Brian R Walker

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

Are you Brian R Walker?

Claim your profile

Publications (178)870.88 Total impact

  • [Show abstract] [Hide abstract]
    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; · 4.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context and objective: 11beta-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 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 38.1years (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 [(2)H]2-cortisone and 9,11,12,12 [(2)H]4-cortisol for 3 hours 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 [(2)H]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 brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in human brain.
    The Journal of clinical endocrinology and metabolism. 11/2014;
  • [Show abstract] [Hide abstract]
    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 ng.ml(-1).min) 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; · 7.90 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    American journal of physiology. Gastrointestinal and liver physiology. 08/2014;
  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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. · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    The Journal of endocrinology. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: 5α-Reductase (5αR) types 1 and 2 catalyse the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone (DHT) in benign prostatic hyperplasia: finasteride inhibits 5αR2; dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. Objective: To test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. Design: Double-blind randomised controlled parallel group study. Setting: Clinical research facility. Participants: 46 men (20-85 years) studied before and after intervention. Intervention: Oral dutasteride (0.5 mg daily; n=16), finasteride (5 mg daily; n=16) or control (tamsulosin; 0.4 mg daily; n=14) for 3 months. Main outcome measure: Glucose disposal during a stepwise hyperinsulinaemic euglycaemic clamp. Data are mean (SEM). Results: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites, reduced circulating DHT, but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high dose insulin (dutasteride by -5.7 (3.2) μ mol/kg fat-free mass/min, versus finasteride +7.2 (3.0), and tamsulosin +7.0 (2.0)). Dutasteride also reduced suppression of non-esterified fatty acids by insulin, and increased body fat (by 1.6 (0.6) %). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose. Conclusion: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.
    The Journal of Clinical Endocrinology and Metabolism 05/2014; · 6.31 Impact Factor
  • Endocrine Abstracts. 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context. Abnormal cortisol metabolism in Polycystic Ovary Syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic-pituitary-adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.Objective. To assess cortisol clearance and whole-body and tissue-specific activities of 11ß-HSD1 in PCOS.Design. Case-control study.Setting. Medical center.Patients. 20 overweight-obese unmedicated Caucasian women with PCOS, aged 18-45 yr, and 20 Caucasian controls matched for age, body mass index, body fat distribution, and HSD11B1 genotypes (rs846910 and rs12086634).Main Outcome Measures. Cortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-2H4-cortisol infusion, cortisol clearance was calculated and whole-body 11ß-HSD1 activity assessed as rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic 11ß-HSD1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose 11ß-HSD1 activity and mRNA were measured, ex vivo, in biopsies.Results. Urinary cortisol metabolite excretion, deuterated-cortisol clearance and the rate of appearance of d3-cortisol did not differ between PCOS and controls. However, hepatic 11ß-HSD1 conversion of oral cortisone to cortisol was impaired (P< 0.05), whereas subcutaneous abdominal adipose tissue 11ß-HSD1 mRNA levels and activity were increased (P< 0.05) in PCOS women with respect to controls.Conclusions. Tissue-specific dysregulation of 11ß-HSD1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.
    European Journal of Endocrinology 04/2014; · 3.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesity-associated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissue-specific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.
    Diabetologia 04/2014; · 6.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Mineralocorticoid receptors (MR) contribute to negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans. Objective: To establish whether loss-of-function mutations in NR3C2, encoding MR, cause activation of the HPA axis. Design and Setting: A case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members. Participants: 12 adult patients with PHA1 (6 men, 6 women) and 20 age-matched healthy controls (7 men, 13 women). Results: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, p=0.02) and increased 24h urinary excretion of cortisol metabolites (985 ± 150 vs 640 ± 46 μ g/mmol creatinine, p=0.03), independently of gender. After adjustment for gender, age, PHA1 diagnosis and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum HDL-cholesterol and higher waist circumference, but not with blood pressure, carotid intima-media thickness or echocardiographic parameters. Conclusions: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolaemia is related to the severity of MR deficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution, but does not adversely affect cardiac and vascular remodelling in the absence of normal signalling through MR.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; · 6.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem and progenitor cells from which it arises. Whereas increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are six visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric, and it is a subject of much debate whether these have a common developmental origin and whether this differs from that for subcutaneous WAT. Here we show that all six visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue arises from Wt1-expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1-expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show that all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated, and provide several lines of evidence that Wt1-expressing mesothelium can produce adipocytes. These results reveal a major ontogenetic difference between visceral and subcutaneous WAT, and pinpoint the lateral plate mesoderm as a major source of visceral WAT. They also support the notion that visceral WAT progenitors are heterogeneous, and suggest that mesothelium is a source of adipocytes.
    Nature Cell Biology 03/2014; · 20.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1(-/-) mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11β-HSD1 reverses the deficits in cognition with ageing, a state of elevated glucocorticoid levels. However, any impact of 11β-HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11β-HSD1 inhibitor UE2316 modifies the effect of stress on hippocampal long-term potentiation and fear conditioning, a learning paradigm that is strongly modulated by glucocorticoids. We found that novelty stress suppresses hippocampal synaptic potentiation. This effect was completely prevented by administration of UE2316 one hour before stress exposure. A single injection of UE2316 also impaired contextual, but not tone-cue-fear conditioning. These observations suggest that local metabolism of glucocorticoids is relevant for the outcome of stress effects on hippocampal synaptic plasticity and contextual fear conditioning. Selective 11β-HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology.
    Neuropharmacology 02/2014; · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24 h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes–Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.
    Psychoneuroendocrinology 01/2014; 39:1–10. · 5.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 01/2014; · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.
    Psychoneuroendocrinology 01/2014; 39:1-10. · 5.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 01/2014; 5:165.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes.
    Nature Reviews Endocrinology 12/2013; · 11.03 Impact Factor

Publication Stats

5k Citations
870.88 Total Impact Points

Institutions

  • 1992–2014
    • The University of Edinburgh
      • • Queen's Medical Research Institute
      • • MRC Centre for Regenerative Medicine
      • • Centre for Cardiovascular Science
      • • School of Clinical Sciences and Community Health
      • • Medical Genetics Unit
      Edinburgh, Scotland, United Kingdom
  • 2013
    • University College London
      Londinium, England, United Kingdom
  • 2011
    • University of Bologna
      • Division of Endocrinology
      Bologna, Emilia-Romagna, Italy
  • 2010
    • University of Birmingham
      • School of Clinical and Experimental Medicine
      Birmingham, ENG, United Kingdom
  • 2009
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
  • 2001–2009
    • Umeå University
      • Department of Public Health and Clinical Medicine
      Umeå, Vaesterbotten, Sweden
  • 2006
    • Policlinico S.Orsola-Malpighi
      Bolonia, Emilia-Romagna, Italy
  • 2003
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
    • University of Helsinki
      • Department of Oral Medicine
      Helsinki, Province of Southern Finland, Finland
  • 1995–2003
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom