Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Megestrol acetate is a synthetic progestin that has been used since the 1970s for the treatment of advanced cancer and subsequently to treat anorexia, cachexia and weight loss in AIDS patients. It has been shown that high doses or prolonged treatment with this drug may cause Cushing's syndrome, new-onset diabetes and suppression of plasma ACTH and cortisol levels. Megestrol acetate may cause suppression of the pituitary-adrenal axis due to the affinity of this compound for the glucocorticoid receptor. Recognising the glucocorticoid-like activity of megestrol and its effects at the axis level is important for the diagnosis of sub-clinical adrenal insufficiency. We present the case of a 74-year-old woman with infiltrating ductal breast carcinoma refractory to prolonged hormonal treatment with megestrol acetate, presenting with adrenal insufficiency.
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PMID:Megestrol acetate-induced adrenal insufficiency. 1841 Nov 98

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

Glucocorticoids have been suggested to play a role in programming late adult disorders like diabetes during fetal life. Recent work in rodents showed their role in pancreas development by modulating the expression of transcription factors. The aim of this work was to investigate their possible implication in human pancreas development. The ontogenesis of glucocorticoid receptor (GR) and several pancreatic transcription factors was studied by immunohistochemistry and RT-PCR on human fetal pancreatic specimens. At 6 wk of development (wd) insulin promoting factor 1 (IPF1) was expressed in the majority of epithelial cells forming tubular structures while GR was present in the mesenchyme, suggesting an early role of glucocorticoids, before endocrine and exocrine differentiation. Only GR alpha (active form) mRNA was expressed from 6 wk onwards while GR beta (inactive form) was never observed. The first insulin cells did not express IPF1 or GR. Islet formation occurred from 10 wd as IPF1-positive cells started to express simultaneously insulin and GR. This coexpression in beta cells persisted until adulthood. The mRNA expression profiles confirmed immunohistochemistry and showed the early expression of crucial transcription factors. In conclusion, the presence of the active GR isoform around islet formation supports the novel idea that glucocorticoids could modulate human pancreas development.
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PMID:Potential role of glucocorticoid signaling in the formation of pancreatic islets in the human fetus. 1853 89

This review covers recent progress in the discovery of selective glucocorticoid receptor (GR) antagonists. Potential therapeutic applications of selective GR antagonists are described including the pharmacological rationale and, in some cases, clinical evidence that underlies these proposed uses. Disease areas that are discussed are Cushing's syndrome, psychotic depression, diabetes, obesity, Alzheimer's disease, neuropathic pain, drug abuse, and glaucoma. Methods for evaluating GR antagonist properties (binding, functional, and in vivo assays) are briefly covered. Early research on steroidal ligands which led to the identification of the non-selective GR antagonist RU-486 (mifepristone) and the GR-selective steroid RU-43044 is reviewed as is subsequent work on related steroidal compounds. Structure activity relationships (SAR) of nonsteroidal GR antagonists from the following structural classes are presented: octahydrophenanthrenes, spirocyclic dihydropyridines, triphenylmethanes and diaryl ethers, chromenes, dibenzyl anilines, dihydroisoquinolines, pyrimidinediones, azadecalins, and aryl pyrazolo azadecalins.
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PMID:Glucocorticoid receptor antagonists. 1853 90

We previously demonstrated that while diabetic animals receiving long-term insulin treatment exhibited some impairment in their corticosterone response to hypoglycemia, the stress response to hypoglycemia was completely absent when these animals were subjected to recurrent hypoglycemia. In the current study, we examined potential mechanisms that may contribute to defects in the adrenocortical response to hypoglycemia in long-term insulin-treated diabetic animals exposed to antecedent hypoglycemia. Whereas insulin-treated diabetic animals exhibited a significant rise in corticotrophin-releasing hormone (CRH) mRNA levels during hypoglycemia, exposure to antecedent hypoglycemia completely abolished this response. Moreover, expression of hippocampal mineralocorticoid receptors (MR) mRNA, which normally act to suppress hypothalamo-pituitary-adrenal activity, decreased in the normal control and insulin-treated diabetic groups in response to hypoglycemia, whereas MR mRNA levels remained at baseline in animals subjected to antecedent hypoglycemia. Interestingly, hippocampal glucocorticoid receptor (GR) mRNA levels decreased in all three treatment groups following the hypoglycemic clamp. While GR mRNA levels in the paraventricular nucleus were lower in normal controls following hypoglycemia, this trend just failed to reach statistical significance in the two diabetic groups. These data suggest that (1) recurrent hypoglycemia, much like uncontrolled diabetes, has a pronounced effect on hippocampal mineralocorticoid receptor mRNA expression that may prevent it, and presumably also the stress axis, from responding properly to a subsequent bout of hypoglycemia, and (2) while long-term insulin treatment was sufficient to restore some of these responses in diabetic animals, tighter glycemic control may be necessary to see full restoration of the stress response.
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PMID:The effect of long-term insulin treatment with and without antecedent hypoglycemia on neuropeptide and corticosteroid receptor expression in the brains of diabetic rats. 1867 33

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

Diabetes is a metabolic disorder that is associated with the dysregulation of a number of systems within the body. In the present study, we investigated glucocorticoid receptor (GR) immunoreactivity and its protein levels in the paraventricular nuclei of 4-, 12-, 20- and 30-week-old Zucker diabetic fatty (fa/fa, ZDF) and in Zucker lean control (fa/+ or +/+, ZLC) rats, because the progressive induction of diabetes is detectable in this model after 7 weeks of age and chronic diabetic conditions are maintained after 12 weeks of age. GR immunoreactivity was detected in parvocellular paraventricular nuclei and this and GR protein levels were exponentially increased according to the ages. In particular, GR immunoreactivities and protein levels were markedly more increased in 30-week-old ZDF rats than in age-matched ZLC group and in younger ZDF group. The present study suggests that GR immunoreactivity and its protein level is associated with a degenerative phenotype in the hypothalamus of from 12-weeks old in the ZDF rat type II diabetes model.
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PMID:Glucocorticoid receptor changes associate with age in the paraventricular nucleus of type II diabetic rat model. 1875 53

Aberrant accumulation of lipids in the liver ("fatty liver" or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of liver function, the molecular mechanisms of fatty liver development remain largely enigmatic. Here we show that liver-specific disruption of glucocorticoid receptor (GR) action improves the steatotic phenotype in fatty liver mouse models and leads to the induction of transcriptional repressor hairy enhancer of split 1 (Hes1) gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. As glucocorticoid action is increased during starvation, myotonic dystrophy, and Cushing's syndrome, the inhibition of Hes1 through the GR might explain the fatty liver phenotype in these subjects.
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PMID:The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. 1876 22

Glucocorticoids, through their interaction with the ubiquitous glucocorticoid receptor (GR), have extensive and disparate effects on different cells and tissues. They have long been used in the treatment of asthma, arthritis and autoimmune diseases based on their anti-inflammatory and immunosuppressive effects. For these reasons, as well as for their ability to induce massive apoptosis in hematological malignancies, they are also commonly used as cotreatment in cancers. Despite their wide usage, chronic glucocorticoid therapy has deleterious side effects, including weight gain, osteoporosis and diabetes mellitus, and has been shown to diminish the tumor toxicity of chemotherapy, preventing the full potential of glucocorticoid treatment from being realized. Technological advances have contributed to a better understanding of the mechanism of glucocorticoid action, prompting the development of tailored therapeutics targeting the desired outcomes of GR signaling. This review discusses recent advances in the development of novel therapeutic agents for inflammation and cancer through targeting the GR.
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PMID:Novel therapeutic agents targeting the glucocorticoid receptor for inflammation and cancer. 1882 68

Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta. Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB. Furthermore, GSK-3beta-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-kappaB transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3beta and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3beta activity can dictate how cells will ultimately respond to glucocorticoids.
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PMID:Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. 1883 40


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