Endocrine Abstracts

Background: Glucocorticoids (GCs) modulate glucose homeostasis by acting on metabolic tissues including liver, adipose, and skeletal muscle. ABCC1 is a transmembrane ‘drug-resistance’ transporter expressed in adipose tissue and skeletal muscle with previously unknown physiological function. We recently showed that ABCC1 modulates intracellular GC concentrations and action in adipose. Here, we tested the hypothesis that Abcc1 regulates GC concentrations in skeletal mu...

Ageing is associated with decline in mitochondrial function whereby dysregulation in carnitine metabolism is highly correlated to poor ageing phenotypes. L-Carnitine transports activated long-chain fatty-acids (FAs) across mitochondrial membranes for β-oxidation and energy production. It is hypothesised that accumulation of long-chain FAs within cells is related to disordered transportation and reflects lower cellular energy upon ageing. Our global aim is to determine the...

Autotaxin (ATX) is a secreted enzyme that generates the lipid signalling molecule LPAs from LPCs. The ATX/lPA axis is strongly linked to fibrotic diseases and therapeutic inhibitors are in development. Assessing the balance of LPC/lPA in diseased target tissues is critical to inform pharmacokinetics/pharmacodynamics (PK-PD) and predict efficacy of ATX inhibitors in vivo. Mass spectrometry imaging (MSI) allows concomitant measurement of multiple molecules with histopat...

Canrenone and mifepristone (RU486) are respectively mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) antagonists commonly used to block or displace steroid for clinical pharmacological or research purposes. The aim of this study was to develop and validate a sensitive, quantitative assay for the combined analysis of glucocorticoids (cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone), mineralocorticoids (aldosterone), canrenoate, and mifepristone...

Canrenone is a mineralocorticoid receptor antagonist used as a diuretic agent to treat hypertension. It is the major active metabolite of spironolactone and may be quantified in clinical studies either to ensure compliance or to gain information about pharmacokinetic-pharmacodynamic interactions.The aim of this study was to develop and validate a sensitive, quantitative assay for the analysis of canrenone in plasma.HPLC mass spectr...

Background: 5α-Reductase (5αR) catalyses conversion of testosterone to its more potent metabolite dihydrotestosterone (DHT) and is inhibited when treating benign prostatic hyperplasia. 5αR has two isozymes; dual isozyme inhibition with dutasteride gives greater DHT suppression than finasteride, which inhibits only 5αR type 2.Aim: To develop a novel assay to simultaneously analyse testosterone, epitestosterone, DHT, androstenedione, du...

Glucocorticoid excess is associated with increased anxiety and accelerated cognitive decline. Concentrations of glucocorticoids within tissues, including the brain, are influenced by local metabolism. 5α-Reductase 1 (5αR1), expressed in brain, converts corticosterone to its A-ring reduced metabolites, which have a different spectrum of activities. Here, we investigated if mice homozygous for disrupted 5αR1 alleles (5αR1-KO) experience heightened anxiety and...

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="...

Background: Visceral fat is a key factor underlying type 2 diabetes. The amount and distribution of body fat is strongly influenced by sex steroids. Androgen receptors (ARs) are present in adipose tissue and are abundant in the detrimental visceral bed. Here, we sought to determine the contribution of the AR in adipose tissue to the pathophysiology of visceral obesity and type 2 diabetes.Methods: Male fat-specific AR-knockout (fARKO) mice (12 weeks; n...

Anti-inflammatory salicylates improve insulin sensitivity, however the mechanism remains unclear. We have observed down-regulation of the glucocorticoid regenerating enzyme 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) by salicylates in cultured adipocytes and in human adipose tissue after oral salsalate therapy, consistent with known transcriptional regulation of 11βHSD1 by pro-inflammatory cytokines. Since inhibition of 11βHSD1 improves insulin sensitivity...