Endocrine Abstracts

Background: CYP11A1 encodes the P450 side chain cleavage enzyme (P450scc) responsible for initiating steroidogenesis and classically gives rise to disordered sex development plus adrenal and gonadal insufficiency. The rs6161 variant in exon 5 of CYP11A1 (c.940G>A; p.E314K) has previously been considered as ‘benign’. When next generation sequencing was performed in patients with primary adrenal insufficiency of unknown etiology the rs6161 variant was foun...

Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to regulate immunity, energy metabolism, and tissue repair. The inactive GR is held in the cytoplasm in a multi-protein complex, which upon ligand binding undergoes a conformational change. Activated GR translocates to the nucleus to regulate gene expression (over hours), but some effects occur more rapidly. Gc inhibit cell migration through an uncertain mechanism. We now show a very rapid effect, and surprising...

Glucocorticoids (GCs) have potent immunomodulatory and anti-inflammatory effects and are widely used in the treatment of inflammatory diseases. Unfortunately, their long term administration causes serious systemic metabolic side effects including osteoporosis, muscle wasting and insulin resistance. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is responsible for the local conversion of inactive GCs to their active counterparts. It has been shown that many of the...

Background: Primary aldosteronism (PA) accounts for a significant proportion of patients with hypertension. There has been a focus on ACTH in the pathogenesis of aldosterone secretion even with suppressed renin. With the link between psychological stress and cardiovascular disease as well as the association between anxiety and PA, there may be broader neurohormonal “stress” stimuli that modulate aldosterone production in PA patients, beyond the HPA axis. PA patients ...

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependant oxo-reductase located in the sarcoplasmic reticulum (SR) lumen of skeletal muscle. It generates active glucocorticoids to regulate permissive and adaptive metabolism. Hexose-6-phosphate dehydrogenase (H6PD) interacts with 11β-HSD1 to generate an appropriate NADPH/NADP+ ratio to support activity. H6PD depletion impairs SR NADPH generation triggering 11β-HSD1 to assume glucocorticoid ina...

Background and aims: HNF1A-MODY causes monogenic diabetes with a lean, insulin sensitive phenotype. Altered glucocorticoid (GC) metabolism has been implicated in the pathogenesis of type 2 diabetes (T2D) and inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which regenerates active cortisol from inactive cortisone have been trialled as a therapeutic approach. 11β-HSD1 is down-regulated in hepatocytes from Hnf1a knock-out mice but the role...