Anna Anderson

11β-HSD1 Inhibitors for the Treatment of Type 2 Diabetes and Cardiovascular Disease

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11β-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11β-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11β-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors.

Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct

The effects of glucocorticoids on fuel metabolism are complex. Acute glucocorticoid excess promotes lipolysis but chronic glucocorticoid excess causes visceral fat accumulation. We hypothesized that interactions between cortisol and insulin and adrenaline account for these conflicting results. We tested the effect of cortisol on lipolysis and glucose production with and without insulin and adrenaline in humans both in vivo and in vitro.

Protecting children in research: Safer ways to research with children who may be experiencing violence or abuse

Children participating in research, like other children, may be being maltreated. There is also potential for exposure to abuse during research. Research training, practices and protocols to respond to disclosure and discovery of abuse to protect both researchers and children may not be sufficiently robust. Our aim was to compare and contrast research practices reported in the literature related to protecting children and to recommend safer ways to conduct research. The simultaneous increase in research with children, along with an increased willingness to listen to child victims of abuse, means that researchers must consider the protection of children in the research setting. Twenty-three papers were identified in a literature review. These studies reported a wide variation of ethical considerations, methods, methodology and came from different disciplines. From the 23 papers, two overarching themes were identified: social justice and research and safer research. To make research safer teams should consider training, safety protocols and support for child protection, which includes support to report safeguarding concerns to social care. Further work is required to ensure that training, protocols and support are effective in facilitating researchers to identify and make appropriate child abuse referrals. Ethics practices in abuse research need further debate.

Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20β-dihydrocortisol (20β-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20β-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20β-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.

An analysis of child protection ‘standard operating procedures for research’ in higher education institutions in the United Kingdom

BackgroundInterest in children’s agency within the research process has led to a renewed consideration of the relationships between researchers and children. Child protection concerns are sometimes not recognised by researchers, and sometimes ignored. Yet much research on children’s lives, especially in health, has the potential to uncover child abuse. University research guidance should be in place to safeguard both researchers and the populations under scrutiny. The aim of this study was to examine university guidance on protecting children in research contexts.MethodsChild protection Standard Operating Procedures (SOPs) were requested from institutions with Research Assessment Exercise (2008) profiles in the top two quartiles according to published league tables. Procedures were included if they applied across the institution and if they were more extensive than stating the university’s general application of the UK Disclosure and Barring Service process. A typology for scoring the SOPs was designed for this study based on the authors’ previous work. The typology and the raw data scoring were reviewed independently by each of the team members and collectively agreed. The raw scores were charted and analysed using descriptive statistics.ResultsSOPs for research conduct amongst vulnerable groups were sought from 83 institutions. Forty HEIs provided policies which met the inclusion criteria. The majority did not mention children, young people or vulnerable adults as a whole, although children in nurseries and young people in universities were addressed. Only three institutions scored over 50 out of a possible 100. The mean score was 17.4. More than half the HEIs made no reference to vetting/barring schemes in research, only eight universities set out a training programme on child protection. Research was often not mentioned in the SOPs and only six mention children in research, with only two fully recognising the extent of child protection in research.DiscussionThere is potential for researchers to recognise and respond to maltreatment of children who participate in research. However, the majority of HEIs do not have an overt culture of safeguarding. There is confusion over what are the roles and responsibilities of HEIs in relation to research that involves children.ConclusionsThe policies that are meant to support and guide research practice, so that children are protected, are in the most part non-existent or poorly developed.