UMLS:C0948265 - FACTA Search

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Query: UMLS:C0948265 (metabolic syndrome)
24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. These hormones influence a large percentage of the expressed human genome and their effects spare almost no organs or tissues. Glucocorticoids influence many functions of the central nervous system, such as arousal, cognition, mood and sleep, the activity and direction of intermediary metabolism, the maintenance of a normal cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, as well as growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems. The presence of multiple GR monomers and dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic. Based on ample evidence, we present our conception that glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common psychiatric and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid component.
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PMID:Glucocorticoid action networks and complex psychiatric and/or somatic disorders. 1751 90

Glucocorticoids are widely used in the treatment of inflammatory and other diseases. However, high-dose or chronic administration often triggers troublesome side effects such as metabolic syndrome and osteoporosis. We recently described that one glucocorticoid receptor gene produces eight translational glucocorticoid receptor isoforms that have distinct gene-regulatory abilities. We show here that specific, but not all, glucocorticoid receptor isoforms induced apoptosis in human osteosarcoma U-2 OS bone cells. Whole human genome microarray analysis revealed that the majority of the glucocorticoid target genes were selectively regulated by specific glucocorticoid receptor isoforms. Real-time PCR experiments confirmed that proapoptotic enzymes necessary for cell death, granzyme A and caspase-6, were induced by specific glucocorticoid receptor isoforms. Chromatin immunoprecipitation assays further suggested that glucocorticoid receptor isoform-dependent induction of proapoptotic genes was likely due to selective coregulator recruitment and chromatin modification. Interestingly, the capabilities to transrepress proinflammatory genes were similar among glucocorticoid receptor isoforms. Together, these findings provide new evidence that translational glucocorticoid receptor isoforms can elicit distinct glucocorticoid responses and may be useful for the development of safe glucocorticoids with reduced side effects.
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PMID:Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor. 1768 54

Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 inhibitor, 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11betaHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC(50) of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases.
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PMID:Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), an inhibitor of 11 -hydroxysteroid dehydrogenase type 1, in cynomolgus monkeys. 1792 Nov 90

The global epidemic of obesity and type-2 diabetes has heightened the need to understand the mechanisms that contribute to its pathogenesis and also to design and trial novel treatments. Patients with glucocorticoid (GC) excess--'Cushing's syndrome'--are phenotypically similar to patients with simple obesity. As such, much research has focused on the manipulation of local GC action as a therapeutic strategy. The majority of the classical actions of GCs are mediated via activation of the glucocorticoid receptor (GR). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive cortisone to cortisol and therefore amplifies local GC action. There is now a wealth of data from rodent and clinical studies implicating this conversion in the pathogenesis of obesity, type-2 diabetes, and the metabolic syndrome. Selective 11beta-HSD1 inhibitors (selective in that they block the activity of 11beta-HSD1 and not 11beta-HSD2 which inactivates cortisone to cortisol in mineralocorticoid target tissues) are currently in development although not yet available for use in clinical studies. Rodent studies utilizing these compounds have shown dramatic improvements in insulin sensitivity as well as improvements in lipid profiles and atherogenesis. A further experimental approach has been to design drugs that antagonize GR activation, and again these compounds appear to improve insulin sensitivity and lower glucose production rates. The key test for both of these research strategies is whether they will translate into clinical studies, and results from these trials are now eagerly awaited.
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PMID:Modulation of glucocorticoid action and the treatment of type-2 diabetes. 1805 38

Adipose tissue inflammation and insulin resistance are central to the pathogenesis of the metabolic syndrome. Spironolactone, an antagonist of mineralocorticoid receptor, glucocorticoid receptor and androgen receptor, and agonist of progesterone receptor, has anti-inflammatory activity. Blockade of the renin-angiotensin-aldosterone system has been shown to improve glucose metabolism. We have investigated whether spironolactone has direct effects on glucose uptake and interleukin-6 secretion in human adipocytes. Spironolactone, but not its active metabolite canrenoic acid, significantly increased basal and insulin-stimulated glucose uptake in cultured IN VITRO-differentiated adipocytes of women, without affecting insulin sensitivity. The effect was not due to changes in abundance of glucose transporters 1 or 4 or in degree of cell differentiation. Spironolactone, but not canrenoic acid, significantly reduced basal interleukin-6 secretion by cultured stromal-vascular cells. These effects of spironolactone were not mediated by ligand-dependent antagonism of the mineralocorticoid, glucocorticoid, or androgen receptors. Spironolactone may have a novel role in increasing glucose uptake into adipose cells and attenuating adipose tissue inflammation, with implications for management of metabolic syndrome.
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PMID:Effects of spironolactone on glucose transport and interleukin-6 secretion in adipose cells of women. 1807 71

Genetic factors are of importance for the development of the metabolic syndrome and type 2 diabetes, but despite extensive research the identification of the underlying genes has not been fruitful. This report focuses on the interactions between intrauterine growth and genes in relation to adult health outcomes based upon findings from the Helsinki Birth Cohort Study. Candidate genes for type 2 diabetes and the metabolic syndrome have been focused upon and we report on interactions between polymorphisms of the peroxisome proliferator-activated receptor (PPAR)gamma-2, plasma cell glycoprotein (PC-1) and the glucocorticoid receptor (GR) genes and - prenatal growth in relation to adult health outcomes. In elderly individuals the effects of the Pro12Pro/Pro12Ala polymorphisms of the PPARgamma-2 gene depend on their body size at birth. Individuals, who had a small body size at birth and were carriers of the Ala allele, seem to be protected against insulin resistance and type 2 diabetes in later life. Similar gene environment interactions will be described in relation to the PC-1 and the GR genes. We propose that these findings reflect gene-early environment interactions and can be attributed to the phenomenon of developmental plasticity.
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PMID:The role of genes in growth and later health. 1819 45

The development of diabetes associated with stress, obesity, and metabolic syndrome involves elevated plasma glucocorticoid levels. It has been shown that short-term (<1 day) exposure to glucocorticoids reduces insulin secretion from pancreatic islets by affecting several steps of glucose signaling in beta-cells. However, longer term direct effects of glucocorticoids on beta-cells remain to be established. In this study, single beta-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assessment of the beta-cell responsiveness to glucose by measuring cytosolic Ca2+ concentration ([Ca2+]i) using fura-2. Following treatment with corticosterone at 10-500 ng/ml for 3 days, the first-phase [Ca2+]i response to 8.3 mM glucose in beta-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the beta-cell [Ca2+]i response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired beta-cell [Ca2+]i responses to glucose. A mineralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca2+]i responses to glucose, while an MR ligand aldosterone attenuated the corticosterone inhibition of [Ca2+]i responses. Neither spironolactone nor aldosterone by itself affected [Ca2+]i responses. These results indicate that long-term treatment with corticosterone impairs beta-cell [Ca2+)]i responses to glucose. This effect is mediated by GR and attenuated partially by simultaneous MR stimulation by corticosterone. The results show a novel function of MR to protect islet beta-cells against deteriorating glucocorticoid action via GR.
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PMID:Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic beta-cells. 1843 52

The adipocyte enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies local glucocorticoid action by generating active glucocorticoids from inactive metabolites and has emerged as a key player in the pathogenesis of central obesity and metabolic syndrome. However, the regulation of adipocyte 11beta-HSD1 is incompletely understood. Therefore, the present study was designed to investigate the effects of insulin and glucocorticoid as well as their underlying molecular mechanisms on 11beta-HSD1 activity and expression in 3T3-L1 adipocytes and determine whether the in vitro findings could be confirmed in vivo. Our main in vitro findings are 1) insulin stimulated whereas dexamethasone inhibited 11beta-HSD1 activity and expression in a time- and concentration-dependent manner; 2) the effect of dexamethasone was mimicked by both cortisol and corticosterone but blocked by the glucocorticoid receptor antagonist RU486; 3) the p38 MAPK inhibitor SB220025, but not the ERK inhibitor U0126 or the phosphatidylinositol 3-kinase inhibitor LY294002, prevented insulin stimulation of 11beta-HSD1 activity; and 4) although dexamethasone did not alter the half-life of 11beta-HSD1 mRNA, insulin doubled it. Taken together, these in vitro results demonstrate that insulin stimulates adipocyte 11beta-HSD1 through a posttranscriptional mechanism that involves activation of the p38 MAPK signaling pathway, whereas dexamethasone exerts an opposite effect by a glucocorticoid receptor-mediated transcriptional mechanism. In contrast, both insulin and dexamethasone augmented 11beta-HSD1 activity and expression in rat white adipose tissue in vivo, thus confirming the role of insulin but revealing a fundamental difference regarding the role of dexamethasone in regulating adipocyte 11beta-HSD1 between the two model systems.
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PMID:Insulin and dexamethasone dynamically regulate adipocyte 11beta-hydroxysteroid dehydrogenase type 1. 1846 33

Prenatal treatment of congenital adrenal hyperplasia (CAH) with dexamethasone to minimize the genital virilization of external genitalia of affected girls has been in use since the mid-1980s. The positive effect of reducing virilization is now established. However, experimental data from animal studies and observations on adverse medical events in human newborns have raised concerns about the long-term safety of the treatment. Most animal studies on prenatal treatment with synthetic glucocorticoids have been designed to mimic treatment for lung maturation in preterm infants. The primary focus has been on a possible impact on fetal programming and the development of the metabolic syndrome with insulin resistance, type 2 diabetes, and high blood pressure. Altered reactivity to stress as a function of differences in reactivity of the HPA axis and glucocorticoid receptor function have been assayed. Effects on cognition, especially memory, have been observed. In children at risk for CAH and treated prenatally with dexamethasone, no overall effects on full-scale IQ have been observed, but a negative effect on verbal working memory has been reported. Contradictory effects on social behavior with respect to shyness and inhibition have been discussed. There is an urgent need for in-depth studies of long-term outcome in prenatal treatment of CAH regarding both maternal side effects and possible negative metabolic as well as cognitive and behavioral effects in the growing fetus and the child in her development into adulthood.
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PMID:Long-term outcome of prenatal treatment of congenital adrenal hyperplasia. 1849 35

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.
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PMID:7-oxysterols modulate glucocorticoid activity in adipocytes through competition for 11beta-hydroxysteroid dehydrogenase type. 1902 97

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