Endocrine Abstracts

5alpha-Reductase 1 (5aR1) catalyses A-ring reduction of glucocorticoids and androgens. We previously demonstrated that transgenic disruption of 5aR1 predisposes male mice to fatty liver and insulin resistance when challenged with a high-fat diet. Here, we have dissected the contributions of androgens and glucocorticoids to the metabolic phenotype using 2 models of enzyme inhibition (trangenesis and pharmacology).Female 5aR1−/− mice (KO) and w...

In order to assess the frequency and timing of recurrence in a group of patients with Graves’ disease and the predictors of recurrence, 197 patients were sampled, who were first seen in the OCDEM clinic in either 2001 or 2002 and put on anti-thyroid medication. Graves’ disease was diagnosed by the presence of low TSH levels ± symmetrical goitre ± uniform radioactive iodine uptake ± eye disease ± high levels of thyroid hormones. Patients with <...

Methyl oxime–trimethylsilyl (MO-TMS) derivatisation with gas chromatography–mass spectrometric (GC-MS) analysis has been well established in the analysis of glucocorticoids and is still used in many laboratories for profiling endogenous steroids for clinical purposes. There appears to be a clinical need to extend the analysis to xenobiotic glucocorticoids, primarily to elucidate cases of patients presenting with adverse symptoms associated with glucocorticoid excess,...

Fatty liver disease is strongly associated with insulin resistance. In order to elucidate the causality of this complex relationship, we studied insulin resistance in a rodent model of fatty liver disease – the choline deficient diet (CDD) – in which fatty liver occurs without generalised obesity. C57Bl/6 mice were fed a low fat (10% calories as fat, ‘Lo’) or isocaloric high fat diet (45% calories as fat, ‘Hi’) for 3 weeks; then half of the animal...

Excessive glucocorticoid exposure has been implicated in the pathogenesis of obesity and the metabolic syndrome. The in vivo conversion of inactive to active glucocorticoids is catalysed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), requiring NADPH as a cofactor. Hexose-6-phosphate dehydrogenase (H6PDH) is co-localised with 11β-HSD1 in the lumen of the endoplasmic reticulum and controls local NADPH availability. Thus H6PDH plays an important role...

Case reports in humans implicate glucocorticoid (GC) excess, through exogenous administration or endogenous overproduction, as a cause of non-alcoholic fatty liver disease. In rodents, massive doses of GCs have induced fatty liver when liver fat was measured in the fasting state. The mechanisms through which GCs might induce fatty liver are unknown, but are thought to be secondary to insulin resistance/hyperinsulinaemia. In this study, we examined the effect of dexamethasone (...

Objective:The activity of hepatic enzymes that metabolise glucocorticoids is altered in the setting of the metabolic syndrome. Westerbacka et al suggested a specific association between fatty liver and increased 5beta-reductase enzyme activity (J Clin Endocrinol Metab 2003). We hypothesised that non-alcoholic fatty liver disease (NAFLD), which is strongly associated with insulin resistance, may be primarily responsible for these changes.<p cla...

Mechanisms underlying the association of low birth weight with the metabolic syndrome in adults remain poorly understood. Epidemiological studies suggest that obesity is not programmed by early life events, but amplifies the risks of intra-uterine growth retardation. We have explored the effects of dietary obesity in rats in which features of the metabolic syndrome have been programmed by prenatal dexamethasone.16 pregnant Wistar rats were treated with d...

Hepatic A-ring reduction of glucocorticoids is enhanced in obesity, perhaps contributing to compensatory activation of the hypothalamic-pituitary-adrenal axis and adrenal androgen excess. One pathway activated is the formation of tetrahydro metabolites by two sequential steps catalysed by 5beta-reductase (5bR) followed by 3alpha-hydroxysteroid dehydrogenases (3HSD). However, regulation of these enzymes is understood poorly. 5bR and 3HSD are also involved in the conversion of c...

Angiogenesis, which is tightly regulated in health and disturbed in many diseases, is inhibited by glucocorticoids. Local glucocorticoid availability within the vessel wall is determined by the pair of enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11HSD-1 and 2) that catalyse the interconversion of active glucocorticoid (corticosterone in mice, cortisol in humans) with inactive 11-dehydrocorticosterone or cortisone. We hypothesized that regeneration of active gluco...