| 1. |
- Ahmad, F., et al.
(author)
-
Cyclic Nucleotide Phosphodiesterase 3 Signaling Complexes
- 2012
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 44:10, s. 776-785
-
Research review (peer-reviewed)abstract
- The superfamily of cyclic nucleotide phosphodiesterases is comprised of 11 gene families. By hydrolyzing cAMP and cGMP, PDEs are major determinants in the regulation of intracellular concentrations of cyclic nucleotides and cyclic nucleotide-dependent signaling pathways. Two PDE3 subfamilies, PDE3A and PDE3B, have been described. PDE3A and PDE3B hydrolyze cAMP and cGMP with high affinity in a mutually competitive manner and are regulators of a number of important cAMP- and cGMP-mediated processes. PDE3B is relatively more highly expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, and pancreatic beta-cells, whereas PDE3A is more highly expressed in heart, platelets, vascular smooth muscle cells, and oocytes. Major advances have been made in understanding the different physiological impacts and biochemical basis for recruitment and subcellular localizations of different PDEs and PDE-containing macromolecular signaling complexes or signalosomes. In these discrete compartments, PDEs control cyclic nucleotide levels and regulate specific physiological processes as components of individual signalosomes which are tethered at specific locations and which contain PDEs together with cyclic nucleotide-dependent protein kinases (PKA and PKG), adenylyl cyclases, Epacs (guanine nucleotide exchange proteins activated by cAMP), phosphoprotein phosphatases, A-Kinase anchoring proteins (AKAPs), and pathway-specific regulators and effectors. This article highlights the identification of different PDE3A- and PDE3B-containing signalosomes in specialized subcellular compartments, which can increase the specificity and efficiency of intracellular signaling and be involved in the regulation of different cAMP-mediated metabolic processes.
|
|
| 2. |
- Ahrén, Bo
(author)
-
GLP-1 and extra-islet effects.
- 2004
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 36:11-12, s. 842-845
-
Research review (peer-reviewed)
|
|
| 3. |
|
|
| 4. |
- Ahrén, Bo, et al.
(author)
-
Improved meal-related insulin processing contributes to the enhancement of B-Cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes
- 2007
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 39:11, s. 826-829
-
Journal article (peer-reviewed)abstract
- The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5 +/- 1.5 years; BMI=29.6 +/- 0.5kg/m(2); FPG = 9.9 +/- 0.2 mmol/l; HbA1c=7.7 +/- 0.1 %) were studied: 29 pateients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4h post-meal) states to evaluate B-cell function. The between-treatment difference (vildaglip-tin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007 +/- 0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010 +/- 0.008 (p = 0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p = 0.023) and postprandially (p = 0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.
|
|
| 5. |
- Ahrén, Bo, et al.
(author)
-
Incretin hormones and insulin secretion.
- 2004
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 36:11-12, s. 733-734
-
Journal article (peer-reviewed)
|
|
| 6. |
|
|
| 7. |
- Arnqvist, Hans
(author)
-
The role of IGF-system in vascular insulin resistance
- 2008
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 40:9, s. 588-592
-
Research review (peer-reviewed)abstract
- Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (=10-8M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10-9-10-10M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/ICF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-l hybrid receptors. © Georg Thieme Verlag KG Stuttgart · New York.
|
|
| 8. |
- Boersma, Greta J., et al.
(author)
-
Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study
- 2018
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 50:8
-
Journal article (peer-reviewed)abstract
- We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r = 0.884, r = 0.574, r = 0.707 and r = 0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r = -0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2 = 0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r = 0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.
|
|
| 9. |
- Cerri, Perparim, et al.
(author)
-
Serum CYR61 Levels are Associated with Graves' Ophthalmopathy and Smoking in Patients with Graves' Disease
- 2021
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 54:3, s. 168-174
-
Journal article (peer-reviewed)abstract
- Smoking is a well-known risk factor for Graves' ophthalmopathy (GO) in patients suffering from Graves' disease (GD). Cysteine-rich angiogenic inducer 61 (CYR61), which has multiple physiological functions, has been shown to be associated with GD and GO. In this study, we aimed to investigate the association between smoking and CYR61 concentrations in GD patients with and without GO. Serum CYR61 was measured by ELISA. The association between CYR61 concentration and GO was assessed with binary logistic regression in all patients and in subgroups of smokers and nonsmokers. The Spearman correlation coefficient was used to determine the correlations between CYR61 concentration and clinical parameters. CYR61 levels were significantly higher in GD patients with GO than in patients without GO, in smokers than in nonsmokers and in individuals older than 50 years than in those younger than 50 years. The subgroup of GO smokers had the highest CYR61 levels [median (IQR), 119 pg/ml (129.8)], compared with GO nonsmokers [84.2 pg/ml (90.8), p=0.04], no GO smokers [88.9 pg/ml (109.8), p=0.01] and no GO nonsmokers [79.4 pg/ml (129.89), p=0.003]. For each unit increase in CYR61 concentration, the odds of having GO in smokers significantly and independently increased by 1% (OR=1.010; 95% CI: 1.002-1.018, p=0.012). In conclusion, our results indicate that smoking and age increase serum CYR61 levels in patients with GD and GO. The role of CYR61 as a predictor of GO in patients with GD should be evaluated in prospective studies.
|
|
| 10. |
- Daskalakis, Kosmas, et al.
(author)
-
Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?
- 2019
-
In: Hormone and Metabolic Research. - : GEORG THIEME VERLAG KG. - 0018-5043 .- 1439-4286. ; 51:9, s. 580-585
-
Journal article (peer-reviewed)abstract
- Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean +/- SD: 2 mm/year +/- 3.4 mm vs. 1.9 mm/year +/- 3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.
|
|
| 11. |
- Delgado, Alberto Verdugo, et al.
(author)
-
Exome Sequencing and CNV Analysis on Chromosome 18 in Small Intestinal Neuroendocrine Tumors : Ruling Out a Suspect?
- 2015
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 47:6, s. 452-455
-
Journal article (peer-reviewed)abstract
- The genetic background in small intestinal neuroendocrine tumors is poorly understood, but several studies have revealed numerical imbalances. Loss of one copy of chromosome 18 is the most frequent genetic aberration in this tumor type, which indirectly suggests that a driver mutation may be present in the remaining allele. The aim of this study was to evaluate the mutation status on chromosome 18 in small intestinal neuroendocrine tumors. DNAs from 7 small intestinal neuroendocrine tumors were subjected to whole exome capture, followed by next generation sequencing and high resolution SNP array followed by copy number variation analysis. Exome capture sequencing generated an average coverage of 50.6-138.2. Only 19 genes were covered less than 8X. No tumor-specific somatic mutation was identified. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 small intestinal neuroendocrine tumors and a number of other aberrancies. Loss of chromosome 18 is the most frequent genetic aberration in small intestinal neuroendocrine tumors, but no evidence for eventual mutations in the remaining allele. This suggests involvement of other mechanisms than point mutations in small intestinal neuroendocrine tumors tumorigenesis.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
- Efendic, S, et al.
(author)
-
Overview of incretin hormones
- 2004
-
In: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. - : Georg Thieme Verlag KG. - 0018-5043. ; 36:11-12, s. 742-746
-
Journal article (peer-reviewed)
|
|
| 15. |
- Ekman, Bertil, et al.
(author)
-
Variable Sensitivity to the Glucocorticoid Activity of Cortisol in Patients with Primary Adrenal Insufficiency : Assessment with ACTH Profiles
- 2010
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag. - 0018-5043 .- 1439-4286. ; 42:13, s. 961-966
-
Journal article (peer-reviewed)abstract
- Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addisons disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 +/- 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2 249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r = -0.56), at 10:00 h (r = -0.51), and at 10.30 h (r = -0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.
|
|
| 16. |
|
|
| 17. |
- El Wakil, Abeer, et al.
(author)
-
Genomic Analysis of Sexual Dimorphism of Gene Expression in the Mouse Adrenal Gland
- 2013
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 45:12, s. 870-873
-
Journal article (peer-reviewed)abstract
- A relevant gender difference exists in adrenal physiology and propensity to disease. In mice, a remarkable sexual dimorphism is present in several components of the hypothalamic-pituitary-adrenal axis, with females displaying higher adrenal weight, plasma ACTH, corticosterone, and aldosterone levels than males. The molecular bases of this sexual dimorphism are little known. We have compared global gene expression profiles in males vs. female mouse adrenal glands and also studied the effect that testosterone treatment and castration have on adrenal gene expression in female vs. male mice, respectively. Our study evidenced a set of 71 genes that are coordinately modulated according to sex and hormonal treatments and represent the core sexually dimorphic expression program in the mouse adrenal gland. Moreover, we show that some genes involved in steroid metabolism have a remarkable sexual dimorphic expression and identify new potential markers for the adrenal X-zone, a transitory cellular layer in the inner adrenal cortex, which spontaneously regresses at puberty in males and during the first pregnancy in females and has an uncertain physiological role. Finally, sexually dimorphic expression of the transcriptional regulators Nr5a1 and Nr0b1 may explain at least in part the differences in adrenal steroidogenesis between sexes.
|
|
| 18. |
- Elfving, Maria, et al.
(author)
-
Epitope Analysis of GAD65 Binding in both Cord Blood and at the Time of Clinical Diagnosis of Childhood Type 1 Diabetes.
- 2007
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 39:11, s. 790-796
-
Journal article (peer-reviewed)abstract
- The GAD65 epitope immunoglobulin binding pattern in cord blood of children (n=37), who later developed type 1 diabetes at 3.2-14.9 years of age, was analyzed. First, the binding at diagnosis was compared with that in the cord blood serum. The next comparison was between the cord blood serum and the mothers' serum taken at delivery. Basal GAD65 binding levels were determined in Protein A Sepharose-based radio-binding assays with S-35-labeled human and rat GAD65, rat GAD67 and GAD65/67 fusion proteins representing N-terminal (N), middle (M) and C-terminal (C) epitopes. In the first comparison, 28/37 children had GAD65 binding above 2.44 relative units (RU) (upper three quartiles), representing a marked increase from birth in the binding to human GAD65 (p < 0.0001), rat GAD65 (p < 0.0001), N- (p = 0.04), M- (p < 0.0001), C- (p=0.001), and M + C-epitopes (p < 0.0001), but not to rat GAD67. At birth, 9/37 had GAD65 binding above 1.56 RU (upper quartile) demonstrating that their binding of human S-35-GAD65 was higher in cord blood than in the mother (p=0.008). Higher cord blood binding was also observed for the N- (p=0.02) terminal epitope but not for rat GAD65, rat GAD67, and the remaining epitopes. These data suggest that differences in the epitope GAD65 binding between mother and child at birth are limited. In contrast, the epitope pattern at diagnosis differed from that at birth, supporting the view that disease-associated epitopes develop between birth and diagnosis.
|
|
| 19. |
- Ernersson, Åsa, et al.
(author)
-
Reduced Health Related Quality of Life, Increased Fatigue and Daytime Sleepiness in Women with Hyperprolactinemia
- 2023
-
In: Hormone and Metabolic Research. - : Thieme Medical Publishers. - 0018-5043 .- 1439-4286. ; 55:4, s. 266-272
-
Journal article (peer-reviewed)abstract
- Prolactin has many physiological effects and seems to be involved in the human quality of life and well-being. The aim of this study was to describe health related quality of life, fatigue and daytime sleepiness in women with untreated hyperprolactinemia. In total 32 women (mean age 37.0 ± 10.9) with verified hyperprolactinemia completed a questionnaire including questions on fatigue, measured with the Swedish version of the Fatigue Impact Scale (FIS), propensity to fall in sleep, measured with the Swedish version of the Epworth Sleepiness Scale (ESS), and Health related quality of life (HRQoL), measured by the Short-Form-36 scale (SF-36). For comparison Swedish normative data were used. The women were also interviewed regarding different symptoms related to hyperprolactinemia and the answers were analyzed using qualitative content analysis. HRQoL, as measured with SF-36, was significantly lower in all dimensions, except in physical function, compared to the Swedish reference population. Total FIS was 54.3 (41.1) and mean score on the ESS was 8.7 (4.2) indicating increased fatigue and deterioration in night sleep. The women felt very tired, and several of them rarely felt rested in the morning. The restless night sleep and the fatigue during the daytime got them to feel feeble and sometimes to find it difficult to concentrate, which affected both their mood and life in general. Women diagnosed with hyperprolactinemia reported deterioration in night sleep, increased rate of fatigue, and a reduced health related quality of life in comparison with the reference population.
|
|
| 20. |
- Essand, Magnus, et al.
(author)
-
Oncolytic Viruses for the Treatment of Neuroendocrine Tumors
- 2011
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 43:12, s. 877-883
-
Research review (peer-reviewed)abstract
- Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.
|
|
| 21. |
- Ewerman, Lea, et al.
(author)
-
Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia
- 2020
-
In: Hormone and Metabolic Research. - Stuttgart : Thieme Medical Publishers. - 0018-5043 .- 1439-4286. ; 52:04, s. 228-235
-
Journal article (peer-reviewed)abstract
- Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Franz, F, et al.
(author)
-
The Transcriptional Regulation of FOXO Genes in Thyrocytes.
- 2016
-
In: Hormone and Metabolic Research. - Stuttgart : Georg Thieme Verlag. - 0018-5043 .- 1439-4286. ; 48:9, s. 601-6
-
Journal article (peer-reviewed)abstract
- FOXO transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO isoforms in thyroid epithelial cells. mRNA expression of FOXO isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally, mRNA expression levels of FOXO isoforms were determined in human epithelial thyroid tumours. Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3 mRNA levels were significantly downregulated in papillary thyroid carcinoma when compared to normal tissues. In contrast, follicular thyroid carcinomas showed significant upregulation of FOXO4 mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced thyroid cancers.
|
|
| 25. |
- Garcez, A, et al.
(author)
-
Salivary Cortisol, Perceived Stress, and Metabolic Syndrome: A Matched Case-Control Study in Female Shift Workers
- 2017
-
In: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. - : Georg Thieme Verlag KG. - 1439-4286. ; 49:7, s. 510-519
-
Journal article (peer-reviewed)abstract
- Although the pathogenesis of metabolic syndrome (MetS) is complex and multifactorial, there is limited information if psychological factors, such as stress exposure, are involved in the etiology of MetS. Therefore, this study investigated the associations between MetS and cortisol levels and perceived stress levels among women shift workers in Southern Brazil. A matched case-control study was conducted, including 50 cases of MetS and 200 age-matched controls (±3 years, 4 for each case). Salivary cortisol levels were evaluated immediately after waking and one upon returning home from work. Perceived stress levels were measured by the Perceived Stress Scale with 10 items (PSS-10). Multivariate-adjusted associations between MetS and salivary cortisol levels and perceived stress levels were assessed by conditional logistic regression. Means±standard deviations of salivary cortisol levels were not significantly different between cases and controls either immediately after waking (5.37±4.10 vs. 6.03±5.39 nmol/l; p = 0.53) or after work (2.74±2.87 vs. 2.78±2.85 nmol/l; p = 0.93). There was no significant difference in perceived stress level between cases and controls (14.2±5.9 vs. 15.5±5.6; p = 0.15). No independent association was observed in the multivariate model between MetS and salivary cortisol level or perceived stress level after these exposures were stratified into tertiles. Overall, there was no difference between women with or without MetS in regard to the free salivary cortisol and perceived stress. Our results do not support an association between stress exposure and MetS among women shift workers.
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
- Johansson, Jan, et al.
(author)
-
C-Peptide: A Molecule Balancing Insulin States in Secretion and Diabetes-associated Depository Conditions
- 2013
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 45, s. 769-773
-
Journal article (peer-reviewed)abstract
- Gradually, the C-peptide part of proinsulin has evolved from being viewed upon as a side product of insulin synthesis and secretion to being considered as a bioactive peptide with endocrine functions. Independent of these, its biophysical properties and peptide interactions point to still further roles of C-peptide, in particular regarding possible links to diabetes-related protein aggregations. Insulin, which can deposit at the injection sites in the treatment of diabetes, and islet amyloid polypeptide (IAPP), which can form amyloid fibrils in the islets of Langerhans in diabetes type 2, are kept nonaggregated by charge-based interactions with C-peptide at defined stoichiometries. It is possible that the conformational stabilization of insulin and IAPP by C-peptide may also counterbalance their aggregational tendencies at the high peptide concentrations in the pancreatic -cell secretory granules. The concentration imbalances of C-peptide, insulin, and IAPP from the hyperpeptidism early in T2DM patients and the insulin-only injections in T1DM patients may distort equilibria of these peptide interactions and promote protein aggregation. Additionally, the chaperone-like actions of C-peptide may increase bioavailability of insulin supplements given to T1DM patients and prevent the formation of insulin deposits. Similarly, peptide interactions may influence depository tendencies in additional peptide systems. In short, biophysical studies are relevant to establish all roles of peptide imbalances in T1DM and T2DM and associated depository diseases.
|
|
| 40. |
- Johansson, T, et al.
(author)
-
Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors
- 2008
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 40:5, s. 354-359
-
Journal article (peer-reviewed)abstract
- The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.
|
|
| 41. |
|
|
| 42. |
- Kockum, Ingrid, et al.
(author)
-
Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus
- 1996
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 28:7, s. 344-347
-
Journal article (peer-reviewed)abstract
- Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune markers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recombination frequency within the HLA region. The frequency of the DR3-DQA1 * 0501-DQB1 * 0201 haplotype and the DR3-DQA1 * 0501 DQB1 * 0201 (DQ2)/DR4-DQA1 * 0301-DQB1 * 0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30. The negatively associated haplotype, DR15-DQA1 * 0102-DQB1 * 0602 was absent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tandem repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive but not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onset and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest sensitivity (54%) was in 0-10 year old boys, while age did not affect the sensitivity in girls. In contrast, the sensitivity of IAA was highest (46%) before the age of 15 but decreased thereafter as did the sensitivity for ICA. Classification of patients who develop IDDM above 20-25 years of age was inadequate since many patients classified with NIDDM either had GAD65Ab or ICA or developed these antibodies after 1-2 years of NIDDM. We conclude that not only age but also gender affects the risk for IDDM associated with HLA, other IDDM genes as well as commonly used immunological markers for IDDM.
|
|
| 43. |
|
|
| 44. |
- Kvasnicka, T, et al.
(author)
-
Apoptosis and growth factors in parathyroid adenomas
- 1997
-
In: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. - : Georg Thieme Verlag KG. - 0018-5043. ; 29, s. 544-
-
Journal article (peer-reviewed)
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
- Liefvendahl, Ellinor, 1974-, et al.
(author)
-
Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I
- 2008
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 40:6, s. 369-374
-
Journal article (peer-reviewed)abstract
- The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (ICF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. The breast cancer cell lines MCF-7 and SKBR-3, and the osteosarcoma cell line SaOS-2 were used. Gene expression was determined by real-time RT-PCR and receptor protein quantified by ELISAs. Receptor phosphorylation was assessed by immuno-precipitation and Western blot. Mitogenic effect was determined as 3H-thymidine incorporation into DNA. The gene expression of insulin receptor (IR) varied between 4.3-7.5-10-3 and the expression of IGF-IR between 7.7-147.7 10-3 in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. The IGF-IR was phosphorylated by IGF-I at a concentration of 10 -10-10-10M. All three polypeptides stimulated DNA synthesis in MCF-7, SKBR-3, and SaOS-2 cells. SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. MCF-7 cells were more sensitive to des(l-3)IGF-I than to IGF-I. In SKBR-3 and SaOS-2 cells, glargine tended to be more potent than human insulin to stimulate DNA synthesis. Our results suggest that glargine, compared to human insulin, has little or no increased mitogenic effect in malignant cells expressing IGF-IRs. © Georg Thieme Verlag KG Stuttgart · New York.
|
|
| 49. |
- Lindhe, Örjan, et al.
(author)
-
Mitotane Effects in a H295R Xenograft Model of Adjuvant Treatment of Adrenocortical Cancer
- 2010
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 42:10, s. 725-730
-
Journal article (peer-reviewed)abstract
- Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, o,p′-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. o,p′-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [11C]methionine (MET), [11C] metomidate (MTO), 2-deoxy-2-[18F]fluoro-d-glucose (FDG), and [18F]-l-tyrosine (FLT) in the aggregates were assessed ± drug treatment in vitro. Tumor growth was significantly inhibited when o,p′-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with o,p′-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 μM o,p′-DDD (p<0.01) in vitro. MeSO2-DDE (15 μM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with o,p′-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with o,p′-DDD. Further studies in humans are needed to investigate this.
|
|
| 50. |
- Lindholm, Daniel P, et al.
(author)
-
Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors
- 2011
-
In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 43:12, s. 832-837
-
Research review (peer-reviewed)abstract
- Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.
|
|
