Adolescent↗
PubMed2006

Obesity-specific circuits in the human brain: exploration by dynamic Brain Self-Reference (dynBSR).

In the last decade many efforts have been made in order to identify brain regions that may be abnormal in obese subjects. Most of the lines of research have examined links between brain circuits, behavioral processing, and overweight. We introduce here a novel analysis to the brain mapping, 'dynamic Brain Self-Reference' (dynBSR), based on the electrical response evoked during passively viewing a simple stimulus. Hypothetically, it should be possible to monitor both task-related networks and task-irrelevant networks during a mental state with low cognitive demand, as shown previously by others using fMRI and establishing the latter as the neural correlates of an 'inherent' brain activation pattern. However, this fact has been usually ignored. Our results showed that a distinct set of interconnected brain regions including, frontal areas (middle, inferior, orbitofrontal, and dorsolateral), dorsal/ventral striatum, thalamus, superior temporal region, insula cortex, post-central gyrus, left supramarginal gyrus, and parietal regions, whose activities seem to be tonically maintained, displays cohesive functional state in obesity during passively viewing a simple stimulus. This organized network is maintained in a dynamic equilibrium with the transient activation of the right supramarginal gyrus. These brain areas have been previously implicated in the regulation of taste, reward, and behavioral processing and most of them have also structural abnormalities regarding normal-weight subjects. Although exploratory, the most important result here is that the evaluation of the visual-evoked responses with dynBSR provides a foundation for investigating the brain circuits in obesity, and becomes the first attempt, to our knowledge, to imply task-irrelevant networks in these individuals.

Adult↗
PubMed2005

Self-monitoring of blood glucose in type 2 diabetes and long-term outcome: an epidemiological cohort study.

AIMS/HYPOTHESIS: The aim of this study was to obtain epidemiological data on self-monitoring of blood glucose (SMBG) in type 2 diabetes and to investigate the relationship of SMBG with disease-related morbidity and mortality. METHODS: The German multicentre Retrolective Study 'Self-monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes' (ROSSO) followed 3,268 patients from diagnosis of type 2 diabetes between 1995 and 1999 until the end of 2003. Endpoints were diabetes-related morbidity (non-fatal myocardial infarction, stroke, foot amputation, blindness or haemodialysis) and all-cause mortality. SMBG was defined as self-measurement of blood glucose for at least 1 year. RESULTS: During a mean follow-up period of 6.5 years, 1,479 patients (45.3%) began SMBG prior to an endpoint and an additional 64 patients started SMBG after a non-fatal endpoint. Interestingly, many patients used SMBG while being treated with diet or oral hypoglycaemic drugs (808 of 2,515, 32%). At baseline, the SMBG cohort had higher mean fasting blood glucose levels than the non-SMBG cohort (p<0.001), suggesting that insufficient metabolic control was one reason for initiating SMBG. This was associated with a higher rate of microvascular endpoints. However, the total rate of non-fatal events, micro- and macrovascular, was lower in the SMBG group than in the non-SMBG group (7.2 vs 10.4%, p=0.002). A similar difference was found for the rate of fatal events (2.7 vs 4.6%, p=0.004). Cox regression analysis identified SMBG as an independent predictor of morbidity and mortality, with adjusted hazard ratios of 0.68 (95% CI 0.51-0.91, p=0.009) and 0.49 (95% CI 0.31-0.78, p=0.003), respectively. A better outcome for both endpoints was also observed in the SMBG cohort when only those patients who were not receiving insulin were analysed. CONCLUSIONS/INTERPRETATION: SMBG was associated with decreased diabetes-related morbidity and all-cause mortality in type 2 diabetes, and this association remained in a subgroup of patients who were not receiving insulin therapy. SMBG may be associated with a healthier lifestyle and/or better disease management.

Aged↗
PubMed2005

[Prevention of diabetes mellitus type 1].

Primary prevention of type 1 diabetes is as yet not feasible. In contrast, prevention of acute and chronic complications of type 1 diabetes is highly effective. With a near normal blood glucose control the appearance and progression of microvascular complications (i.e. retinopathy, nephropathy and neuropathy) can be significantly reduced. Intensive insulin therapy is the gold standard for treatment of type 1 diabetes.

Acute Disease↗
PubMed2005

Adrenal pheochromocytoma with contralateral cortisol-producing adrenal adenoma: diagnostic and therapeutic management.

There is evidence for a close interrelation between the adrenomedullary and adrenocortical tissues, and there are well-characterized models of their paracrine interaction. To contribute to the studies of systemic interactions between these tissues, we studied a 52-year-old female patient with a pheochromocytoma and a contralateral cortisol-producing adenoma. Due to a misunderstanding, she presented to her family doctor to have an inherited kidney disease ruled out. An adrenal mass was discovered incidentally by ultrasound. A computerized tomography of the abdomen revealed bilateral adrenal masses. Due to excess catecholamine secretion, bilateral pheochromocytomas based on multiple endocrine neoplasia syndrome were suspected. Laboratory work-up, selective adrenal venous sampling and magnetic resonance imaging studies established the diagnosis of a pheochromocytoma in the right-hand adrenal gland and a cortisol-producing adenoma on the left. Simultaneous bilateral laparoscopic subtotal adrenalectomy was performed. Immunohistochemistry showed positive staining against chromogranin A in a histological specimen obtained from the right-hand adrenal gland, while the left was negative; the left-hand adrenal gland stained positive against the ACTH receptor (MC2R) while the right was negative. Genetically, the patient was negative for MEN2, von Hippel-Lindau disease, and mutations in subunits B, C, and D of the succinate dehydrogenase gene. Although presence of bilateral adrenal adenomas or bilateral adrenal pheochromocytomas in certain inherited disorders are possible, this rare case of an adrenal pheochromocytoma combined with a contralateral cortisol-producing adrenal adenoma may further underline the wide range of complex interactions between the two endocrine systems.

Adrenal Cortex Neoplasms↗
PubMed2005

Relevance of TSH receptor stimulating and blocking autoantibody measurement for the prediction of relapse in Graves' disease.

Recently, we demonstrated that higher levels of autoantibodies to the human TSH receptor (TBII) predict relapse of hyperthyroidism in Graves' disease (GD). The aim of this study was to extend this outcome prediction by dividing TBII into stimulating (TSAb) and blocking (TBAb) TSH receptor autoantibodies. Altogether, ninety patients (81 female, 9 male) were retrospectively analyzed; sixty-four patients (71 %) did not go into remission or relapsed, whereas twenty-six patients (29 %) went into remission (median follow-up: 17.5 months). TSAb and TBAb measurement was performed in a CHO cell bioassay with cAMP readout at the time of their first visit in our outpatient clinic (single point measurement in median 6.5 months after initial diagnosis). In the remission group, eighteen of twenty-six patients (69 %) were TSAb-positive, whereas fifty-three of sixty-four patients (83 %) were TSAb-positive in the relapse group (p = ns). The mean stimulation indices (SI) were 4.1 in the remission group and 12.9 in the relapse group, respectively (p = 0.015). By using a threshold of 10 SI, the specificity for relapse was 96.0 %, as only one in twenty patients with an SI above 10 went into remission during follow-up (PPV 95 %). Most TSAb-positive patients also had high levels of TBII. Neither group showed any difference with respect to blocking type autoantibodies, which were mostly negative in both groups. In summary, high TSAb levels are similar but not superior to TBII for predicting relapse in GD patients. In contrast, TBAb measurement does not add any valuable information in this context. In the clinical routine, TSAb/TBAb measurement may not play an important role for diagnosis or outcome prediction of GD, since sensitive 2 (nd) generation TBII assays are easier to perform and offer similar information to the clinician. Bioassays should be reserved for special clinical questions such as Graves' disease in pregnancy.

Adolescent↗
PubMed2005

Molecular mechanisms of insulin resistance.

Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with Type 2 diabetes the resistance of fat, muscle and liver to insulin is the central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and Type 2 diabetes is still largely unknown. However, recent studies have contributed to a deeper understanding of the molecular mechanisms underlying this process. In this review we therefore summarize the current developments in understanding the pathophysiological process of insulin resistance and Type 2 diabetes. Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)-2, the protein kinase B (PKB)-beta isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in-vivo. Furthermore, we have now increasing evidence that the adipose tissue not only produces free fatty acids that contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. The identification of the molecular pathophysiological mechanisms of insulin resistance and Type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and Type 2 diabetes.

Adipose Tissue↗
PubMed2004

Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves' disease.

The aim of this study was to evaluate the ability of the more sensitive second-generation TSH receptor (TRAb) assay to predict recurrent Graves' disease (GD) vs. remission depending on TRAb levels. 93 patients with active GD were included in the study. By using a cut-off limit of 1.0 IU/l, all 93 patients were positive for TRAb (median: 4.6 IU/l) at the time of their first visit (single point measurement in median 5.1 months after initial diagnosis). Subsequently, 33 patients went into remission and were euthyroid during follow-up (median follow-up: 21.7 months), whereas 60 patients did not go into remission or developed relapse over the following 24 months. Median TRAb levels in the group of remission were significantly (p < 0.0001) lower than TRAb values in the relapse group (2.1 compared to 8.6 IU/l). Applying ROC plot analysis to compare different TRAb thresholds, a cut-off of 10 IU/l was established. Here, the specificity for relapse was 97 % as only 1 of 29 patients with TRAb values above 10 IU/l went into remission during follow-up, whereas all other 28 patients developed a relapse (positive predictive value for relapse: 96.4 %). In contrast, TRAb values lower than 10 IU/l had no impact on the prediction of remission. In conclusion, our data clearly indicate that TRAb measurement is useful for identifying patients that will not benefit from long-term antithyroid drug treatment.

Adolescent↗
PubMed2004

Pheochromocytoma during pregnancy: laparoscopic and conventional surgical treatment of two cases.

Pheochromocytoma is a rare entity. When it presents during pregnancy, rapid recognition and diagnosis are crucial in order to avoid the maternal and fetal morbidity and mortality associated with severe, uncontrolled hypertension. Difficulties arise from the differential diagnosis of pre-eclampsia. We report two patients operated on for pheochromocytoma during pregnancy. The first patient developed new-onset hypertension in early pregnancy. Prior to presentation, there had been non-specific signs of endocrine disorder, namely a mild diabetes, but no hypertension requiring medication. The second patient sought medical care for irregular heartbeat, shortness of breath, and fatigue during the 6th week of pregnancy. She was found to be hypertensive; diagnostic evaluation revealed substantially increased catecholamine levels. The diagnosis was made by elevated urinary catecholamines and by MRI scan as well as ultrasonography, both of which demonstrated an adrenal mass. Both patients underwent surgical extirpation of the affected adrenal gland. The procedure was performed laparoscopically in the case of the second patient. Pre-operatively, both patients were pre-treated with alpha-blockade followed by secondary beta-blockade. Patient two also received methyldopa for control of hypertension. Both patients were readily weaned from antihypertensive medications post-operatively, with complete resolution of hypertension within a few hours. Each pregnancy progressed normally to term.

Adrenal Gland Neoplasms↗