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Werner A Scherbaum

Publications and source records attributed to Werner A Scherbaum.

36 records · Page 2Linked to original sources
PubMed2004

Cellular models for the analysis of signaling by protein kinase B and the forkhead transcription factor FKHR (Foxo1a).

The transcription factor FKHR (FOXO1a) is regulated by protein kinase B (PKB) and insulin controls the expression of hepatic genes like glucose-6-phosphatase (G6Pase) at least in part via these proteins. However, insulin is known to activate several pathways and it is therefore difficult to establish which effects of the hormone are attributed to PKB and FKHR signaling. The aim of the present study was the generation of cellular models which allow the specific analysis of molecular events controlled by PKB and FKHR, respectively. We generated two H4IIEC3 rat hepatoma cell lines stably expressing either a hydroxytamoxifen-regulatable form of PKB (myristoylated PKB estrogen receptor chimera; MER-PKB) or FKHR (FKHR estrogen receptor chimera; FKHR-ER) by retroviral infection and determined the regulation of the G6Pase transcript by Northern blotting and enzyme assays. Activation of the regulatable PKB fusion protein almost completely reduced the dexamethasone/cAMP-stimulated G6Pase mRNA levels comparable to the effect of insulin. In contrast, stimulation of FKHR-ER with tamoxifen increased the expression of the dexamethasone/cAMP-induced G6Pase mRNA and the G6Pase enzymatic activity about 2.5- to 3-fold. The present data demonstrate that activation of PKB is sufficient to mimic the effect of insulin on the expression of G6Pase and that FKHR acts as an activator of the G6Pase gene indicating that the established cellular models are suitable for the specific analysis of downstream targets of these signaling molecules. Therefore, these cell systems might serve as useful tools for the development of anti-diabetic drugs.

Animals↗
PubMed2004

Classical conditioning and conditionability of insulin and glucose effects in healthy humans.

We examined whether the effects of intravenously injected insulin and glucose (the physiological endogenous insulin production stimulus) could be classically conditioned in healthy humans. We expected a conditioned blood glucose decrease to a conditioned stimulus (CS) previously paired with insulin and an, albeit lower, blood glucose decrease to a CS paired with glucose injection. In addition, we analyzed glucoregulatory hormone and symptom conditionability. Thirty healthy males were divided into three groups and were given the CS and an intravenous injection of either insulin (0.05 IU/kg) in Group 1, glucose (15%, 0.5 g/kg) in Group 2, or placebo [physiological saline (0.9%)] in Group 3 during the acquisition phase on 4 days. All participants were given the olfactory CS (rosewood-peppermint smell) and placebo injection on Day 5 (test). On Day 5, the total blood glucose decrease tended to be higher in Group 1 than in Group 3 (P<.10), especially at CS presentation (P<.10) and previous unconditioned hypoglycemia time-point (P<.05). The conditioned blood glucose decrease was statistically nonsignificant in Group 2, but shortly after CS presentation, insulin level and blood glucose changes were negatively correlated in Groups 1 and 2 in contrast to positive correlation in Group 3. Furthermore, Group 1 showed an increase in noradrenaline (P<.05), a temporarily delayed increase in growth hormone (GH; P<.05), and an increase of autonomic and neuroglycopenic symptoms, reaching a medium and small effect size, respectively. Group 2 responded with an increase in cortisol (P<.01) and neuroglycopenic symptoms (P<.05) at the time-point of the previous unconditioned blood glucose minimum. To conclude, the effects of exogenously applied insulin can be conditioned in a reliable way. In correspondence with the lower intensity of the unconditioned stimulus (US), conditioning effects with glucose-and, thus, endogenously produced insulin-are weaker but also reflect the actions of central insulin. Future studies will examine the diverse actions of insulin within the brain further.

Adult↗
PubMed2004

Fat cells may be the obesity-hypertension link: human adipogenic factors stimulate aldosterone secretion from adrenocortical cells.

Obesity has become an epidemic problem in Western societies contributing to several disease processes including metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone suggesting a direct link between obesity hypertension and increased mineralocorticoid levels. The adipocyte has long been suggested to be directly involved in the regulation of the body's homeostasis and recent evidence now proves that human fat is a highly active endocrine tissue. We therefore tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Indeed, secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R), as well as in bovine adrenocortical cells with a predominant effect on mineralocorticoid secretion. In conclusion, a possible direct link exists between fat tissue metabolism and adrenal mineralocorticoid secretion that may be responsible for obesity-related hypertension.

Adipocytes↗
PubMed2004

Corticotropin-releasing hormone system in human adipose tissue.

Mounting evidence exists for a role of the CRH system in energy balance, including a direct influence on human adipocytes, the regulation of adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity, and cortisol formation. We characterized the expression of CRH receptors 1 and 2 and CRH-like peptides stresscopin and urocortin in human adipose tissue in comparison with other peripheral tissues, adrenal, and heart. The effect of CRH on CRH receptor and CRH-like peptide expression was analyzed in isolated human adipocytes using quantitative TaqMan PCR. CRH receptors were detectable in fat tissue at mRNA and protein levels. CRH-R2 expression in fat was comparable with its expression in the heart, the organ with the highest CRH-R2 expression known. CRH-R1:CRH-R2 ratio varied according to fat-depot type; whereas CRH-R1 expression was higher in sc fat than in visceral fat, the opposite was true for CRH-R2. Adipose tissue also expressed urocortin and stresscopin, the predominant ligands of peripheral CRH-R2. CRH down-regulated CRH-R1 and CRH-R2 mRNA expression in isolated adipocytes. These data, together with the recently published observation that CRH regulates adipocyte metabolism by down-regulating 11 beta-hydroxysteroid dehydrogenase, indicate that a CRH system exists within human adipose tissue. This system could be implicated in energy homeostasis and in mediating the anorexic effects of CRH at adipose level.

Adipose Tissue↗
PubMed2004

Dendritic cell-based immunotherapy in thyroid malignancies.

A new approach for anti-tumor immunotherapy is to use dendritic cells (DCs) as adjuvants in order to actively immunize cancer patients with antigens specifically expressed in tumor cells. DCs possess a unique capacity to effectively activate CD4+ T helper cells and CD8+ cytotoxic T cells. During the last years, several clinical trials in various malignancies demonstrated that immunizations with tumor antigen pulsed DCs could break the tolerance of the immune system against antigens expressed by the tumor cells resulting in partial or complete remission in some cases. This review describes the most important findings on the interaction between DCs and T cells as well as natural killer cells and summarizes recent data on DC vaccination of endocrine and non-endocrine malignancies. The results from current pilot studies suggest that DC vaccination may represent a promising strategy for the development of an anti-cancer vaccine to treat chemotherapy and radioresistant endocrine malignancies.

Animals↗
PubMed2003

[Novel aspects in the mechanisms of steroid diabetes and the regulation of hepatic glucose production by insulin and steroids].

Glucocorticoids are known to increase blood glucose levels, and an impairment of glucose tolerance is a common side effect of glucocorticoid therapy and a central feature of Cushing's disease. A major pathophysiological event in this process is an increased glucose production of the liver on the basis of glucocorticoid-induced insulin resistance resulting in an increment in hepatic gluconeogenesis. Both, glucocorticoids and insulin are known to affect the expression of the two gluconeogenic key enzymes, phosphoenolpyruvate-carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). While glucocorticoids are known to stimulate the expression of the PEPCK- and G6Pase gene, insulin decreases hepatic glucose production through an inhibition of PEPCK- and G6Pase gene expression. Recently, considerable progress has been made in the understanding of the signal transduction involved in the glucocorticoid- and insulin-dependent regulation of hepatic gluconeogenesis. In this article, we will review the most recent advances and assemble the current knowledge into a clinically relevant pathophysiological model.

Blood Glucose↗
PubMed2002

Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination.

In this study, we investigated the immune response following immunotherapy with calcitonin-pulsed dendritic cells (DC) in 7 patients with metastasized medullary thyroid carcinoma. After immunization with 1-5 x 10(6) autologous DC, significant calcitonin-specific T cell proliferation was detectable in 3 patients. Measurement of cytokine release from T lymphocytes demonstrated high post-treatment interferon-gamma (IFN-gamma) secretion after stimulation with calcitonin in 5 patients, one of whom experienced significant tumor regression. In contrast, antigen-specific interleukin-4 (IL-4) production was only slightly increased in 4 patients. All 7 patients developed a strong delayed-type hypersensitivity (DTH) skin reaction, which was confirmed to be mediated by infiltrating CD4+ T-helper cells and CD8+ cytotoxic T cells in all 3 patients who underwent skin biopsy. This is the first study to show that a polypeptide hormone can be used to develop a DC vaccination strategy for the immunotherapy of highly malignant endocrine cancers.

Adult↗
PubMed2002

Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes.

Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1/CRH-R2 = 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10(-7) M and up-regulated mRNA levels of 3 beta- hydroxysteroid dehydrogenase/Delta(5-4) isomerase, although it did not affect cell viability, cell proliferation, or IL-1 beta-induced IL-8 release. CRH, dehydroepiandrosterone, and 17 beta-estradiol did not modulate CRH-R expression, whereas testosterone at 10(-7) M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Wisconsin Card Sorting Test synchronizes the prefrontal, temporal and posterior association cortex in different frequency ranges and extensions.

Current findings show some brain regions consistently related to performance of the Wisconsin Card Sorting Test (WCST). An increase of local cerebral blood flow or metabolic demands has been detected in those regions. Functional integration of the neuronal circuits that subserve the task performance, based upon the identification of the oscillations and their distributed cerebral sources, has not been accomplished previously. The event-related tonic oscillations within a period of 2,000 msec after the stimulus onset and the probable neural substrate were evaluated in healthy volunteers by variable-resolution brain electrical tomography (VARETA). The WCST induced a significant increase of delta, theta, beta-2, and gamma oscillations, but decrease of alpha. Areas such as the frontal subregions, temporal, cingulate, parahippocampal, parietal, occipitotemporal cortex, and occipital poles showed modified activity during the task, with EEG spectral band selectivity as well as some overlapping among them. Frontal and temporal regions generated the delta/theta oscillations. Additionally, the occipitotemporal and parietal regions were the source of the delta activity, lacking theta activation. The parietal region also showed tonic alpha, beta-2 and gamma changes. These data imply that different processes have been simultaneously mediated during task performance. Relationships among the individual bands, the neural substrata and the specific cognitive process that support the task were established. The selectively distributed delta, theta, alpha, beta-2 and gamma oscillations reflect communication networks through variable populations of neurons, with functional relations to the working memory functions and the information processing that subserve the WCST performance.

Adult↗
PubMed2002

Role of interleukin-6 in stress response in normal and tumorous adrenal cells and during chronic inflammation.

Interleukin-6 (IL-6) is the end-product of a cytokine signaling cascade and is secreted by specialized immune cells during inflammation. It has a great influence on many functions, including differentiation, stimulation, and activation of immune cells, or other cells of neuroendocrine origin. Thus, IL-6 serves as a key messenger in its communication with the neuroendocrine system, and serves as a potent activator of the hypothalamic-pituitary-adrenal axis at all levels. Changes in the levels of expression of this cytokine and its receptor have been observed during chronic inflammatory disease, and have been associated with tumorigenesis. Therefore, we studied the effect of IL-6 on normal and adenomatous human adrenal cells in vitro. The expression of IL-6 receptor mRNA was quantified within the same tissue. IL-6 potently stimulated cortisol secretion from dispersed normal human adrenal cells. We found immunoreactivity for the IL-6 receptor on cultured cells and paraffin-embedded sections of adrenal tissues. Further, there was a more pronounced expression of IL-6 mRNA in adrenal adenomas of patients with Cushing's syndrome, compared to normal human adrenals. Despite this fact, the sensitivity of cells of adenomatous adrenal glands to IL-6 was significantly decreased relative to cells from normal controls. These results were confirmed employing the permanent adrenocortical cancer cell line model NCI-H295. We infer that the loss of responsivity of tumorous adrenal cells to IL-6, and in part corticotropin, is an important step in the process of adrenal tumorigenesis by which regulation by differentiating proteins is bypassed.

Adenoma↗
PubMed2002

Effect of proinflammatory cytokines on gene expression of the diabetes-associated autoantigen IA-2 in INS-1 cells.

Cytokines released from activated antigen-presenting cells and T-lymphocytes are crucially involved in the pathogenesis of type 1 diabetes. Previous studies have shown that proinflammatory cytokines play an important role in the induction of autoimmunity and beta-cell damage. Inhibition of insulin expression has been described, but their effects on other major target autoantigens, such as the tyrosine phosphatase-like protein IA-2, is not known. In the present study, we established sensitive real-time RT-PCR to measure IA-2, insulin, and inducible nitric oxide (NO) synthase (iNOS) mRNA expression. Rat insulinoma INS-1 cells were stimulated with IL-1beta, TNF-alpha, interferon (IFN)-gamma, and IL-2 as well as with two combinations of these cytokines (C1: IL-1beta + TNF-alpha + IFN-gamma; C2: TNF-alpha + IFN-gamma). Treatment with IL-1beta, TNF-alpha, or IFN-gamma alone caused a significant down-regulation of IA-2 and insulin mRNA levels in a time and dose-dependent manner, whereas IL-2 had no effect. Exposure to cytokine combinations strongly potentiates the inhibitory effects. Incubation of cells with C1 and C2 for 24 h induces a significant inhibition of IA-2 mRNA levels by 78% and 58%, respectively. Under these conditions, an up to 5 x 10(4)-fold increase of iNOS gene expression was observed. The hypothesis that the formation of NO is involved in IA-2 regulation was confirmed by the finding that the coincubation of C1 with 4 mM L-N(G)-monomethyL-L-arginine, an inhibitor of the iNOS, partly reversed the down-regulation of IA-2. Further, incubation with the synthetic NO-donor S-nitroso-N-acetyl-D-L-penicillamine significantly decreased IA-2 mRNA level to 51% of basal levels. In conclusion, we have demonstrated for the first time that IL-1beta, TNF-alpha, and IFN-gamma exert a strong inhibitory effect on expression of the diabetes autoantigen IA-2. The action of IL-1beta may be partly mediated by the activation of the NO pathway.

Animals↗
PubMed2002

Basal and postglucagon C-peptide levels in Ethiopians with diabetes.

OBJECTIVE: To study basal C-peptide (BCP) and postglucagon C-peptide (PGCP) levels in Ethiopians with diabetes. RESEARCH DESIGN AND METHODS: A total of 56 subjects with type 1 diabetes, 97 subjects with type 2 diabetes, and 50 control subjects were recruited from a hospital in Ethiopia. BCP was determined in all subjects and PGCP in 86 subjects. RESULTS: Mean (+/- SEM) BCP, PGCP, and the increment after glucagon in type 1 diabetic subjects (0.14 +/- 0.04, 0.22 +/- 0.11, and 0.08 +/- 0.05 nmol/l, respectively) were lower (P < 0.001) than those in type 2 diabetic subjects (0.66 +/- 0.04, 1.25 +/- 0.10, and 0.56 +/- 0.06 nmol/l, respectively) or control subjects (0.54 +/- 0.04, 1.52 +/- 0.26, and 1.11 +/- 0.24 nmol/l, respectively). The mean BCP level was higher in type 2 diabetic subjects than control subjects (P=0.015), whereas the mean increment was lower (P=0.005). Insulin-treated type 2 diabetic subjects, compared with non-insulin-treated type 2 diabetic subjects, had lower mean BCP (0.55 +/- 0.08 nmol/l [n=37] vs. 0.73 +/- 0.04 [n=60], P=0.001), lower PGCP (0.97 +/- 0.20 nmol/l [n=18] vs. 1.40 +/- 0.11 [n=35], P=0.010), and a lower C-peptide increment (0.34 +/- 0.06 [n=18] vs. 0.67 +/- 0.07 nmol/l [n=35], P=0.003). In both the type 1 and type 2 diabetic groups, those with BCP levels <0.2 nmol/l had lower BMI than those with higher BCP levels (P=0.023 and P < 0.001, respectively). CONCLUSIONS: Combined with clinical criteria, C-peptide levels are good discriminators between type 1 and type 2 diabetes in Ethiopians and may also be useful in identifying subjects with type 2 diabetes who require insulin therapy. There is a subgroup of type 2 diabetic subjects with features of type 1 diabetes.

Adult↗
PubMed2002

[Evidence-based medicine in diabetes mellitus. Expert guidelines a the basis for medical practice and information for patients and the population in general].

The integrated DDG diabetes guidelines, comprising an evidence-based version compiled by experts, one generated by therapists and practitioners and a patient/citizen version, are adequate tools for improving the care of patients in daily medical practice. It is the goal of this guidelines programme to ensure that the core statements on diabetes mellitus, its concomitant diseases and sequelae be imparted uniformly, so as to highlight medical care deficits and improve significantly communication and co-operation with regard to the treatment of chronically ill patients.

Diabetes Mellitus↗
PubMedDate not supplied

Insulin therapy in Europe.

The prevalence of type 1 diabetes is rising in all European countries, particularly in Scandinavia and the UK. Insulin therapy in Europe is strongly influenced by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), both of which showed the importance of tight metabolic control in patients with diabetes. The importance of tight glycemic control is also emphasized in the Saint Vincent Declaration, which established 5-year goals for antidiabetic therapy in Europe. Insulin therapy in Europe has been significantly improved over the past 10 years, owing to a number of developments. These include increased use of intensive insulin therapy in patients with type 1 diabetes; the development of new insulin analogs, including insulin glargine for injection therapy and short-acting agents that are particularly suitable for use in pumps and the establishment of comprehensive and standardized treatment goals and guidelines. Nevertheless, important obstacles must still be overcome to optimize therapy for patients with diabetes and reduce the long-term complications of this disease. These obstacles include low public awareness of diabetes and its symptoms, training of physicians as well as patients that is often insufficient to ensure adherence to professional guidelines for diabetes care, and limitations in communication among professional care providers.

Blood Glucose↗