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12. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study

Author

Hawcutt DB, Francis B, Carr DF, Jorgensen AL, Yin P, Wallin N, O'Hara N, Zhang EJ, Bloch KM, Ganguli A, Thompson B, McEvoy L, Peak M, Crawford AA, Walker BR, Blair JC, Couriel J, Smyth RL, and Pirmohamed M

Subjects
medicine.medical_specialty, Endocrinology, business.industry, medicine.drug_class, Internal medicine, medicine, Corticosteroid, Genome-wide association study, Adrenal suppression, business
Published
2019

13. 11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI

Author

Mylonas, KJ, Turner, NA, Bageghni, SA, Kenyon, CJ, White, CI, McGregor, K, Kimmitt, RA, Sulston, R, Kelly, V, Walker, BR, Porter, KE, Chapman, KE, and Gray, GA

Subjects
Journal Article, hormones, hormone substitutes, and hormone antagonists
Abstract

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'host' myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

Published
2017

14. Moral Emotions and Corporate Psychopathy: A Review

Author

Walker, BR, Jackson, CJ, Walker, BR, and Jackson, CJ

Abstract

© 2016, Springer Science+Business Media Dordrecht. While psychopathy research has been growing for decades, a relatively new area of research is corporate psychopathy. Corporate psychopaths are simply psychopaths working in organizational settings. They may be attracted to the financial, power, and status gains available in senior positions and can cause considerable damage within these roles from a manipulative interpersonal style to large-scale fraud. Based upon prior studies, we analyze psychopathy research pertaining to 23 moral emotions classified according to functional quality (positive vs. negative signal) and target (self vs. other). Based upon our review, we suggest that psychopaths are high in moral emotions associated with other-directed negative signals, low in self-directed negative signals, and low in other-directed positive signals. We found no empirical articles related to self-directed positive signals. This understanding of the specific moral emotion deficits of corporate psychopaths provides greater theoretical understanding and practical implications of knowing which individuals not to promote, though more research is needed on moral emotions that are faked for manipulative reasons.

Published
2017

15. Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.

Author

Rietschel, L, Streit, F, Zhu, G, McAloney, K, Frank, J, Couvy-Duchesne, B, Witt, SH, Binz, TM, CORtisolNETwork (CORNET) Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC), McGrath, J, Hickie, IB, Hansell, NK, Wright, MJ, Gillespie, NA, Forstner, AJ, Schulze, TG, Wüst, S, Nöthen, MM, Baumgartner, MR, Walker, BR, Crawford, AA, Colodro-Conde, L, Medland, SE, Martin, NG, Rietschel, M, Rietschel, L, Streit, F, Zhu, G, McAloney, K, Frank, J, Couvy-Duchesne, B, Witt, SH, Binz, TM, CORtisolNETwork (CORNET) Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC), McGrath, J, Hickie, IB, Hansell, NK, Wright, MJ, Gillespie, NA, Forstner, AJ, Schulze, TG, Wüst, S, Nöthen, MM, Baumgartner, MR, Walker, BR, Crawford, AA, Colodro-Conde, L, Medland, SE, Martin, NG, and Rietschel, M

Abstract

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

Published
2017

16. Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Author

Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, Zeggini, E, Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, and Zeggini, E

Published
2017

17. 5[alpha]-THB as a novel anti-inflammatory drug: The roles of the glucocorticoid and mineralocorticoid receptors

Author

Abernethie, Amber, primary, Gastaldello, A, additional, Morgan, RA, additional, Mitchell, C, additional, McInnes, KJ, additional, Beck, K, additional, Odermatt, A, additional, Houtman, R, additional, Melchars, D, additional, Meijer, OC, additional, Hadoke, PWF, additional, Livingstone, DEW, additional, Walker, BR, additional, and Andrew, R, additional

Published
2017
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18. Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

Author

Warner, P, Weir, CJ, Hansen, CH, Douglas, A, Madhra, M, Hillier, SG, Saunders, PTK, Iredale, JP, Semple, S, Walker, BR, and Critchley, HOD

Abstract

INTRODUCTION: Heavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that 'rescue' of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding. METHODS AND ANALYSIS: DexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11βHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to 'adapt' at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose-response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo. ETHICS AND DISSEMINATION: Dexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been obtained from Scotland A Research Ethics Committee (12/SS/0147). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures, and our websites. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.

Published
2015

19. What does Hans Eysenck mean for young researchers?

Author

Walker, BR and Walker, BR

Abstract

In some people's eyes, Hans Eysenck holds a mixed legacy with remarkable achievements alongside engagement with some, apparently, futile research areas. I suggest that rather than perceiving his career as having successes and failures, an alternative way to understand Eysenck is to appreciate that he had an underlying willingness to push the boundaries and explore new frontiers, and the outcome of this is unsurprisingly some less productive areas as well as achievements. He was willing to seek the truth despite the perceptions of his peers. A lesson for young researchers from Eysenck's biography is a choice of whether to play it safe and engage in relatively incremental research or aim for big picture research, which may change a whole field but may — to use a football analogy, which because of his interest in the sport, Eysenck may have approved — put people offside.

Published
2016

20. Q&A: Dan Heller

Author

Clear="none"/>, --David Walker<Br Clear="None"/><Br

Subjects
eBay Inc., Computer services industry, Computer services industry, Business, general
Abstract

PDN: Why do you think the $2 billion figure underestimates the size of the stock photo market? DH: Because it just aggregates the sales volumes of what are perceived to [...]

Published
2007

21. Market Report: Salt Lake City

Author

Clear="none"/>, --David Walker<Br Clear="None"/><Br

Subjects
Business, general
Abstract

Utah was the third fastest growing state in the U.S. in 2005 (behind Idaho and Nevada), and the state had a job growth rate of 4.8 percent, well above the [...]

Published
2007

23. How the five factor model and revised reinforcement sensitivity theory predict divergent thinking

Author

Walker, BR, Jackson, CJ, Walker, BR, and Jackson, CJ

Abstract

From revised Reinforcement Sensitivity Theory (r-RST), we hypothesized revised Behavioural Approach System (r-BAS) would positively predict divergent thinking and revised Fight/Flight/Freezing System (r-FFFS) would negatively predict divergent thinking. Moreover, we hypothesized that r-FFFS would incrementally predict divergent thinking after controlling for significant FFM traits. Consistent with Elliot and Thrash (2010), we also hypothesized an indirect effects model with r-BAS predicting divergent thinking through mastery. Using 130 participants, we found support or partial support for all hypotheses. Our results indicate that biological factors of personality associated with r-RST as well as openness to experience predict divergent thinking. The distinction between fear and anxiety in r-RST was also supported with fear and not anxiety negatively predicting divergent thinking. © 2013 Elsevier Ltd.

Published
2014

36. Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization.

Author

Nixon M, Wake DJ, Livingstone DE, Stimson RH, Esteves CL, Seckl JR, Chapman KE, Andrew R, Walker BR, Nixon, Mark, Wake, Deborah J, Livingstone, Dawn E, Stimson, Roland H, Esteves, Cristina L, Seckl, Jonathan R, Chapman, Karen E, Andrew, Ruth, and Walker, Brian R

Abstract

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1-deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with (3)H-steroid. Two weeks' administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates. [ABSTRACT FROM AUTHOR]

Published
2012
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37. Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure.

Author

Turban S, Liu X, Ramage L, Webster SP, Walker BR, Dunbar DR, Mullins JJ, Seckl JR, Morton NM, Turban, Sophie, Liu, Xiaoxia, Ramage, Lynne, Webster, Scott P, Walker, Brian R, Dunbar, Donald R, Mullins, John J, Seckl, Jonathan R, and Morton, Nicholas M

Abstract

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell-specific, 11β-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal-related kinase and p21 signaling pathways. 11β-HSD1(-/-) mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2012
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39. Increased whole-body and sustained liver cortisol regeneration by 11beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition.

Author

Stimson RH, Andrew R, McAvoy NC, Tripathi D, Hayes PC, Walker BR, Stimson, Roland H, Andrew, Ruth, McAvoy, Norma C, Tripathi, Dhiraj, Hayes, Peter C, and Walker, Brian R

Abstract

Objective: The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects.Research Design and Methods: Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[(2)H](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution.Results: In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[(2)H](3)cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P < 0.05), splanchnic 9,12,12-[(2)H](3)cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged.Conclusions: Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects. [ABSTRACT FROM AUTHOR]

Published
2011
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40. Morning cortisol levels and cognitive abilities in people with type 2 diabetes: the Edinburgh type 2 diabetes study.

Author

Reynolds RM, Strachan MW, Labad J, Lee AJ, Frier BM, Fowkes FG, Mitchell R, Seckl JR, Deary IJ, Walker BR, Price JF, Edinburgh Type 2 Diabetes Study Investigators, Reynolds, Rebecca M, Strachan, Mark W J, Labad, Javier, Lee, Amanda J, Frier, Brian M, Fowkes, F Gerald, Mitchell, Rory, and Seckl, Jonathan R

Abstract

Objective: People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.Research Design and Methods: This was a cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.Results: In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).Conclusions: High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2010
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41. Insulin response in relation to insulin sensitivity: an appropriate beta-cell response in black South African women.

Author

Goedecke JH, Dave JA, Faulenbach MV, Utzschneider KM, Lambert EV, West S, Collins M, Olsson T, Walker BR, Seckl JR, Kahn SE, Levitt NS, Goedecke, Julia H, Dave, Joel A, Faulenbach, Mirjam V, Utzschneider, Kristina M, Lambert, Estelle V, West, Sacha, Collins, Malcolm, and Olsson, Tommy

Abstract

Objective: The purpose of this study was to characterize differences in the acute insulin response to glucose (AIR(g)) relative to insulin sensitivity (S(I)) in black and white premenopausal normoglycemic South African women matched for body fatness.Research Design and Methods: Cross-sectional analysis including 57 black and white South African women matched for BMI, S(I), AIR(g), and the disposition index (AIR(g) x S(I)) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.Results: S(I) was significantly lower (4.4 +/- 0.8 vs. 9.4 +/- 0.8 and 2.9 +/- 0.8 vs. 6.0 +/- 0. 8 x 10(-5) min(-1)/[pmol/l], P < 0.001) and AIR(g) was significantly higher (1,028 +/- 255 vs. 352 +/- 246 and 1,968 +/- 229 vs. 469 +/- 246 pmol/l, P < 0.001), despite similar body fatness (30.9 +/- 1.4 vs. 29.7 +/- 1.3 and 46.8 +/- 1.2 vs. 44.4 +/- 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of beta-cell function, was not different between ethnic groups (3,811 +/- 538 vs. 2,966 +/- 518 and 3,646 +/- 485 vs. 2,353 +/- 518 x 10(-5) min, P = 0.10). Similar results were obtained for the OGTT-derived measures.Conclusions: Black South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate beta-cell response for the level of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Published
2009
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42. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans.

Author

Stimson RH, Andersson J, Andrew R, Redhead DN, Karpe F, Hayes PC, Olsson T, Walker BR, Stimson, Roland H, Andersson, Jonas, Andrew, Ruth, Redhead, Doris N, Karpe, Fredrik, Hayes, Peter C, Olsson, Tommy, and Walker, Brian R

Abstract

Objective: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo.Research Design and Methods: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein.Results: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected.Conclusions: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling. [ABSTRACT FROM AUTHOR]

Published
2009
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45. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study.

Author

Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts ACG, Leufkens HGM, and Walker BR

Abstract

OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Published
2004
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47. Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Author

Cleasby, ME, Livingstone, DE, Nyirenda, MJ, Seckl, and Walker, BR

Abstract

OBJECTIVE: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tIssue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. DESIGN AND METHODS: Rats were treated with dex (100 microg/kg per day) or saline during the third week of pregnancy. In 5-8-Month-old male offspring, GR expression in insulin target tIssues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n=7-8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. RESULTS: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0.11+/-0.01 ratio to beta-actin, vs ADX 0.22+/-0.02, CORT 0.23+/-0.02, (values expressed as means+/-s.e.m.), P<0.001). Rosiglitazone reduced GR mRNA by approximately 30% in liver of dex- and saline-treated offspring (P<0.05), but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0.14+/-0.01 vs 0.10+/-0.01; P=0.03). CONCLUSIONS: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.

Published
2003

48. Therapeutic and Economic Controversies in Antihypertensive Therapy

Author

Walker Br, Hare Le, and McCarron Da

Subjects
Drug, medicine.medical_specialty, Office Visits, Total cost, Office visits, medicine.medical_treatment, media_common.quotation_subject, Adrenergic beta-Antagonists, Alpha (ethology), medicine, Humans, In patient, Diuretics, Intensive care medicine, Initial therapy, Adrenergic alpha-Antagonists, Antihypertensive Agents, media_common, Pharmacology, Clinical Laboratory Techniques, business.industry, Hypertension, Costs and Cost Analysis, Diuretic, Cardiology and Cardiovascular Medicine, business, Adrenergic alpha-Agonists
Abstract

Diuretics are recommended for initial antihypertensive therapy because of their low cost and lack of subjective side effects. Unlike alpha- and beta-adrenergic agents, however, diuretics frequently induce metabolic abnormalities that necessitate supplemental therapy and increased monitoring of clinical laboratory tests. These factors increase the total cost of diuretic therapy, making it comparable to that of the alpha- or beta-adrenergic drugs. We show that the total yearly costs of therapy, exclusive of office visits, for patients treated with any of these three classes of agents is approximately $175 to $250, regardless of the drug used. Diuretics are cost effective only in patients who do not require laboratory follow-up or supplemental therapy. Thus, the choice of a drug for initial therapy of hypertension may be based more appropriately on medical (particularly side effects and metabolic abnormalities) rather than financial considerations.

Published
1984

49. Renal and Cardiovascular Responses to Acute Hypercapnic Acidosis in Conscious Dogs

Author

R. J. Anderson, Robert M. Carey, D L Kaiser, A. L. Erickson, Walker Br, and Charles E. Rose

Subjects
medicine.medical_specialty, Captopril, Renal function, Plasma renin activity, Renal Circulation, Hypercapnia, Renin-Angiotensin System, Excretion, Dogs, Internal medicine, Renin, Renin–angiotensin system, medicine, Animals, Normocapnia, Pharmacology, business.industry, Angiotensin II, Hemodynamics, Endocrinology, Anesthesia, Renal blood flow, Female, Blood Gas Analysis, medicine.symptom, Acidosis, Cardiology and Cardiovascular Medicine, business
Abstract

Patients with pulmonary dysfunction and CO2 retention have renal hemodynamic abnormalities accompanied by increased plasma renin activity. To determine if hypercapnia impairs renal function, particularly through the renin-angiotensin system, the effects of acute hypercapnic acidosis (HC), using 8.5% CO2, were measured in five unanesthetized dogs during (a) the intact state; (b) renin-angiotensin antagonism using either 1-sarcosine, 8-glycine angiotensin II ( [Sar1, Gly8] AII) or SQ 14,225; and (c) exogenous angiotensin II infusion. As partial arterial carbon dioxide pressure (PaCO2) increased (p less than 0.05) from control (C) of 35 +/- 1 (SEM) to 48 +/- 1 mm Hg during HC, arterial pH fell (p less than 0.05) from 7.36 +/- 0.01 to 7.24 +/- 0.005. Renal function was uncompromised with HC, and glomerular filtration rate (GFR) and urinary sodium excretion increased (p less than 0.05) despite a fourfold rise in plasma renin activity from C of 0.6 +/- 0.3 to 2.2 +/- 0.8 ng AI ml-1 h-1 during HC. Administration of [Sar1, Gly8] AII during HC did not consistently alter systemic or renal hemodynamic responses, and effects of SQ 14,225 during HC were also observed during normocapnia. Although systemic vascular responses to exogenous AII infusion were similar, the renal vasoconstrictor response was antagonized during HC with unchanged GFR and renal blood flow. These findings indicate that despite activation of the renin-angiotensin system, acute hypercapnic acidosis is unassociated with impairment of renal function in unanesthetized dogs. This may be related to diminished renal vascular AII responsiveness during hypercapnia.

Published
1982

50. 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver

Author

Jamieson, PM, Walker, BR, Chapman, KE, Andrew, R, Rossiter, S, and Seckl

Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11 beta-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11 beta-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44+/-5% of 11-dehydrocorticosterone (11-DHC) recovered was 11 beta-reduced to corticosterone, whereas 10+/-1% of corticosterone was 11 beta-dehydrogenated to 11-DHC. 11 beta-Reduction was less in female liver (21+/-2%, P<0.01) and was significantly greater with perfusion of all substrate via the portal vein (50+/-3%) than via the hepatic artery (30+/-2%, P<0.05). 11 beta-Reductase activity was not saturated by 11-DHC (10(-)(9)-10(-)(6) M). Perfusion with carbenoxolone (CBX, 10(-)(6)-10(-)(3 )M) did not alter 11 beta-reduction of 11-DHC. In contrast, pretreatment with CBX in vivo (10 mg/day) for 7 days inhibited 11 beta-reductase (19+/-4% conversion, P<0.01). Concentrations of 11-DHC in male rat plasma were 44+/-6 nM. Thus 11 beta-HSD-1 is predominantly an 11 beta-reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11 beta-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.

Published
2000
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