The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Brian R Walker - One of the best experts on this subject based on the ideXlab platform.
-
Glucocorticoid treatment and impaired mood memory and metabolism in people with diabetes the edinburgh type 2 diabetes study
European Journal of Endocrinology, 2012Co-Authors: Rebecca M Reynolds, Javier Labad, Alison V Sears, Rachel M Williamson, Mark W J Strachan, Ian J Deary, Gordon D O Lowe, Jackie F Price, Brian R WalkerAbstract:Objective: Both type 2 diabetes and Glucocorticoid therapy are highly prevalent. Although people with type 2 diabetes may be more susceptible to adverse effects of Glucocorticoids, and it is recommended that Glucocorticoid therapy is avoided for fear of worsening glycaemic control, the extent to which this advice is followed and the consequences when Glucocorticoids are prescribed are poorly documented. The aim was to assess the characteristics of people with type 2 diabetes prescribed Glucocorticoids in a real-world setting and to quantify resulting adverse effects. Design: Cross-sectional cohort study. Methods: Cardiometabolic variables, body fat distribution, cognitive function and mood were studied in the 1066 participants of the Edinburgh Type 2 Diabetes Study, of whom 162 (15%) were taking systemic, topical or inhaled Glucocorticoids. Results: Glucocorticoid therapy was more common in women and in smokers but was not avoided in patients with diabetic complications or cardiovascular risk factors. People taking Glucocorticoids were more centrally obese with slightly higher HbA1c and total serum cholesterol but were no more likely to have hepatic steatosis or hypertension. Glucocorticoid treatment was associated with substantially lower mood and greater anxiety. Women taking Glucocorticoid therapy were twice as likely to report depressive symptoms compared with those not taking treatment. Glucocorticoid therapy was also associated with poorer cognitive function among those with subclinical atherosclerosis, as indicated by low ankle–brachial pressure index. Conclusions: Glucocorticoids are prescribed commonly for people with type 2 diabetes despite being associated with adverse indices of glycaemic control, cardiovascular risk factors, mood and cognitive function.
-
Glucocorticoids and fatty acid metabolism in humans fuelling fat redistribution in the metabolic syndrome
Journal of Endocrinology, 2008Co-Authors: David P Macfarlane, Shareen Forbes, Brian R WalkerAbstract:Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of Glucocorticoid excess (Cushing's syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of Glucocorticoids is not manifest in long-term weight loss in humans. The effects of Glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in Glucocorticoid concentrations in the plasma and/or in tissue sensitivity to Glucocorticoids are important in metabolic syndrome. The effects of Glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of Glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of Glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of Glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.
-
11 beta hydroxysteroid dehydrogenase type 1 11beta hsd1 inhibitors in type 2 diabetes mellitus and obesity
Expert Opinion on Investigational Drugs, 2008Co-Authors: Katherine A Hughes, Scott P Webster, Brian R WalkerAbstract:Background: Glucocorticoids such as cortisol are important regulators of fuel metabolism during starvation and stress. Chronic Glucocorticoid excess induces obesity with multiple features of the metabolic syndrome. Objective: In this article, we review the importance of Glucocorticoids in metabolic syndrome and the approaches that have been explored to reduce Glucocorticoid action as the basis for novel therapy of Type 2 diabetes and obesity. Method: We focus on the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies Glucocorticoid concentrations in key metabolic tissues including liver and adipose tissue. Results/conclusion: Several 11β-HSD1 inhibitors are in late preclinical or early clinical development and we review here the properties of the class leaders and their potential as the next generation of drugs with multiple benefits in metabolic syndrome.
John A. Cidlowski - One of the best experts on this subject based on the ideXlab platform.
-
Glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye
Experimental Eye Research, 2016Co-Authors: Mahita Kadmiel, Agnes K Janoshazi, John A. CidlowskiAbstract:Glucocorticoids play diverse roles in almost all physiological systems of the body, including both anti-inflammatory and immunosuppressive roles. Synthetic Glucocorticoids are one of the most widely prescribed drugs and are used in the treatment of conditions such as autoimmune diseases, allergies, ocular disorders and certain types of cancers. In the interest of investigating Glucocorticoid actions in the cornea of the eye, we established that multiple cell types in mouse corneas express functional Glucocorticoid receptor (GR) with corneal epithelial cells having robust expression. To define Glucocorticoid actions in a cell type-specific manner, we employed immortalized human corneal epithelial (HCE) cell line to define the Glucocorticoid transcriptome and elucidated its functions in corneal epithelial cells. Over 4000 genes were significantly regulated within 6 h of dexamethasone treatment, and genes associated with cell movement, cytoskeletal remodeling and permeability were highly regulated. Real-time in vitro wound healing assays revealed that Glucocorticoids delay wound healing by attenuating cell migration. These functional alterations were associated with cytoskeletal remodeling at the wounded edge of a scratch-wounded monolayer. However, Glucocorticoid treatment improved the organization of tight-junction proteins and enhanced the epithelial barrier function. Our results demonstrate that Glucocorticoids profoundly alter corneal epithelial gene expression and many of these changes likely impact both wound healing and epithelial cell barrier function.
-
hes1 is a master regulator of Glucocorticoid receptor dependent gene expression
Science Signaling, 2013Co-Authors: Javier Revollo, Nick Z Lu, Mahita Kadmiel, Maheer Gandhavadi, Robert H. Oakley, John A. CidlowskiAbstract:Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of Glucocorticoids are mediated by Glucocorticoid receptor–dependent regulation of nearly 25% of the genome. Here, we established a genome-wide molecular link between HES1 and Glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This Glucocorticoid-dependent repression of HES1 was necessary for the Glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded Glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper Glucocorticoid signaling.
-
a role for Glucocorticoids in stress impaired reproduction beyond the hypothalamus and pituitary
Endocrinology, 2013Co-Authors: Shannon Whirledge, John A. CidlowskiAbstract:In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by Glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic Glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary-gonadal axis. Indeed, as central regulators of the immune response, Glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through Glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of Glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show Glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success.
-
Glucocorticoid receptor signaling in health and disease
Trends in Pharmacological Sciences, 2013Co-Authors: Mahita Kadmiel, John A. CidlowskiAbstract:Glucocorticoids are steroid hormones regulated in a circadian and stress-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic Glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the past few years has begun to unravel the profound complexity of Glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the Glucocorticoid receptor (GR), a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we provide an update on Glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body.
-
Glucocorticoids sensitize the innate immune system through regulation of the nlrp3 inflammasome
Journal of Biological Chemistry, 2011Co-Authors: John M Busillo, Kathleen M Azzam, John A. CidlowskiAbstract:Glucocorticoids have long been recognized as powerful anti-inflammatory compounds that are one of the most widely prescribed classes of drugs in the world. However, their role in the regulation of innate immunity is not well understood. We sought to examine the effects of Glucocorticoids on the NOD-like receptors (NLRs), a central component of the inflammasome and innate immunity. Surprisingly, we show that Glucocorticoids induce both NLRP3 messenger RNA and protein, which is a critical component of the inflammasome. The Glucocorticoid-dependent induction of NLRP3 sensitizes the cells to extracellular ATP and significantly enhances the ATP-mediated release of proinflammatory molecules, including mature IL-1β, TNF-α, and IL-6. This effect was specific for Glucocorticoids and dependent on the Glucocorticoid receptor. These studies demonstrate a novel role for Glucocorticoids in sensitizing the initial inflammatory response by the innate immune system.
Andrew H Miller - One of the best experts on this subject based on the ideXlab platform.
-
when not enough is too much the role of insufficient Glucocorticoid signaling in the pathophysiology of stress related disorders
FOCUS, 2011Co-Authors: Charles L Raison, Andrew H MillerAbstract:Objective: Previous theories have emphasized the role of excessive Glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient Glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of Glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). Method: The literature on neuroendocrine function and Glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results: Although not occurring together, both hypocortisolism and reduced responsiveness to Glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychitric disorders were also associated ...
-
interactions between the hypothalamic pituitary adrenal axis and immune system during viral infection pathways for environmental effects on disease expression
Comprehensive Physiology, 2011Co-Authors: Andrew H Miller, Bradley D Pearce, Melanie C Ruzek, Christine A BironAbstract:The sections in this article are: 1 Immune Responses to Viral Infection 1.1 Early Innate Immunity 1.2 Late Adaptive Immunity 2 Pathology During Viral Infection 2.1 Cell-Mediated Pathology 2.2 Cytokine-Mediated Pathology 3 Cytokine Pathways for Glucocorticoid Induction During Viral Infection [“Starting the Loop”] 3.1 Glucocorticoid Induction during Viral Infection 3.2 Cytokines and Glucocorticoid Induction during Viral Infection 4 Central Nervous System/Neuroendocrine Pathways for Glucocorticoid Induction During Viral Infection (“Making the Connection”) 4.1 Pathways by which Peripheral Cytokine Signals Reach the Brain 4.2 Cytokine Network in the Central Nervous System 4.3 Cytokines and Behavior 5 Viral Infection, Glucocorticoid Availability, and Glucocorticoid Receptor Expression and Function (“Delivering and Receiving The Signal”) 5.1 Corticosteroid-Binding Globulin and 11β-Hydroxysteroid Dehydrogenase 5.2 Glucocorticoid Receptor Changes during Viral Infection 5.3 Cytokines as Potential Mediators of Glucocorticoid Receptor Changes during Viral Infection 6 Endogenous Glucocorticoids and Host Responses to Viral Infection (“Shaping The Response, Protection, and Closing the Loop”) 6.1 Impact of Stress on Immune Responses to Viral Infection 6.2 Glucocorticoids as the Mediator of Stress Effects on Viral Immunity 7 Summary
-
when not enough is too much the role of insufficient Glucocorticoid signaling in the pathophysiology of stress related disorders
American Journal of Psychiatry, 2003Co-Authors: Charles L Raison, Andrew H MillerAbstract:Objective: Previous theories have emphasized the role of excessive Glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient Glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of Glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). Method: The literature on neuroendocrine function and Glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results: Although not occurring together, both hypocortisolism and reduced responsiveness to Glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient Glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced Glucocorticoid signaling. Conclusions: Neuroendocrine data provide evidence of insufficient Glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced Glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient Glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance Glucocorticoid signaling pathways.
John C. Wingfield - One of the best experts on this subject based on the ideXlab platform.
-
Allostatic load, social status and stress hormones: the costs of social status matter
Animal Behaviour, 2004Co-Authors: Wolfgang Goymann, John C. WingfieldAbstract:Cooperation and social support are the major advantages of living in social groups. However, there are also disadvantages arising from social conflict and competition. Social conflicts may increase allostatic load, which is reflected in increased concentrations of Glucocorticoids. We applied the emerging concept of allostasis to investigate the relation between social status and Glucocorticoid concentrations. Animals in a society experience different levels of allostatic load and these differences may predict relative Glucocorticoid concentrations of dominant and subordinate individuals. We reviewed the available data from free-ranging animals and generated, for each sex separately, phylogenetic independent contrasts of allostatic load and relative Glucocorticoid concentrations. Our results suggest that the relative allostatic load of social status predicts whether dominants or subordinates express higher or lower concentrations of Glucocorticoids. There was a significant correlation between allostatic load of dominance and relative Glucocorticoid concentrations in both females and males. When allostatic load was higher in dominants than in subordinates, dominants expressed higher levels of Glucocorticoids; when allostatic load was similar in dominants and subordinates, there were only minor differences in Glucocorticoid concentrations; and when allostatic load was lower in dominants than in subordinates, subordinates expressed higher levels of Glucocorticoids than dominants. To our knowledge, this is the first model that consistently explains rank differences in Glucocorticoid concentrations of different species and sexes. The heuristic concept of allostasis thus provides a testable framework for future studies of how social status is reflected in Glucocorticoid concentrations.
W. Waldhäusl - One of the best experts on this subject based on the ideXlab platform.
-
11β-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes
Diabetologia, 2004Co-Authors: T. M. Stulnig, W. WaldhäuslAbstract:Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of Glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing’s syndrome, as well as Glucocorticoids’ functional antagonism to insulin. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates functionally inert Glucocorticoid precursors (cortisone) to active Glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local Glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11β-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11β-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11β-HSD1 activity.