Brian R Walker

Heart Research Institute (UK), Norwich, England, United Kingdom

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Publications (210)1180.19 Total impact

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    ABSTRACT: Global deficiency of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis and reduces acute infarct expansion following myocardial infarction (MI) suggesting that 11β-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11β-HSD1 deficiency could prevent the development of heart failure following MI, and examined whether 11β-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11β-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase) underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11β-HSD1 deficient mice had reduced infarct size (34.7±2.1%LV vs 44.0±3.3%LV, P=0.02), improved function (ejection fraction 33.5±2.5% vs 24.7±2.5%, P=0.03) and reduced ventricular dilation (LVEDV 0.17±0.01ml vs 0.21±0.01ml, P=0.01). This was accompanied by a reduction in hypertrophy, pulmonary edema and in the expression of genes encoding atrial natriuretic peptide and β-myosin heavy chain. None of these outcomes, nor promotion of peri-infarct angiogenesis during infarct repair, were recapitulated when 11β-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11β-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11β-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease.
    Endocrinology 10/2015; DOI:10.1210/en.2015-1630 · 4.50 Impact Factor

  • 10/2015; DOI:10.1530/endoabs.38.OC4.3
  • Tracy C S Mak · Dawn E W Livingstone · Brian R Walker · Ruth Andrew ·

    10/2015; DOI:10.1530/endoabs.38.OC4.4
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    ABSTRACT: The health behaviours of pregnant women with very severe obesity are not known, though these women are at high risk of pregnancy complications. We carried out a prospective case-control study including 148 very severely obese (BMI >40 kg/m²) and 93 lean (BMI <25 kg/m²) pregnant women. Diet, physical activity, smoking, alcohol and folic acid consumption were assessed by questionnaire in early and late (16 and 28 weeks gestation) pregnancy. Circulating levels of iron, vitamin B12 and folate and other essential trace elements and minerals were measured in a subset at each time point. The findings biochemically confirmed that very severely obese women consumed diets that were energy-rich but poor in essential micronutrients. A third of all women met physical activity recommendations for pregnancy. A third of very severely obese women and two thirds of lean women took folic acid supplements prior to pregnancy. Very severely obese women were more likely to smoke but less likely to drink alcohol than lean women (all p < 0.05). Women with very severe obesity have low self-reported intakes and circulating levels of essential micronutrients in pregnancy and few follow current recommendations for pregnancy nutrition and lifestyle. These high-risk women represent a group to target for education about health behaviours prior to and during pregnancy.
    Nutrients 10/2015; 7(10):8431-8443. DOI:10.3390/nu7105403 · 3.27 Impact Factor
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    ABSTRACT: Background: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. Method: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. Results: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25pmol/L (95% CI -0.45 to -0.043pmol/L) per/day increase in gestation). Conclusion: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
    Psychoneuroendocrinology 09/2015; 63. DOI:10.1016/j.psyneuen.2015.09.019 · 4.94 Impact Factor
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    ABSTRACT: Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including following intracerebroventricular drug administration to the CNS alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of beta amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid-regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline, but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology, and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia.
    Endocrinology 08/2015; 156(12):en.2015-1395. DOI:10.1210/en.2015-1395 · 4.50 Impact Factor
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    ABSTRACT: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case-control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy (n = 10/group). Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy.
    Diabetologia 08/2015; 58(11). DOI:10.1007/s00125-015-3708-3 · 6.67 Impact Factor
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    ABSTRACT: Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes. We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs ≥40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843. Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0·029, 95% CI -0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74-17·50; p=0·11). Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes. The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership. Copyright © 2015 Chiswick et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
    07/2015; 3(10). DOI:10.1016/S2213-8587(15)00219-3
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    ABSTRACT: The generation and analysis of vascular lesions in appropriate animal models is a cornerstone of research into cardiovascular disease, generating important information on the pathogenesis of lesion formation and the action of novel therapies. Use of atherosclerosis-prone mice, surgical methods of lesion induction, and dietary modification has dramatically improved understanding of the mechanisms that contribute to disease development and the potential of new treatments. Classically, analysis of lesions is performed ex vivo using 2-dimensional histological techniques. This article describes application of optical projection tomography (OPT) to 3-dimensional quantitation of arterial lesions. As this technique is non-destructive, it can be used as an adjunct to standard histological and immunohistochemical analyses. Neointimal lesions were induced by wire-insertion or ligation of the mouse femoral artery whilst atherosclerotic lesions were generated by administration of an atherogenic diet to apoE-deficient mice. Lesions were examined using OPT imaging of autofluorescent emission followed by complementary histological and immunohistochemical analysis. OPT clearly distinguished lesions from the underlying vascular wall. Lesion size was calculated in 2-dimensional sections using planimetry, enabling calculation of lesion volume and maximal cross-sectional area. Data generated using OPT were consistent with measurements obtained using histology, confirming the accuracy of the technique and its potential as a complement (rather than alternative) to traditional methods of analysis. This work demonstrates the potential of OPT for imaging atherosclerotic and neointimal lesions. It provides a rapid, much needed ex vivo technique for the routine 3-dimensional quantification of vascular remodelling.
    Journal of Visualized Experiments 05/2015; 2015(99). DOI:10.3791/50627 · 1.33 Impact Factor
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    ABSTRACT: Introduction Increasing evidence suggests obesity has its origins prior to birth. There is clear correlation between maternal obesity, high birthweight and offspring risk of obesity in later life. It is also clear that women who are obese during pregnancy are at greater risk of adverse outcomes, including gestational diabetes and stillbirth. The mechanism(s) by which obesity causes these problems is unknown, although hyperglycaemia and insulin resistance are strongly implicated. We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications. Methods and analysis The Efficacy of Metformin in Pregnant Obese Women, a Randomised controlled (EMPOWaR) trial is a double-masked randomised placebo-controlled trial to determine whether metformin given to obese (body mass index >30 kg/m2) pregnant women from 16 weeks’ gestation until delivery reduces the incidence of high birthweight babies. A secondary aim is to test the mechanism(s) of any effect. Obese women with a singleton pregnancy and normal glucose tolerance will be recruited prior to 16 weeks’ gestation and prescribed study medication, metformin or placebo, to be taken until delivery. Further study visits will occur at 28 and 36 weeks’ gestation for glucose tolerance testing and to record anthropometric measurements. Birth weight and other measurements will be recorded at time of delivery. Anthropometry of mother and baby will be performed at 3 months postdelivery. As of January 2014, 449 women had been randomised across the UK. Ethics and dissemination The study will be conducted in accordance with the principles of Good Clinical Practice. A favourable ethical opinion was obtained from Scotland A Research Ethics Committee, reference number 10/MRE00/12. Results will be disseminated at conferences and published in peer-reviewed journals. Trial registration number ISRCTN51279843.
    BMJ Open 01/2015; 5(1):e006854-e006854. DOI:10.1136/bmjopen-2014-006854 · 2.27 Impact Factor
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    ABSTRACT: Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150×3mm, 2.6µm), using a gradient run of 19min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289→97), DHT (m/z 291→255), androstenedione (m/z 287→97), dutasteride (m/z 529→461), finasteride (m/z 373→317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.
    Talanta 12/2014; 131. DOI:10.1016/j.talanta.2014.07.087 · 3.55 Impact Factor
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    ABSTRACT: High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 12/2014; 91. DOI:10.1016/j.neuropharm.2014.12.005 · 5.11 Impact Factor
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    ABSTRACT: Context and Objective: 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses regeneration of cortisol in liver, adipose tissue, and skeletal muscle, making a substantial contribution to circulating cortisol as demonstrated in humans by combining stable isotope tracer infusion with arteriovenous sampling. In the brain, 11βHSD1 is a potential therapeutic target implicated in age-associated cognitive dysfunction. We aimed to quantify brain 11βHSD1 activity, both to assess its contribution to systemic cortisol/cortisone turnover and to develop a tool for measuring 11βHSD1 in dementia and following administration of 11βHSD1 inhibitors. Design, Setting, and Participants: With ethical approval and informed consent, 8 healthy men aged 38.1 years (sd 16.5) underwent an ECG-gated phase-contrast magnetic resonance scan to quantify internal jugular vein blood flow and were infused with 1,2 [2H]2-cortisone and 9,11,12,12 [2H]4-cortisol for 3 h before samples were obtained from the internal jugular vein and an arterialized hand vein. Steroids were quantified by liquid chromatography-tandem mass spectrometry. Main Outcome Measures and Results: Steady state tracer enrichments were achieved and systemic indices of cortisol/cortisone interconversion were consistent with previous studies in healthy men. However, there was no measurable release or production of cortisol, 9,12,12 [2H]3-cortisol or cortisone into the internal jugular vein. Conclusions: Although cerebral 11βHSD1 reductase activity may be greater in cognitively impaired patients, in healthy men any contribution of 11βHSD1 in the brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in the brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in the human brain.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; 100(2):jc20143277. DOI:10.1210/jc.2014-3277 · 6.21 Impact Factor
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    ABSTRACT: Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1(tg/+) mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1(tg/+) mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1(tg/+) islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.
    Frontiers in Endocrinology 10/2014; 5:165. DOI:10.3389/fendo.2014.00165
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    ABSTRACT: 5α-Reductase 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the Metabolic Syndrome.Male mice, homozygous for a disrupted 5α-R1 allele (5αR1-KO), were studied following metabolic (high fat diet) and fibrotic (carbon-tetrachloride) challenge. The effect of the 5α-reductase inhibitor, finasteride, on metabolism was investigated in male obese Zucker rats.On high fat diet male 5αR1-KO mice demonstrated greater weight gain (21.6±1.4 vs 16.2±2.4 g), hyperinsulinaemia (insulin AUC during glucose tolerance test, 609±103 vs 313±66 and hepatic steatosis (liver triglycerides: 136.1±17.0 vs 89.3±12.1 micromol.g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 (37% increase in collagen staining). The non-selective 5α-reductase inhibitor finasteride induced hyperinsulinaemia and hepatic steatosis (10.6±1.2 vs 7.0±1.0 micromol.g(-1)) in obese male Zucker rats, both intact and castrated.5α-R1 deficiency induces insulin resistance and hepatic steatosis, consistent with intra-hepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with non-selective 5α-reductase inhibition in men with prostate disease may have important consequences for onset and progression of metabolic liver disease.
    Diabetes 09/2014; 64(2). DOI:10.2337/db14-0249 · 8.10 Impact Factor
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    ABSTRACT: To investigate the potential of therapies which reduce glucocorticoid action in patients with type 2 diabetes we performed a randomised, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance (Ra) of glucose, glycerol and free fatty acids (FFAs), including during a low dose (10mU/m(2)/min) hyperinsulinaemic clamp, and sub-group analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n=7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels, and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Amongst this population with type 2 diabetes high liver fat was associated with hyperinsulinaemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinaemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in type 2 diabetes with and without fatty liver.
    AJP Gastrointestinal and Liver Physiology 08/2014; 307(7). DOI:10.1152/ajpgi.00030.2014 · 3.80 Impact Factor
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    ABSTRACT: 11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11β-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11β-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11β-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11β-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.
    Neurobiology of Aging 07/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.007 · 5.01 Impact Factor
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    ABSTRACT: 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 alpha1-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.
    PLoS Genetics 07/2014; 10(7-7):e1004474. DOI:10.1371/journal.pgen.1004474 · 7.53 Impact Factor
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    ABSTRACT: : Mice lacking the glucocorticoid regenerating enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), responsible for local regeneration of corticosterone, have increased peri-infarct angiogenesis (Small et al ., 2005) and improved cardiac function (McSweeney et al ., 2010) following myocardial infarction (MI). The aim of the present study was to investigate whether these beneficial outcomes could be reproduced by a pharmacological inhibitor of 11βHSD1, UE2316. MI was induced in 45 male C57Bl6 mice by coronary artery ligation. UE2316 (10 mg/kg/day) or vehicle was administered by osmotic minipump implanted at the time of MI induction. Cardiac function was assessed by high resolution ultrasound at 7 days and 21 days after MI after which tissue was collected for assessment of infarct area (Massons trichrome) and blood vessel density (vessels immunopositive for CD31). An additional group of mice UE2316 was administered orally for 2 weeks prior to MI, followed by implantation of mini-pump as above. Treatment with UE2316 did not result in any alteration in plasma concentration of troponin I at 24 h after MI. However, by 3 weeks after induction of MI ejection fraction (EF) was reduced from 72 ± 5% to 30 ± 3% in vehicle treated animals, but in mice that that received UE2316 from the time of MI, EF was significantly increased to 43 ± 5 mmHg (P < 0.05). Additional treatment prior to induction of MI did not cause a further improvement in EF (43 ± 10%). 7 days after induction of MI, vascular density was increased in the infarct and peri-infarct zone in UE2316 compared to vehicle treated mice (P < 0.05) and this was associated with a reduction in infarct area from from 35 ± 7% LV in vehicle group, to 20 ± 2% LV in U12316 group. These data demonstrate that the beneficial effects of 11βHSD1 genetic deletion can be recapitulated by pharmacological inhibition of this enzyme. Importantly, reduction of infarct size and enhancement of ejection fraction can be achieved by delivery of drug at the time of infarction, supporting potential therapeutic utility of this intervention. This study was supported by the Wellcome Trust (PG-WT091720) and by a BHF Centre of Research Excellence Award.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A118. DOI:10.1136/heartjnl-2014-306118.216 · 5.60 Impact Factor
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    ABSTRACT: Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as 'relative adrenal insufficiency'. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and 2 and 5β-reductase, resulting in compensatory down-regulation of the hypothalamic-pituitary-adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1 compared with wild type control mice, clearance of corticosterone was lower after acute or chronic (8-fold, p<0.05) administration. In intact 5α-reductase deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, p<0.05), handling stress (2.5-fold lower, p<0.05) and restraint stress (43% lower, p<0.05) compared with wild type mice. mRNA levels of GR, CRH and AVP in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause 'relative adrenal insufficiency' in mice, an observation with important implications in patients with critical illness or hepatic failure, and in patients receiving 5α-reductase inhibitors for prostatic disease.
    Journal of Endocrinology 05/2014; 222(2). DOI:10.1530/JOE-13-0563 · 3.72 Impact Factor

Publication Stats

9k Citations
1,180.19 Total Impact Points


  • 2015
    • Heart Research Institute (UK)
      Norwich, England, United Kingdom
  • 1991-2015
    • The University of Edinburgh
      • • Queen's Medical Research Institute
      • • Centre for Cardiovascular Science
      • • Medical Genetics Unit
      Edinburgh, Scotland, United Kingdom
  • 2012
    • California College San Diego
      San Diego, California, United States
  • 2005-2007
    • University of Helsinki
      • Department of Oral Medicine
      Helsinki, Uusimaa, Finland
  • 1994-2003
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2002
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 2000
    • University of Birmingham
      Birmingham, England, United Kingdom