Searchable abstracts of presentations at key conferences in endocrinology

ea0013oc12 | Clinical and translational endocrinology | SFEBES2007

Local and systemic consequences of glucocorticoid metabolism in synovium

Hardy Rowan , Cooper Mark Stewart Paul , Buckley Chris , Raza Kirim , Rabbitt Elizabeth , Cooper Mark

Therapeutic glucocorticoids are used in rheumatoid arthritis (RA) to reduce inflammation and bone destruction. We recently reported that primary synovial fibroblasts generate active glucocorticoids via expression of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme activates cortisol from inactive cortisone (and prednisolone from prednisone) and this activity is up-regulated by inflammation. We have now examined glucocorticoid metabolism in synovial tissu...

ea0013oc21 | Novartis Basic Endocrinology Award | SFEBES2007

Muscle cell differentiation is regulated by glucocorticoids, a process which is potentiated through the induction of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Sherlock Mark , Lavery Gareth , Horsburgh Jenny , Slabbert Ana , Toogood Andy , Stewart Paul

In vivo the 11β-HSD1 enzyme converts inactive cortisone to the active glucocorticoid cortisol. 11β-HSD1 is implicated in the metabolic syndrome through its expression in liver and adipose tissue by increasing local cortisol concentrations. However, little is known regarding the expression and function of 11β-HSD1 in muscle.Murine C2C12 muscle cells (myocytes) were differentiated from myoblasts to myotubules for 8 days, with and without the...

ea0013p178 | Diabetes, metabolism and cardiovascular | SFEBES2007

Abnormalities in lipogenesis and lipolysis in Mice Lacking Hexose-6-Phosphate Dehydrogenase (H6PDH)

Hewitt Kylie , Bujalska Iwona , Lavery Gareth , Hauton David , Walker Elizabeth , Stewart Paul

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. In adipose tissue, GCs are regulated at the prereceptor level by oxo-reductase activity of 11beta-hydroxysteroid dehydrogenases type 1 (11β-HSD1). The hexose-6-phosphate dehydrogenase null mouse (H6PDH/KO) has shown that H6PDH is required for generating NADPH within the endoplasmic reticulum which determines the direction of 11β-HSD1 enzyme. We have shown that mRNA f...

ea0013p283 | Steroids | SFEBES2007

Regulation of insulin signalling across differentiation and following glucocorticoid treatment in human skeletal myocytes

Morgan Stuart , Gathercole Laura , Bujalska Iwona , Stewart Paul , Smith David , Tomlinson Jeremy

Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite the increasing use of GCs as therapeutic agents, the molecular mechanisms that underpin the GC mediated changes in insulin signalling are not clear. The majority of previous studies have used rodent models and have shown regulation at the level of the insulin receptor (IR), IRS-1 and PI3 kinase.Primary cultures of human skeletal myocytes ...

ea0012s14 | New frontiers in steroid hormone metabolism | SFE2006

P450 oxidoreductase and androgen metabolism

Dhir Vivek , Krone Nils , Ivison Hannah E , Stewart Paul M , Shackleton Cedric HL , Arlt Wiebke

P450 oxidoreductase (POR) has a pivotal role as electron donor to all cytochrome P450 enzymes that are microsomally located, i.e. CYP type II enzymes. Importantly, those include key enzymes involved in glucocorticoid and sex steroid biosynthesis such as CYP17 and CYP21. In addition, the activity of hepatic CYP enzymes involved in drug metabolism and detoxification also crucially depend on the transfer of electrons from NADPH via POR. Recently, mutations in P450 oxidoreductase ...

ea0038p211 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2015

Longitudinal changes in adipose tissue gene expression profile are asociated with deteriorating glucose tolerance

Woods Conor , Crowley Rachel , Gathercole Laura , Hughes Beverly , Gray Joanna , McCarthy Theresa , Crabtree Nicola , Stewart Paul , Tomlinson Jeremy

Increased adiposity is associated with insulin resistance, type 2 diabetes and metabolic dysfunction. Altered adipokine secretion, changes in local and systemic glucocorticoid metabolism and increased inflammation have all been postulated as contributory mechanisms. We have previously described changes in subcutaneous adipose tissue (SAT) gene expression that are associated with obesity and glucose intolerance in cross-sectional studies. However, the effects of longitudinal ch...

ea0038p399 | Steroids | SFEBES2015

Glucocorticoid-induced lipolysis across human ageing and the relationship to fat mass and androgens

Hassan-Smith Zaki , Taylor Angela , Hughes Beverly , Brady Theresa , Jones Pamela , Morgan Stuart , Lavery Gareth , Tomlinson Jeremy , Stewart Paul

Background: Excess glucocorticoid (GC) exposure is associated with an adverse body composition and metabolic profile characterised by increasing fat mass, muscle atrophy, insulin resistance, fatty liver, and dyslipidaemia culminating in increased cardiovascular risk. GCs are widely prescribed with increasing age where their effects can have deleterious effects.Objectives: To investigate the impact of GC exposure on subcutaneous adipose lipid metabolism a...

ea0037gp.04.03 | Steroids | ECE2015

Using a morning cortisol to predict adrenal reserve and guide management

Woods Conor , Argese Nicola , Chapman Matthew , Webster Rachel , Toogood Andrew , Arlt Wiebke , Stewart Paul , Crowley Rachel , Tomlinson Jeremy

Background: The short Synacthen test (SST) is the most widely used dynamic assessment of adrenal reserve. In some situations, the SST may be difficult to perform. Random basal cortisol levels could provide an alternative screening assessment to rationalize which patients need dynamic testing. This is highly clinically relevant, given the large numbers of patients taking prescribed glucocorticoids who are at risk of iatrogenic adrenal suppression.Methods:...

ea0034oc3.1 | Steroids | SFEBES2014

Lack of 11β-hydroxysteroid dehydrogenase type 1 ameliorates the adverse features of Cushing's syndrome

Morgan Stuart , McCabe Emma , Gathercole Laura , Hassan-Smith Zaki , Larner Dean , Bujalska Iwona , Stewart Paul , Tominson Jeremy , Lavery Gareth

Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have a significant adverse effect profile, leading to a Cushingoid phenotype. In the present study, we test the hypothesis that reactivation of glucocorticoids, in peripheral tissues by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), is a major determinant of exogenous Cushing’s syndrome.WT, global 11β-HSD1 knockout (GKO), liver-specific 11β-HSD...

ea0034p260 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2014

Longitudinal changes in glucocorticoid metabolism predict the development of metabolic phenotype

Crowley Rachel , Hughes Beverly , Gray Joanna , McCarthy Theresa , Hughes Susan , Shackleton Cedric , Crabtree Nicola , Nightingale Peter , Stewart Paul , Tomlinson Jeremy

Dysregulation of the enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistant states, however longitudinal changes in glucocorticoid metabolism over time have not been investigated. This study was designed to evaluate the role of pre-receptor glucocorticoid metabolism in the development of insulin resistance and obesity. 24 h urinary glucocorticoid and mineralocorticoid metabolites were measured by gas chroma...