Cartilage and bone are severely affected by glucocorticoids (GCs), steroid hormones that are frequently used to treat inflammatory diseases. Major complications associated with long-term steroid therapy include impairment of cartilaginous bone growth and GC-induced osteoporosis. Particularly in arthritis, GC application can increase joint and bone damage. Contrarily, endogenous GC release supports cartilage and bone integrity. In the last decade, substantial progress in the understanding of the molecular mechanisms of GC action has been gained through genome-wide binding studies of the GC receptor. These genomic approaches have revolutionized our understanding of gene regulation by ligand-induced transcription factors in general. Furthermore, specific inactivation of GC signaling and the GC receptor in bone and cartilage cells of rodent models has enabled the cell-specific effects of GCs in normal tissue homeostasis, inflammatory bone diseases, and GC-induced osteoporosis to be dissected. In this review, we summarize the current view of GC action in cartilage and bone. We further discuss future research directions in the context of new concepts for optimized steroid therapies with less detrimental effects on bone.

In edible dormice (Glis glis) reproduction is synchronised with the intermittent masting of the European beech (Fagus sylvatica). In years of mast failure dormouse males seem to anticipate future low food availability and fail to develop functional testes. We hypothesised that the availability of high-quality food is linked to male reproductive capacity, because of high male energetic demands during gonad maturation. We therefore evaluated the relationship between beech seed production and male reproductivity in the field between 1993 and 2005. In order to know whether the energy content of the food as such triggers sexual capacity, we supplemented high-quality food in the field for 3 years and investigated reproductive output, reproductive capacity, and body mass changes. Results revealed that male reproductive capacity was positively linked with beech seed production. Body mass changes of reference males during the high reproductive year further revealed high energetic demands of male reproduction, which were counter balanced in food-supplemented males. However, in contrast to our assumptions, artificial food supply during a year of mast failure failed to evoke high reproductivity in edible dormice. The availability of high-quality food can therefore be ruled out from being the primary trigger for sexual activity in male edible dormice.

Background: Noninvasive glucose monitoring (NIGM) in diabetes is a long-sought-for technology. Among the many attempts Raman spectroscopy was considered as the most promising because of its glucose specificity. In this study, a recently developed prototype (GlucoBeam, RSP Systems A/S, Denmark) was tested in patients with type 1 diabetes to establish calibration models and to demonstrate proof of concept for this device in real use. Methods: The NIGM table-top prototype was used by 15 adult subjects with type 1 diabetes for up to 25 days at home and in an in-clinic setting. On each day, the subjects performed at least six measurement units throughout the day. Each measurement unit comprised two capillary blood glucose measurements, two scans with an intermittent scanning continuous glucose monitoring (CGM) system, and two NIGM measurements using the thenar of the subject’s right hand. Results: Calibration models were established using data from 19 to 24 days. The remaining 3-8 days were used for independent validation. The mean absolute relative difference of the NIGM prototype was 23.6% ± 13.1% for the outpatient days, 28.2% ± 9.9% for the in-clinic day, and 26.3% ± 10.8% for the complete study. Consensus error grid analysis of the NIGM prototype for the complete study showed 93.6% of values in clinically acceptable zones A and B. Conclusions: This proof of concept study demonstrated a practical realization of a Raman-based NIGM device, with performance on par with early-generation CGM systems. The findings will assist in further performance improvements of the device.

Background Continuous glucose monitoring-derived parameters are becoming increasingly important in the treatment of people with diabetes. The aim of this study was to assess whether these parameters, as calculated from different continuous glucose monitoring systems worn in parallel, are comparable. In addition, clinical relevance of differences was investigated. Methods A total of 24 subjects wore a FreeStyle Libre (A) and a Dexcom G5 (B) sensor in parallel for 7 days. Mean glucose, coefficient of variation, glucose management indicator and time spent in different glucose ranges were calculated for each system. Pairwise differences between the two different continuous glucose monitoring systems were computed for these metrics. Results On average, the two CGM systems indicated an identical time in range (67.9±10.2 vs. 67.9±11.5%) and a similar coefficient of variation; both categorized as unstable (38.1±5.9 vs. 36.0±4.8%). In contrast, the mean time spent below and above range, as well as the individual times spent below, in and above range differed substantially. System A indicated about twice the time spent below range than system B (7.7±7.2 vs. 3.8±2.7%, p=0.003). This could have led to different therapy recommendations in approximately half of the subjects. Discussion The differences in metrics found between the two continuous glucose monitoring systems may result in different therapy recommendations. In order to make adequate clinical decisions, measurement performance of CGM systems should be standardized and all available information, including the HbA1c, should be utilized.

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Background: Measurement accuracy has been assessed for many different blood glucose monitoring systems (BGMS) over the years by different study groups. However, the choice of the comparison measurement procedure may impact the apparent level of accuracy found in such studies. Materials and Methods: Measurement accuracy of 18 different BGMS was assessed in a setting based on ISO 15197 using two different comparison methods in parallel: a glucose oxidase (GOD)-based and a hexokinase (HK)-based method. Accuracy limits of ISO 15197 were applied, and additional analyses were performed, including bias, linear regression, and mean absolute relative difference (MARD) to assess the impact of possible differences between comparison methods on the apparent level of accuracy. Results: While ≈80% of BGMS met the accuracy criteria of ISO 15197 when compared with the respective manufacturers’ reference measurement procedure, only two-thirds did so against both comparison methods. The mean relative bias ranged from −6.6% to +5.7% for the analysis against the GOD-based method and from −11.1% to +1.3% for the analysis against the HK-based method, whereas MARD results ranged from 3.7% to 9.8% and from 2.3% to 10.5%, respectively. Results of regression analysis showed slopes between 0.85 and 1.08 (GOD-based method) and between 0.81 and 1.01 (HK-based method). Conclusions: The results of this study indicate that there are systematic differences between the reference measurement procedures used for BGMS calibration as well as for system accuracy assessment. Because of the potential impact on therapy of patients with diabetes resulting from these differences, further steps toward harmonization of the measurement procedures’ results are important.

Transcriptional activity of nuclear receptors is the result of transactivation capability and the concentration of the receptor protein. The concentration of ecdysteroid receptor (EcR) isoforms, constitutively expressed in mammalian CHO cells, is dependent on a number of factors. As shown previously, ligand binding stabilizes receptor protein concentration. In this paper, we investigate the degradation of EcR isoforms and provide evidence that N-terminal degradation is modulated by isoform-specific ubiquitination sites present in the A/B domains of EcR-A and -B1. This was demonstrated by the increase in EcR concentration by treatment with carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), an inhibitor of ubiquitin-mediated proteasomal degradation and by deletion of ubiquitination sites. In addition, EcR is degraded by the peptidyl-dipeptidase cathepsin B (CatB) and the endopeptidase cathepsin S (CatS) at the C-terminus in an isoform-specific manner, despite identical C-termini. Ubiquitin-proteasome-mediated degradation and the proteolytic action are modulated by heterodimerization with Ultraspiracle (USP). The complex regulation of receptor protein concentration offers an additional opportunity to regulate transcriptional activity in an isoform- and target cell-specific way and allows the temporal limitation of hormone action.

Background: The increased use of continuous glucose monitoring (CGM) and automated insulin delivery systems raises the question about therapeutic targets for glucose profiles in people with diabetes. This study aimed to assess averaged pre- and postprandial glucose profiles in people without diabetes to provide guidance for normal glucose patterns in clinical practice. For that, number and timing of meal intake were predefined. Material and Methods: To assess glucose traces in 36 participants without diabetes (mean age = 23.7 ± 5.7 years), CGM was performed for up to 14 days, starting with a run-in phase (first 3 days, excluded from analysis) followed by 4 days with fixed meal times at 8:00 am, 1:00 pm, and 6:00 pm and the remaining 7 days spent under everyday life conditions. Data from two simultaneously worn CGM sensors were averaged and adjusted to capillary plasma-equivalent glucose values. Glucose data were evaluated through descriptive statistics. Results: Median glucose concentration on days with fixed meal times and under everyday life conditions was 95.0 mg/dL (91.6-99.1 mg/dL, interquartile range) and 98.1 mg/dL (93.7-100.8 mg/dL), respectively. On days with fixed meal times, mean premeal glucose was 92.8 ± 9.4 mg/dL, and mean peak postmeal glucose was 143.3 ± 23.5 mg/dL. Conclusions: By defining the time of meal intake, a clear pattern of distinct postprandial glucose excursions in participants without diabetes could be demonstrated and analyzed. The presented glucose profiles might be helpful as an estimate for adequate clinical targets in people with diabetes.