Searchable abstracts of presentations at key conferences in endocrinology

ea0011oc28 | Diabetes and metabolism | ECE2006

11β-Hydroxysteroid dehydrogenase type 1 oxo-reductase activity is increased in patients with alcoholic chronic liver disease: the key to the phenotype of the alcoholic pseudo-Cushing’s state?

Ahmed A , Saksena S , Elias E , Stewart PM

The pseudo-Cushing’s syndrome that accompanies both acute alcohol ingestion and alcohol withdrawal is an important differential diagnosis of hypercortisolism that is poorly understood. Two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) interconvert hormonally active cortisol (F) and inactive cortisone (E). Previously we have shown higher urinary F:E metabolite ratios (a reflection of total body 11βHSD activity) in patients with alcoholic liver disea...

ea0011p334 | Diabetes, metabolism and cardiovascular | ECE2006

Regulation of hexose-6-phosphate dehydrogenase (H6PDH) in human fetal liver WRL-68 cells

Swali A , Bujalska I , Stewart PM , Walker EA

Excessive glucocorticoid exposure has been implicated in the pathogenesis of obesity and the metabolic syndrome. The in vivo conversion of inactive to active glucocorticoids is catalysed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), requiring NADPH as a cofactor. Hexose-6-phosphate dehydrogenase (H6PDH) is co-localised with 11β-HSD1 in the lumen of the endoplasmic reticulum and controls local NADPH availability. Thus H6PDH plays an important role...

ea0019p135 | Diabetes, Metabolism and Cardiovascular | SFEBES2009

Knockdown of H6PDH in C2C12 muscle cells impairs 11β-HSD1 activity and myogenic differentiation

Saqib KM , Sherlock M , Walker EA , Stewart PM , Lavery GG

NADPH generated by hexose-6-phosphate dehydrogenase (H6PDH) within the lumen of the endoplasmic reticulum (ER) drives the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) allowing the production of active glucocorticoids. H6PDH knockout (H6PDHKO) mice develop a vacuolating myopathy, reduced muscle mass and display activation of the ER stress response. However, the role of glucocorticoids and 11β-HSD1 in the myopathy phenotype is not clear...

ea0011p38 | Bone | ECE2006

Glucocorticoid metabolism in mouse osteoblasts: a model for the effects of local glucocorticoid generation on bone

Crook R , Hewitt K , Stewart PM , Rabbitt EH , Cooper MS

Human studies have suggested that local glucocorticoid (GC) generation within osteoblasts plays a critical role in bone loss seen during aging, in response to inflammation and treatment with GCs. Human osteoblasts express the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that converts inactive GCs (cortisone, dehydrocorticosterone, prednisone) to their active counterparts (cortisol, corticosterone, prednisolone). Enzyme expression increases with age, in r...

ea0011p307 | Diabetes, metabolism and cardiovascular | ECE2006

Altered cholesterol and bile acid homeostasis in the hexose-6-phosphate dehydrogenase (H6PDH) knockout mouse

Hewitt KN , Bujalska IJ , Lavery GG , Stewart PM , Walker EA

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD type 1 (11β-HSD1) predominantly displays oxo-reductase activity, converting cortisone in man, 11-dehydrocorticosterone in rodents, to cortisol and corticosterone respectively – a reaction requiring the cofactor NADPH. The generation of a hexose-6-phosphate ...

ea0011p406 | Diabetes, metabolism and cardiovascular | ECE2006

Dehydroepiandrosterone inhibits differentiation, proliferation and 11β-hydroxysteroid dehydrogenase type 1 activity in human preadipocytes

McNelis J , Bujalska IJ , Stewart PM , Arlt W

The adrenal steroid dehydroepiandrosterone (DHEA) has been shown in vivo, to mimic the effects of peroxosome proliferator-activated receptor (PPAR) ligands and oppose those of glucocorticoids, thus producing beneficial effects on insulin sensitivity and adipogenesis in obese and diabetic rodents. Furthermore, DHEA treatment has recently been shown to reduce subcutaneous and visceral fat in humans in vivo. However, the mechanism by which DHEA produces these anti-a...

ea0011p584 | Neuroendocrinology and behaviour | ECE2006

The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis

Agha A , Tomlinson J , Clark PM , Holder G , Stewart PM

The high dose short Synacthen (corticotropin) test (SST) is widely used to investigate suspected secondary adrenal insufficiency but concern remains about falsely reassuring results with potentially serious clinical consequences.In order to evaluate the long-term safety of the SST, we retrospectively evaluated the clinical outcome in 178 patients who achieved 30-minute cortisol values in the lowest 15th percentile of normal healthy responses. This subgro...

ea0011p745 | Steroids | ECE2006

Tissue specific regulation of insulin signalling: a mechanism of glucocorticoid induced obesity?

Gathercole LL , Bujalska IJ , Stewart PM , Tomlinson JW

The pathological effects of glucocorticoids (GC) are exemplified by patients with Cushing’s syndrome who develop central obesity, insulin resistance and in some cases, type 2 diabetes mellitus. It is generally accepted that GC cause insulin resistance, however, both insulin and GC increase adipocyte differentiation. The question therefore arises as to how GC stimulate adipocyte differentiation whilst apparently making adipocytes insulin resistant. We have hypothesized tha...

ea0011p757 | Steroids | ECE2006

11beta-hydroxysteroid dehydrogenase is an early and essential marker of human adipogenesis

Bujalska IJ , Gatherocole LL , Tomlinson JW , Darimont C , Stewart PM

The prevalence of obesity and its association with many health complications have evoked a high interest in adipose tissue metabolism. In man, glucocorticoid (GC) excess increases fat mass and the risk of developing Metabolic Syndrome. The enzyme responsible for modifying intracellular GC concentrations in adipose tissue is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The aim of this study was to characterise the novel human preadipocyte cell line (Chub-S7) an...

ea0011p768 | Steroids | ECE2006

Phenotypic variability in P450 oxidoreductase deficiency may be caused by differential effects of P450 oxidoreductase mutations on steroidogenesis

Dhir V , Ivison HE , Doherty AJ , Stewart PM , Arlt W

Without adequate treatment patients with acromegaly die prematurely from cardiovascular disease (CVD); however the contribution of atherosclerosis in this process is controversial. Increased carotid IMT is an early morphological marker of atherosclerosis and predictor of subsequent cardiovascular events. Contradictory data exist regarding IMT in patients with acromegaly.We measured carotid IMT in 79 patients with acromegaly (47 male, mean age 55±14 ...