Searchable abstracts of presentations at key conferences in endocrinology
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Society for Endocrinology BES 2011

ea0025oc2.1 | Steroids | SFEBES2011

Regulation of 11β-hydroxysteroid dehydrogenase type 1 by NF-κB in stromal cells: towards tissue specific enzyme inhibition

Ahasan Mohammad , Jones Chris , Hardy Rowan , Hassan-Smith Zaki , Lavery Gareth , Rabbitt Elizabeth , Buckley Cristopher , Raza Karim , Stewart Paul , Cooper Mark

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is a tissue specific regulator of glucocorticoid action that is linked to the development of osteoporosis, inflammatory arthritis and myopathy. Systemic inhibition of 11β-HSD1 enzyme activity has been proposed as a therapeutic option in these conditions. However, 11β-HSD1 activity has also been reported to be important in regulation of the immune response and the HPA axis. We have previously demo...

ea0025oc2.2 | Steroids | SFEBES2011

Anti-inflammatory mechanisms of 5α-reduced glucocorticoids: potential dissociated steroids

Nixon Mark , Yang Chenjing , Rossi Adriano , Walker Brian , Andrew Ruth

We recently showed that 5α-reduced metabolites of corticosterone (B), namely 5α-dihydrocorticosterone (5αDHB) and 5α-tetrahydrocorticosterone (5αTHB), possess similar anti-inflammatory properties to B, but have lesser metabolic effects. Here, we explored the anti-inflammatory mechanisms of these 5α-reduced metabolites in vitro. Data are mean % suppression/induction, compared by one way ANOVA, *P<0.05 versus vehicle.<p class="...

ea0025oc2.3 | Steroids | SFEBES2011

APEX1, a novel, negative regulator of aldosterone synthase activity, differentially binds to a single nucleotide polymorphism in the aldosterone synthase gene and represses transcriptional activity both in vitro and in vivo

McManus Frances , Sands William , Fraser Robert , Davies Eleanor , Connell John

Aldosterone synthesis is heritable; a single nucleotide polymorphism (SNP) in the promoter of the aldosterone synthase gene (position −344, rs1799998) has been associated with an increased plasma aldosterone levels and hypertension. However, deletion of this site has no effect on gene transcription in vitro and therefore the mechanism that links genotype with phenotype is unclear.We identified a polymorphism at position −1651 T/C (rs13...

ea0025oc2.4 | Steroids | SFEBES2011

Altered miR-125 and miR-134 expression in aldosterone-producing adenoma and post-transcriptional regulation of the CYP11B2 gene

Wood Stacy , Ejaz Ayesha , Livie Craig , MacKenzie Scott , Connell John , Davies Eleanor

Essential hypertension is known to have a large genetic component. Variation in the CYP11B2 gene, which encodes the aldosterone synthase enzyme, is associated with excess aldosterone production and hypertension but the causative mechanism remains elusive. miRNAs are a class of post-transcriptional regulatory molecules, implicated in cardiovascular disease, development and tumourogenesis. They act by targeting the 3′ untranslated region (UTR) of mRNAs, inhibiting t...

ea0025oc2.5 | Steroids | SFEBES2011

A novel entity of isolated adrenal insufficiency caused by partial inactivation of P450 side-chain cleavage (CYP11A1) enzyme

Parajes Silvia , Kamrath Clemens , Rose Ian , Taylor Angela , Mooij Christiaan , Dhir Vivek , Grotzinger Joachim , Arlt Wiebke , Krone Nils

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, facilitating conversion of cholesterol to pregnenolone. Cholesterol, transported by steroidogenic acute regulatory protein (StAR) into the inner mitochondrial membrane, is converted by CYP11A1 into 22R-hydroxycholesterol. Subsequently, CYP11A1 converts 22R-hydroxycholesterol by 20alpha-hydroxylation and cleavage of the C20–C22 bond into pregnenolone. All pat...

ea0025oc2.6 | Steroids | SFEBES2011

Novel non-steroidal glucocorticoids that dissociate rapid signalling effects from gene transcription

Trebble Peter , Simpson Karen , Matthews Laura , Farrow Stuart , Ray David

Glucocorticoids (GCs) are used extensively in the treatment of inflammatory disease. Unfortunately, as GC act on virtually every organ system they also carry a broad range of serious side-effects which limits their clinical use.The structure of the bound GC strongly impacts the final conformation of the glucocorticoid receptor (GR) and thereby dictates downstream events. Designing drugs with different GR binding properties therefore offers a plausible ro...

ea0025oc2.7 | Steroids | SFEBES2011

Depot specific differences in the sensitivity to glucocorticoid and insulin action in human adipose tissue

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

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Differences in gene expression between omental (om) and subcutaneous (sc) adipose have been described, but molecular mechanisms underpinning differences in adipose biology are not known. Patients with glucocorticoid excess, Cushing’s syndrome, develop a phenotype characterized by central obesity. We have characterized the regulation of lipogenesis by gluco...

ea0025oc2.8 | Steroids | SFEBES2011

Metformin increases in vivo 11β-hydroxysteroid dehydrogenase type 1 activity in euglycaemic obese men

Stimson Roland , Andrew Ruth , Jones Gregory , Livingstone Dawn , Smith Kenneth , Walker Brian

Inhibiting cortisol regeneration by 11β-HSD1 is a promising therapy for type two diabetes. In obesity, 11β-HSD1 activity is increased in adipose tissue but decreased in the liver, the latter putatively mediated by hyperinsulinaemia. We tested whether insulin sensitisation with metformin regulates 11β-HSD1 activity in whole body and in liver in obesity.Five obese men (age 48±5 years, BMI 39.8±3.6 kg/m2) participated in ...