Contributions of cortisol and corticosterone to metabolic regulation in humans

Both cortisol and corticosterone circulate in human plasma however corticosterone has been relatively neglected in human research to date. There is evidence of distinct regulation within different tissues with the transmembrane transporter ABCB1, highly expressed in the brain, exporting cortisol but not corticosterone. This may account for the relative accumulation of corticosterone in the CNS. In contrast, ABCC1, highly expressed in adipose tissue and skeletal muscle, exports corticosterone but not cortisol, suggesting cortisol is the principal glucocorticoid acting in these tissues. We tested the hypotheses that: (i) corticosterone physiology in humans is different to that of cortisol; (ii) inhibition of ABCC1 increases binding of corticosterone to corticosteroid receptors in adipose tissue and skeletal muscle but has no central CNS effect; and (iii) corticosterone is superior to cortisol as a basis for glucocorticoid replacement therapy with fewer metabolic side effects. We compared paired salivary and plasma samples from 10 healthy individuals. Plasma corticosterone showed a similar diurnal variation to cortisol but salivary corticosterone was low and did not correlate with plasma concentrations. A placebo-controlled randomised crossover study was carried out in 14 healthy individuals comparing receptor occupancy of glucocorticoids centrally and peripherally with and without ABCC1 inhibition. Receptor occupancy was assessed through displacement with MR and GR antagonists potassium canrenoate and mifepristone. Centrally, ABCC1 inhibition caused increased activation of the HPA axis after MR and GR antagonism. Peripherally, we were unable to show displacement from adipose tissue or skeletal muscle. A further placebo-controlled randomised crossover study is still ongoing in 16 patients with congenital adrenal hyperplasia, comparing metabolic effects of placebo, cortisol and corticosterone infusions over 6 hours. We present interim data for n=8. ACTH and 17-OHP were suppressed with corticosterone. Metabolic parameters were similar between placebo, cortisol and corticosterone phases. These data suggest corticosterone physiology is distinct compared with cortisol in humans. We have shown ABCC1 inhibition alters the HPA axis after receptor antagonism which suggests ABCC1 may play more of a key role centrally than previously thought. Corticosterone suppresses ACTH and 17-OHP in the short term in congenital adrenal hyperplasia, highlighting the possibility of its use as an alternative glucocorticoid replacement therapy in the future

ABCC1 modulates negative feedback control of the hypothalamic-pituitary-adrenal axis in vivo in humans

BACKGROUND: Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular effects. ABCB1 (expressed in brain) exports cortisol not corticosterone while ABCC1 (expressed in adipose and skeletal muscle) exports corticosterone not cortisol. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans. METHODS: A randomised double-blind crossover study was conducted in 14 healthy men comparing placebo and ABCC1 inhibitor probenecid. Blood sampling, including from veins draining adipose and muscle, was undertaken before and after administration of mineralocorticoid receptor antagonist potassium canrenoate and glucocorticoid receptor antagonist mifepristone (RU486). RESULTS: During placebo, systemic plasma cortisol and corticosterone concentrations increased promptly after canrenoate. Cortisol uptake was detected from adipose but not muscle following canrenoate + RU486. Probenecid significantly increased systemic cortisol concentrations, and tended to increase corticosterone and ACTH concentrations, after combined receptor antagonism but had no effects on net glucocorticoid balance in either adipose or muscle. Using quantitative PCR in brain bank tissue, ABCC1 expression was 5-fold higher in human pituitary than hypothalamus and hippocampus. ABCB1 was more highly expressed in hypothalamus compared to pituitary. CONCLUSIONS: Although displacement of corticosterone and/or cortisol from receptors in adipose and skeletal muscle could not be measured with sufficient precision to detect effects of probenecid, ABCC1 inhibition induced a greater incremental activation of the hypothalamic-pituitary-adrenal axis after combined receptor blockade, consistent with ABCC1 exporting corticosterone from the pituitary and adding to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity

Cellular and Hormonal Disruption of Fetal Testis Development in Sheep Reared on Pasture Treated with Sewage Sludge

The purpose of this study was to evaluate whether experimental exposure of pregnant sheep to a mixture of environmental chemicals added to pasture as sewage sludge (n = 9 treated animals) exerted effects on fetal testis development or function; application of sewage sludge was undertaken so as to maximize exposure of the ewes to its contents. Control ewes (n = 9) were reared on pasture treated with an equivalent amount of inorganic nitrogenous fertilizer. Treatment had no effect on body weight of ewes, but it reduced body weight by 12–15% in male (n = 12) and female (n = 8) fetuses on gestation day 110. In treated male fetuses (n = 11), testis weight was significantly reduced (32%), as were the numbers of Sertoli cells (34% reduction), Leydig cells (37% reduction), and gonocytes (44% reduction), compared with control fetuses (n = 8). Fetal blood levels of testosterone and inhibin A were also reduced (36% and 38%, respectively) in treated compared with control fetuses, whereas blood levels of luteinizing hormone and follicle-stimulating hormone were unchanged. Based on immunoexpression of anti-Müllerian hormone, cytochrome P450 side chain cleavage enzyme, and Leydig cell cytoplasmic volume, we conclude that the hormone changes in treated male fetuses probably result from the reduction in somatic cell numbers. This reduction could result from fetal growth restriction in male fetuses and/or from the lowered testosterone action; reduced immunoexpression of α-smooth muscle actin in peritubular cells and of androgen receptor in testes of treated animals supports the latter possibility. These findings indicate that exposure of the developing male sheep fetus to real-world mixtures of environmental chemicals can result in major attenuation of testicular development and hormonal function, which may have consequences in adulthood

Substantial metabolic activity of human brown adipose tissue during warm conditions and cold-induced lipolysis of local triglycerides

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate

Developing a Global Community of Practice for Pharmacy Workforce Resilience—Meet GRiT

From MDPI via Jisc Publications RouterHistory: accepted 2021-06-07, pub-electronic 2021-06-10Publication status: PublishedWorkforce resilience in pharmacy is required to ensure the practice, education, and administrative systems remain viable and sustainable over time and when facing challenges. Whether it is addressing burnout of pharmacists or students, or the structure and policies/procedures of employment and professional organizations, working to increase resilience across all individuals and sectors is essential to relieve pressure and promote better well-being, especially during the recent pandemic. The purpose of this article is to describe the development of a community of practice global group focused on development of resilience within the pharmacy workforce that is inclusive of students, pharmacy interns/preregistration and registered pharmacists. The steering group meets monthly and has representation of 24 members across eight countries. Members meet to discuss pertinent issues they are facing in practice, as well as to share and progress ideas on education, research, and practice initiatives. To date, members have collectively implemented resilience training in pharmacy education, researched burnout and resilience in both students and pharmacists, and facilitated international collaborations both within and outside core group members. Future activities will focus on strengthening the community of practice in order to harness the power of the collective

Developing a global community of practice for pharmacy workforce resilience— meet GRiT

Workforce resilience in pharmacy is required to ensure the practice, education, and administrative systems remain viable and sustainable over time and when facing challenges. Whether it is addressing burnout of pharmacists or students, or the structure and policies/procedures of employment and professional organizations, working to increase resilience across all individuals and sectors is essential to relieve pressure and promote better well-being, especially during the recent pandemic. The purpose of this article is to describe the development of a community of practice global group focused on development of resilience within the pharmacy workforce that is inclusive of students, pharmacy interns/preregistration and registered pharmacists. The steering group meets monthly and has representation of 24 members across eight countries. Members meet to discuss pertinent issues they are facing in practice, as well as to share and progress ideas on education, research, and practice initiatives. To date, members have collectively implemented resilience training in pharmacy education, researched burnout and resilience in both students and pharmacists, and facilitated international collaborations both within and outside core group members. Future activities will focus on strengthening the community of practice in order to harness the power of the collective

The association of hydration status with physical signs, symptoms and survival in advanced cancer-The use of Bioelectrical Impedance Vector Analysis (BIVA) technology to evaluate fluid volume in palliative care: An observational study

Background Hydration in advanced cancer is a controversial area; however, current hydration assessments methods are poorly developed. Bioelectrical impedance vector analysis (BIVA) is an accurate hydration tool; however its application in advanced cancer has not been explored. This study used BIVA to evaluate hydration status in advanced cancer to examine the association of fluid status with symptoms, physical signs, renal biochemical measures and survival. Materials and methods An observational study of 90 adults with advanced cancer receiving care in a UK specialist palliative care inpatient unit was conducted. Hydration status was assessed using BIVA in addition to assessments of symptoms, physical signs, performance status, renal biochemical measures, oral fluid intake and medications. The association of clinical variables with hydration was evaluated using regression analysis. A survival analysis was conducted to examine the influence of hydration status and renal failure. Results The hydration status of participants was normal in 43 (47.8%), 'more hydrated' in 37 (41.1%) and 'less hydrated' in 10 (11.1%). Lower hydration was associated with increased symptom intensity (Beta = -0.29, p = 0.04) and higher scores for physical signs associated with dehydration (Beta = 10.94, p = 0.02). Higher hydration was associated with oedema (Beta = 2.55, p<0.001). Median survival was statistically significantly shorter in 'less hydrated' patients (44 vs. 68 days; p = 0.049) and in pre-renal failure (44 vs. 100 days; p = 0.003). Conclusions In advanced cancer, hydration status was associated with clinical signs and symptoms. Hydration status and pre-renal failure were independent predictors of survival. Further studies can establish the utility of BIVA as a standardised hydration assessment tool and explore its potential research application, in order to inform the clinical management of fluid balance in patients with advanced cancer

The Diagnostic Sensitivity of Dengue Rapid Test Assays Is Significantly Enhanced by Using a Combined Antigen and Antibody Testing Approach

Dengue is a serious public health concern with around 3 billion people at risk of infection. Severe forms of the infection can be fatal and with no licensed vaccine or effective therapeutic currently available, early detection is important to assist with the clinical management of symptoms. Isolation of the virus and the detection of viral RNA using RT-PCR are commonly used methods for early diagnosis but are time-consuming, expensive and require skilled operation. Rapid immunochromatographic tests (ICT) are relatively simple, inexpensive and easy to perform at or near the point of care. Here, we report on the clinical performance of a new rapid ICT for the non-structural protein 1 (NS1) of dengue virus, a marker of acute infection. At two clinical study sites, NS1 was detected in 60–70% of laboratory-confirmed dengue cases and specificity of the test was >95%. We have also shown that a combined testing approach for both circulating NS1 antigen and antibody responses to the glycoprotein E of the virus can significantly improve diagnostic sensitivity compared to the detection of NS1 alone. Importantly, the combined antigen and antibody testing approach also provides an expanded window of detection from as early as day 1 post-onset of illness

Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium

Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4α-phorbol 12,13-didecanoate (4-αPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-αPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25 mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4αPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months' streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the molecular and functional expression of TRPV4 channels in retinal microvascular endothelial cells. These changes may contribute to diabetes induced endothelial dysfunction and retinopathy