Endocrine Abstracts

Adipose exposure to glucocorticoids (GCs) results in visceral adiposity and insulin resistance. Only the unbound, free fraction of GC can diffuse into cells. Corticosteroid binding globulin (CBG) is the major GC carrier, binding 80–85% of circulating GCs with high affinity. Targeted proteolysis of CBG by neutrophil elastase (NE) significantly reduces CBG binding affinity. This suggests that neutrophil-mediated inflammation provides a regulatory mechanism for delivery of G...

Adipose exposure to glucocorticoids (GCs) results in visceral adiposity and insulin resistance. Only the unbound, free fraction of GC can diffuse into cells. Corticosteroid binding globulin (CBG) is the major GC carrier, binding 80–85% of circulating GCs with high affinity. Targeted proteolysis of CBG by neutrophil elastase (NE) significantly reduces CBG binding affinity. This suggests that neutrophil-mediated inflammation provides a regulatory mechanism for delivery of G...

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="...

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...

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...

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...

Background: Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol and controls the circulating free cortisol pool. Proteolytic cleavage by neutrophil elastase is proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. The CORtisol NETwork (CORNET) consortium found that genetic variation at a locus spanning SERPINA1 (encoding alpha-1 antitrypsin, A1AT, the endogenous inhibitor of neutrophil elastase) and SE...

Glucocorticoids (GCs) are highly effective anti-inflammatory drugs, however their use is limited by serious side effects. We have previously shown that 5αTHB binds GC receptor (GR) and suppresses inflammation in vitro and in vivo, without affecting metabolism. Here the underlying molecular mechanisms were explored in cell models of ligand-induced GR phosphorylation, nuclear localisation and gene transcription. Data are mean±S.E.M. (th...

Introduction: Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol and modulates free cortisol levels. Observations in vitro show that CBG is cleaved by neutrophil elastase (NE), a mechanism proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. However, detection of cleaved CBG in vivo in human plasma is controversial, and any influence of NE on CBG cleavage has not been tested in vivo...