11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects

A combination of polymorphisms in HSD11B1 associates with in vivo 11{beta}-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome.

OBJECTIVE: Regeneration of cortisol by 11\u3b2-hydroxysteroid dehydrogenase type 1 (11\u3b2-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11\u3b2-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11\u3b2-HSD1 expression and activity are unknown. METHODS: We explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11\u3b2-HSD1 expression and activity in a nested study of 40 women from this cohort. RESULTS: HSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort=2.77 (95% confidence interval (CI) 1.16-6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1\ub10.7\u200anmol/min versus 12.1\ub11.1, P=0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion. CONCLUSIONS: We conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11\u3b2-HSD1 expression and activity, which associates with the metabolic syndrome

The functions of Australian towns, revisited

This paper reports an inter-temporal investigation of urban employment and spatial trends in Australian urbanisation over nearly a half century using city classification methodology. Published in this journal in 1965, Robert Smith's classic paper, 'The Functions of Australian Towns', provides the benchmark analysis. Smith used 1954 employment census data to group the then national total of 422 urban places into functional categories which provided a succinct description of the pattern of early postwar urbanisation. The present study revisits (without exactly replicating) Smith's study, employing 1996 data for 741 urban centres. A two-stage procedure using principal components and cluster analyses identifies 13 functional town groupings which capture both enduring and new patterns of employment distribution across the Australian urban system. Copyright (c) 2003 by the Royal Dutch Geographical Society KNAG.