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Background Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol and controls the circulating free cortisol pool. Proteolytic cleavage by neutrophil elastase is proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. The CORtisol NETwork (CORNET) consortium found that genetic variation at a locus spanning SERPINA1 (encoding alpha-1 antitrypsin, A1AT, the endogenous inhibitor of neutrophil elastase) and SERPINA6 (CBG) contributes to morning total plasma cortisol variation. We hypothesised that A1AT deficiency increases CBG cleavage and hence free plasma cortisol, resulting in increased tissue cortisol delivery in adipose and in HPA axis negative feedback. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1. Methods 16 healthy carriers of one of the two most common A1AT-deficiency single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. Participants underwent combined receptor antagonist stimulation of the HPA axis (‘CRASH’) testing using RU486 400mg and spironolactone 200mg, or placebo in a double blind randomised crossover design. Plasma free cortisol was measured by isotopic dilution and ultrafiltration, total cortisol by LC-MS/MS, total CBG by ELISA, CBG binding capacity by radioligand displacement assay, and ACTH by immunoassay. Serum A1AT was measured by ELISA. Tissue cortisol (LC-MS/MS) and expression of glucocorticoid dependent transcripts (qPCR) were measured in subcutaneous adipose samples collected by needle biopsy. Results Serum A1AT was confirmed lower in those with heterozygous mutations vs wild type controls (411.3 +/- 27.44 vs 565.1 +/- 23.38 mg/dL, p=0.0002). No measurable differences in total CBG or CBG binding capacity were observed. However, plasma free cortisol fraction was higher in those carrying A1AT mutations (16.13 +/- 0.2 vs 13.88 +/- 0.04 %, p Conclusion Alpha-1 antitrypsin mutation heterozygosity, common in the general population, is associated with higher free cortisol fraction, consistent with enhanced cleavage of CBG. This is associated with evidence of enhanced delivery of glucocorticoid to adipose tissues but reduced HPA negative feedback, suggesting tissue-specific control of cortisol delivery by CBG.

OBJECTIVE The diagnostic value of a single measurement of serum cortisol as a first step in the investigation of suspected adrenal insufficiency remains unclear. Previously proposed criteria have not been validated, and little is known regarding the performance of the test outwith morning samples in outpatients. We aimed to identify and validate criteria for morning and afternoon serum cortisol which could be used to determine which individuals require dynamic testing, in both outpatient and medical inpatient settings. METHODS We performed a retrospective analysis of 2768 patients attending endocrinology clinics and patients admitted to general medical units in two hospitals in Edinburgh, UK. In baseline samples from the short synacthen test, thresholds which identified a subnormal-stimulated serum cortisol (

Congenital adrenal hyperplasia (CAH) is associated with poor health outcomes. This is, in part, because doses of glucocorticoid which are sufficient to suppress excess adrenal androgens are also associated with adverse metabolic effects such as insulin resistance. This toxicity occurs with efficacious doses of all commonly prescribed glucocorticoids (hydrocortisone, prednisolone and dexamethasone). However, the glucocorticoid corticosterone may have an improved therapeutic index because of its unusual susceptibility to export from cells by ATP-binding cassette (ABC) transporters. ABCB1 is expressed in the brain and exports cortisol (hydrocortisone), prednisolone and dexamethasone, limiting their potency at suppressing ACTH. However, corticosterone is not exported by ABCB1 but is exported by the alternative ABCC1 transporter. Expression of ABCC1 is relatively low compared to ABCB1 in the brain, however ABCC1 is expressed in the absence of ABCB1 in adipose tissue, muscle and bone, potentially limiting corticosterone action in these tissues. We hypothesized that corticosterone may be more efficacious at suppressing ACTH and adrenal androgens but with less metabolic toxicity than hydrocortisone. Fourteen adults with classic CAH due to 21-hydroxylase deficiency were recruited to a double-blind randomised crossover study comparing intravenous infusions of placebo, hydrocortisone and deuterated (D8) corticosterone. Subjects attended after omitting their usual glucocorticoid for 12h and were administered glucocorticoid/placebo for 5.5 hours in a two-step infusion designed to achieve concentrations of 400 and 800nM. Blood samples were collected regularly. Circulating D8-corticosterone concentrations were approximately 30% higher than hydrocortisone. D8-corticosterone suppressed ACTH, androstenedione and 17-hydroxyprogesterone to a greater extent than hydrocortisone. However, hydrocortisone increased circulating insulin compared with D8-corticosterone and placebo (10.0±1.3 vs 8.3±1.2 vs 7.2±1.3mU/L respectively, P

Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.

Renal dysfunction is prevalent in the US among African Americans. Air pollution is associated with renal dysfunction in mostly white American populations, but not among African Americans. We evaluated cross-sectional associations between 1-year and 3-year fine particulate matter (PM2.5) and ozone (O3) concentrations and renal function among 5090 African American participants in the Jackson Heart Study. We used mixed-effect linear regression to estimate associations between 1-year and 3-year PM2.5 and O3 and estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), serum creatinine, and serum cystatin C, adjusting for: sociodemographic factors, health behaviors, and medical history and accounting for clustering by census tract. At baseline, JHS participants had mean age 55.4 years, and 63.8% were female; mean 1-year and 3-year PM2.5 concentrations were 12.2 and 12.4 μg/m3, and mean 1-year and 3-year O3 concentrations were 40.2 and 40.7 ppb, respectively. Approximately 6.5% of participants had reduced eGFR (30 μg/g), both indicating impaired renal function. Annual and 3-year O3 concentrations were inversely associated with eGFR and positively associated with serum creatinine; annual and 3year PM2.5 concentrations were inversely associated with UACR. We observed impaired renal function associated with increased O3 but not PM2.5 exposure among African Americans.

Numerous treatments are available for type 2 diabetes mellitus (T2DM), which can improve insulin sensitivity or stimulate its secretion. These are usually unable to halt progression. Inhibition of glucose reabsorption from the renal filtrate was proposed as a novel therapeutic target. Sodium/glucose co-transporter 2 (SGLT2) inhibitors were developed accordingly, with canagliflozin the first to launch in the US in 2013.The mechanism of action of canagliflozin, its pharmacokinetic data and its clinical applications and efficacy data from clinical studies of both subjects with T2DM controlled on diet and exercise, and those on glucose-lowering agents and insulin. The evaluation focuses primarily on the safety of canagliflozin in clinical trials conducted for initial registration due to limited post-marketing data, discusses safety in special populations, before comparing its safety with existing therapies.Canagliflozin offers a novel therapeutic approach to T2DM; advantages include weight loss and blood pressure lowering with a low intrinsic risk of hypoglycaemia. The main adverse effects likely to be seen are a very small increase in risk of urinary tract infections and a modest risk of developing genital fungal infections. Studies suggest no increased risk of cardiovascular (CV) disease, but longer duration outcome studies are essential.

Type 2 diabetes mellitus (T2DM) is a public health challenge globally. Numerous treatments are available which can improve insulin sensitivity or stimulate its secretion including biguanides, sulphonylureas and glitazones, as well as insulin, GLP-1 agonists and DPP-IV inhibitors. These are usually unable to halt progression with high resulting morbidity and mortality. New therapies are, therefore, being developed; inhibition of glucose reabsorption from the renal filtrate has been proposed as a novel therapeutic target, and sodium/glucose co-transporter 2 (SGLT2) inhibitors have been developed accordingly.This review summarises the challenge that T2DM poses and describes established therapies. The market for these therapies and likely changes are examined, as well as the scientific rationale behind the development of SGLT2 inhibitors. SGLT2 inhibitors in clinical trials worldwide are reviewed and issues affecting their development are discussed.SGLT2 inhibitors offer a novel therapeutic approach to the management of T2DM; advantages over other agents include weight loss and blood pressure lowering with a low intrinsic risk of hypoglycaemia. The main adverse effects likely to be seen in clinical practice are a very small increase in risk of urinary tract infections, and a modest risk of developing genital fungal infections - which appear more common in the first few months of treatment. Meta-analyses suggest no increased risk of cardiovascular disease, but longer duration outcome studies are essential to prove long-term safety and efficacy.

Background and Purpose— Short-term elevations in fine particulate matter air pollution (PM 2.5 ) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM 2.5 on cerebrovascular function and hemodynamics are unknown. Methods— We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO 2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM 2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season. Results— An interquartile range increase (3.0 µg/m 3 ) in mean PM 2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%–13.8%; P P 2.5 levels. Conclusions— In this cohort of community-dwelling seniors, exposure to PM 2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.

Objectives: To evaluate the association between residential distance to nearest major roadway, as a marker of long-term exposure to traffic pollution, and cognitive function in older adults. Design: Prospective cohort study with median follow-up of 16.8 months. Setting: Community. Participants: Seven hundred sixty-five community-dwelling seniors. Measurements: The Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), category and letter fluency tests, and Clock-in-the-Box Test were administered during home visits on two occasions. The residential distance to the nearest major roadway was calculated, and generalized estimating equations were used to evaluate the association between performance on each test and residential distance to nearest major roadway, adjusting for participant demographics, education, socioeconomic status, and past medical history. Results: Shorter distance to major roadway was associated with statistically significantly poorer performance on the immediate and delayed recall components of the HVLT-R, TMT Part B, TMT delta, and letter and category fluency tests. Generally, participants residing less than 100 m from a major roadway performed worst. Performance improved monotonically with increasing distance. Conclusion: In this cohort of community-dwelling older adults, residential proximity to a major roadway was associated with poorer performance on cognitive tests of verbal learning and memory, psychomotor speed, language, and executive functioning. If causal, these results add to the growing evidence that living near major roadways is associated with adverse health outcomes.