In mammals, many daily cycles are driven by a central circadian clock, which is based on the cell-autonomous rhythmic expression of clock genes. It is not clear, however, how peripheral cells are able to interpret the rhythmic signals disseminated from this central oscillator. Here we show that cycling expression of the clock gene Period1 in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2b receptor, which occurs through the nocturnal activation of melatonin mt1 receptors. Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Period1 and evokes an increase in the release of pituitary prolactin. Our findings expose a mechanism by which two convergent signals interact within a temporal dimension to establish high-amplitude, precise and robust cycles of gene expression.

Germany continues to be iodine deficient despite considerable improvement in the past years. To assess the current prevalence of diffuse and/or nodular thyroid disorders, a cross-sectional observational study in a nonrandom sample of the working population was carried out throughout Germany in 2001 and 2002. A total of 96,278 employees 18-65 years of age from 214 companies or other private or public institutions voluntarily underwent ultrasonographic examinations by 230 experienced investigators. To compare the prevalence of different abnormal findings in relation to age and gender, descriptive statistics and the Kruskal-Wallis test were used. Data from volunteers with previous thyroid treatment (13.0% of total sample) were not included in the analysis. Abnormal findings (goiter and/or nodules > 0.5 cm) were observed in 33.1% (men, 32.0%; women, 34.2%) of the examined patient population, an enlarged thyroid without nodules in 9.7% (men, 11.9%; women, 7.6%), nodules only without enlargement of the thyroid in 14.3% (men, 11.5%; women, 17.0%), and nodular goiter in 9.1% (men, 8.6%; women, 9.6%). Nodules (with or without goiter) between 0.5 and up to 1.0 cm were found in 10.0%, and nodules above 1.0 cm in 11.9% of the population. Rates of abnormal findings increased with age in both genders. Goiter was more common in men, nodules in women. In light of these findings, the prevalence of thyroid disorders in Germany continues to be high. Although the study may slightly overestimate the prevalence, about one third of the working population is affected and remains unaware of this condition. These results emphasize the importance of effective sonographic screening to detect early thyroid abnomalities in order to initiate preventive and therapeutic measures to prevent the onset or progression of disease and its sequels.

Detection of autoantibodies to the TSH receptor (TSH-R) in Graves' disease has found widespread use in clinical routine and is performed mostly by commercial RRAs measuring TSH binding inhibitory activity. We report in this study on a second generation TSH binding inhibitory assay using the human recombinant TSH-R with two major improvements: 1) superior diagnostic sensitivity for Graves' disease, and 2) for the first time, nonradioactive and radioactive coated tube (CT) technology. Full-length human recombinant TSH-R was expressed in the K562 leukemia cell line and grown in suspension at a high density. A murine monoclonal antibody was selected for binding to the native TSH-R without interfering with autoantibodies or TSH and was coated to polystyrene tubes. After detergent extraction, TSH-R was affinity immobilized on antibody-coated tubes. The binding of TSH to the TSH-R could be demonstrated by the addition of 125I- or acridinium ester-labeled bovine TSH, and this binding could be inhibited by sera from patients with Graves' disease up to 95%. Subsequently, these novel assays, a CT RRA and a CT luminescence receptor assay, were compared to the conventional RRA based on porcine antigen in a blinded clinical multicenter trial. Sera from 328 patients with Graves' disease (86 untreated, 116 treated, and 126 in remission) and 520 controls (comprised of healthy blood donors and patients with autoimmune diseases or goiter) were tested in all 3 assays. Receiver-operating characteristic plot analysis resulted in a specificity of 99.6% with a sensitivity of 98.8% for both CT assays, compared to 99.6% specificity and 80.2% sensitivity for the conventional RRA (P < 0.001). In all 3 groups of patients with Graves' disease, the 2 CT assays were significantly more sensitive for the disease than the conventional assay, without loss of specificity in the control groups. This increase in sensitivity and the nonradioactive or radioactive CT format constitute a significant improvement over the currently available assays.

The results of this large-scale study suggest that insulin omission/non-adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non-adherence and lead to improved clinical outcomes.

Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients’ physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.