Endocrine Abstracts

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...

Cortisol is regenerated from cortisone by 11βHSD1 reductase in cells from VAT. Mice overexpressing 11βHSD1 in adipocytes have more glucocorticoids in the portal vein (PV) and hepatic insulin resistance. In humans, hepatic vein (HV) sampling during D4-cortisol tracer infusion confirmed substantial splanchnic cortisol generation, and indirect modelling suggested major contributions from both liver and VAT. PV sampling in dogs, however, did not reveal cortisol release f...

The rate limiting steps of hepatic glucocorticoid clearance are via A-ring reduction by 5α- and 5β-reductases. Our recent in vitro studies suggested that products of 5α-reduction (eg 5α-tetrahydrocorticosterone) can activate glucocorticoid receptors and hence may contribute to glucocorticoid action in liver. Here we compared the effects of administering 5α-tetrahydrocorticosterone (5αTHB) in vivo with those of corticosterone (B)....

PPARgamma-agonists improve insulin sensitivity and discourage visceral fat accumulation but mechanisms remain uncertain. In rodents, PPARgamma-agonists downregulate 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in adipose tissue (AT), thereby potentially decreasing intra-adipose glucocorticoid (GC) concentrations. We tested whether PPARgamma-agonists regulate 11b-HSD1 in humans, and if their insulin-sensitising effect is GC-dependent.12 healthy m...

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...

Background: Glucocorticoids (GCs) modulate glucose homeostasis by acting on metabolic tissues including liver, adipose and skeletal muscle. GC access to corticosteroid receptors in these tissues is regulated e.g. by pre-receptor metabolism. We recently identified a role for ABCC1, a transmembrane ‘drug-resistance’ transporter, as a GC exporter which limits intracellular GC concentrations and action in adipose tissue. Here, we tested the hypothesis that ABCC1, which i...

A genome wide meta-analysis by the CORtisol NETwork (CORNET) consortium1 has identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with changes in morning plasma cortisol and predictive of cardiovascular disease (Crawford et al, Unpublished). SERPINA6 encodes Corticosteroid Binding Globin (CBG) which binds most cortisol in blood and influences delivery of cortisol to target tissues. We hypothesised th...

Background: Adipose tissue dysfunction could partially explain the well-demonstrated association between obesity and survival in breast cancer (BC). Oestrogen and glucocorticoid concentrations and their respective activation enzymes, oestrogenic 17β-hydroxysteroid dehydrogenases (17βHSDs) and aromatase, and 11βHSD1 are increased in adipocyte hyperplasia and hypertrophy, supporting the hypothesis of a potential role for locally generated steroids in obesity-assoc...

Intracellular cortisol is regulated by 11βHSD1. Although the field has focused on regeneration of cortisol from inert cortisone by 11β-reductase activity of 11βHSD1, we have used stable isotope tracers and arteriovenous sampling to quantify simultaneous dehydrogenase (cortisone generation) and reductase (cortisol regeneration) in human adipose and skeletal muscle. In vitro studies suggest insulin regulates this balance of reductase vs dehydrogenase acti...

Congenital adrenal hyperplasia (CAH) is associated with poor health outcomes. This is, in part, because doses of glucocorticoid sufficient to suppress excess adrenal androgens are also associated with adverse metabolic effects such as insulin resistance. This toxicity occurs with efficacious doses of all commonly prescribed glucocorticoids (hydrocortisone, prednisolone and dexamethasone). However, the glucocorticoid corticosterone may have an improved therapeutic index because...