Brian R Walker

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (282)1383.29 Total impact

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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.
    American journal of physiology. Gastrointestinal and liver physiology. 08/2014;
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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;
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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. · 5.01 Impact Factor
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    ABSTRACT: Context: Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development and adult final height (FH) is a measure of effective treatment. We hypothesized that shorter adults will have more severe underlying disease and worse health outcomes. Methods: This was a cross-sectional analysis of 199 adults with CAH. FH and quality of life were expressed as z-scores adjusted for midparental target height or UK population height. Results: FH correlated inversely with age (men, r = -0.38; women, r = -0.26, P < .01). Men and women had z-scores adjusted for midparental target height of -2 and -1, respectively, and both groups had UK population height z-scores of -1 below the UK population (P < .01). In women, FH was shorter in non-salt-wasting than salt-wasting classic CAH (P < .05) and in moderately affected genotype group B women than either more severely affected groups null and A (P < .01) or the mildest group C (P < .001). Short stature and a higher prevalence of hypertension were observed in classic CAH patients diagnosed late (after 1 y) compared with those diagnosed early and in women treated with glucocorticoid only compared with those treated with both glucocorticoids and mineralocorticoids (P < .05). FH did not associate with insulin sensitivity, lipid profile, adiposity, or quality of life. Conclusions: Adult CAH patients remain short, although height prognosis has improved over time. The shortest adults are those diagnosed late with moderate severity CAH and are at increased risk of adult hypertension; we hypothesize that these patients are exposed in childhood to high androgens and/or excessive glucocorticoids with potential programming of hypertension. Another possibility is inadequate mineralocorticoid treatment early in life in the late-diagnosed patient group. Prospective studies are now required to examine these hypotheses.
    The Journal of clinical endocrinology and metabolism. 05/2014;
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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.
    The Journal of endocrinology. 05/2014;
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    ABSTRACT: Background Black women have lower visceral adipose tissue (VAT) but are less insulin sensitive than white women; the mechanisms responsible are unknown.Objective The study aimed to test the hypothesis that variation in subcutaneous adipose tissue (SAT) sensitivity to glucocorticoids might underlie these differences.Methods Body fatness (dual energy x-ray absorptiometry) and distribution (computerized tomography), insulin sensitivity (SI, intravenous and oral glucose tolerance tests), and expression of 11β-hydroxysteroid dehydrogenase-1 (11HSD1), hexose-6-phosphate dehydrogenase (H6PDH), and glucocorticoid receptor-α (GRα), as well as genes involved in adipogenesis and inflammation were measured in abdominal deep SAT (DSAT), superficial SAT (SSAT), and gluteal SAT (GLUT) depots of 56 normal-weight or obese black and white premenopausal South African (SA) women. We used a combination of univariate and multivariate statistics to evaluate ethnic-specific patterns in adipose gene expression and related body composition and insulin sensitivity measures.ResultsAlthough 11HSD1 activity and mRNA did not differ by ethnicity, GRα mRNA levels were significantly lower in SAT of black compared to white women, particularly in the GLUT depot (0.52±0.21 vs 0.91±0.26 AU, respectively, P<0.01). In black women, lower SAT GRα mRNA levels were associated with increased inflammatory gene transcript levels and abdominal SAT area, and reduced adipogenic gene transcript levels, VAT/SAT ratio and SI. Abdominal SAT 11HSD1 activity associated with increased VAT area and decreased SI in white, but not black women.Conclusions In black SA women, down-regulation of GRα mRNA levels with obesity and reduced insulin sensitivity, possibly via increased SAT inflammation, is associated with reduced VAT accumulation.International Journal of Obesity accepted article preview online, 23 May 2014; doi:10.1038/ijo.2014.94.
    International journal of obesity (2005) 05/2014; · 5.22 Impact Factor
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    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; · 6.50 Impact Factor
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    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
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    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
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    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; · 6.50 Impact Factor
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    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
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    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
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    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
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    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. · 5.14 Impact Factor
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    ABSTRACT: Background The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ⩾4000 g) and prolonged pregnancy (⩾41 weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes. Method Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05 ± 3.98 kg/m2) and 137 lean (BMI 22.71 ± 1.66 kg/m2) pregnant women. In subsets (n = 20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay; progesterone, estradiol (E2), estriol (E3) and sex-hormone-binding-globulin (SHBG) by ELISA; and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen’s equation. Results Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p < 0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r = −0.46, p < 0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ⩾ 41 weeks and in women with macrosomic babies (p < 0.05); and correlated negatively with gestation at delivery in obese (r = −0.557, p < 0.05). Conclusion Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy.
    Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 01/2014; 4(3):238.
  • Talanta 01/2014; · 3.50 Impact Factor
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    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. · 5.14 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 Genet. 01/2014; 10(7):e1004474.
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    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
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    ABSTRACT: The University of Edinburgh is currently inviting applications for a unique training programme intended to develop a new generation of veterinary researchers, who are able to conduct internationally competitive research while still being grounded in clinical practice. Modelled on the Edinburgh Clinical Academic Track (ECAT) programme for medical trainees, the ECAT-V programme will allow successful applicants to develop both their clinical and research skills. Here, David Argyle, head of the Royal (Dick) School of Veterinary Studies, and his medical colleagues, John Iredale, Andrew Jackson and Brian Walker, describe the initiative and explain why it is important.
    The Veterinary record. 10/2013; 173(15):364-5.

Publication Stats

9k Citations
1,383.29 Total Impact Points

Institutions

  • 1991–2014
    • 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
    • University of Cape Town
      • MRC/UCT Research Unit for Exercise Science & Sports Medicine (ESSM)
      Cape Town, Province of the Western Cape, South Africa
    • Policlinico S.Orsola-Malpighi
      Bolonia, Emilia-Romagna, Italy
  • 2003
    • University of Helsinki
      • Department of Oral Medicine
      Helsinki, Province of Southern Finland, Finland
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 1993–2003
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 1998–2001
    • University of Southampton
      • Developmental Origins of Health and Disease
      Southampton, ENG, United Kingdom
  • 1994
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia