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)

In the present study, we have determined the specific glucocorticoid receptors in cultured human skin fibroblasts with [3H]dexamethasone as the ligand. The whole-cell assay was employed for determination of glucocorticoid receptor densities and binding affinities in fibroblast cultures established either from 16 healthy control subjects, from 4 patients with active progressive systemic sclerosis (PSS), from 3 patients with keloids and 3 patients with diabetes mellitus. The receptor densities in PSS, keloid, diabetes and control fibroblasts were in the same range, the values being 6.3 +/- 4.9, 7.7 +/- 3.6, 5.3 +/- 1.3 and 7.9 +/- 6.2 fmol/micrograms DNA (mean +/- SD), respectively. In further studies, the cells were incubated with 10(-7) M dexamethasone for 4 or 9 days before the receptors were assayed. The specific binding of [3H]dexamethasone in steroid treated cultures was 62 and 13% of that observed in controls, suggesting down-regulation. In contrast, incubation of fibroblasts with 10(-5) M all-trans-retinoic acid did not alter the binding of [3H]dexamethasone, suggesting lack of pharmacologic interference at the receptor level.
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PMID:Glucocorticoid receptors in cultured human skin fibroblasts: evidence for down-regulation of receptor by glucocorticoid hormone. 245 69

This investigation examined the effects of Streptozotocin diabetes in pregnancy on several parameters of glucocorticoid action in the rat placenta. Pregnant diabetic rats showed reduced body weight, increased adrenal weight and serum corticosterone concentrations. Glucocorticoid receptors in placental cytosol of labyrinthine zone, measured in the absence of MoO4Na2 were similar in control and diabetic rats, but after addition of MoO4Na2 receptor number were moderately, but significantly reduced in diabetic placentas (P less than 0.01). No changes in affinity were detected in saturation analysis. Furthermore, transformation of the receptor assessed by its capacity for binding to DNA-cellulose, was enhanced in diabetic animals, suggesting increased efficiency of the receptor-bound hormone. Since the function of the glucocorticoid receptor of rat placenta may be the inhibition of local progesterone production (Heller and De Nicola, J. steroid Biochem. 19 (1983) 1339-1343), we determined progesterone synthesis in vitro and found that diabetic placentas synthesized significantly less progesterone than control tissue (P less than 0.05). Lastly, we found that the metabolism of corticosterone to 11-dehydrocorticosterone, while declining in control placentas as pregnancy advanced, it was sustained in diabetic pregnancy. It is suggested that diabetic rat placentas showed increased activity towards the glucocorticoid receptor, resulting in reduction in progesterone synthesis and sustained catabolism of corticosterone. The latter may possibly constitute a compensatory mechanism to protect the fetal compartment from high levels of maternal glucocorticoids.
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PMID:Steps of glucocorticoid action in normal and diabetic rat placenta. 339 25

As one step in characterizing the effectiveness of glucocorticoid hormones in states of abnormal carbohydrate metabolism, the number and affinity of glucocorticoid receptors in cytosolic extracts of liver and kidney from ob/ob mice and pancreata from streptozotocin-treated rats were determined and compared to values derived from normals. Scatchard analysis revealed that each tissue contained the same number of glucocorticoid receptors as its control when expressed in terms of receptor number per mg of cytosolic protein. Similarly, the affinity of these receptors for dexamethasone was unchanged. It is concluded that these two forms of diabetes are not associated with abnormalities of glucocorticoid receptor number.
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PMID:Glucocorticoid receptor number in ob/ob mice and streptozotocin-treated rats. 405 27

The aim of this study was to investigate whether mutations in the glucocorticoid receptor could account for the increasing unresponsiveness of patients with chronic lymphatic leukemia (CLL) to combination chemotherapy. The receptor was tested immunocytochemically, in steroid binding assays, and by a mutation screening (denaturing gradient gel electrophoresis) of the receptor-cDNA. The receptor concentration, as measured by staining and steroid binding test, varied considerably but showed no clear correlation to clinical response. Using a highly sensitive mutation screening assay of the DNA- and the steroid-binding region, none of the treated patients revealed any mutation, suggesting that the glucocorticoid receptor in the CLL patients tested is not altered in these domains. In one individual who had not been treated before analysis a silent mutation was found in one receptor allele. The results suggest that mechanisms other than altered ligand or DNA binding of the receptor may be responsible for the lack of response to chemotherapy. This conclusion is discussed in relation to the mechanism of corticoid resistance in mouse and human lymphoma cells in culture.
Exp Clin Endocrinol Diabetes 1995
PMID:The DNA and steroid binding domains of the glucocorticoid receptor are not altered in mononuclear cells of treated CLL patients. 758 20

Inhibitors of steroid synthesis such as o,p'-DDD, aminoglutethimide, metyrapone, trilostane and ketoconazole are usually used for treatment of Cushing's syndrome in order to reduce the steroid production in the patients showing several complications, including severe hypertension and diabetes mellitus, and also an incomplete remission after the surgical treatment. o,p'-DDD and metyrapone are recommended to use for treatment of adrenocortical cancer and rapid reduction of cortisol levels, respectively. Aminoglutethimide and trilostane do not always have any side effects, although ketoconazole which is commonly used for treatment of Cushing's disease shows severe hepatic damage. RU 486 is effective for inhibiting the activity of glucocorticoid receptor, and will be used for treatment of Cushing's syndrome in near future.
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PMID:[Clinical usefulness of pharmacological treatment of Cushing's syndrome]. 816 84

The nuclear hormone receptors NUC-1 (PPAR delta) and PPAR alpha are members of the peroxisome proliferator-activated receptor (PPAR) family. The members of this receptor family are activated by agents that stimulate peroxisome proliferation, free fatty acids, prostaglandin 12 metabolites, and agents considered for the therapy of insulin-independent diabetes mellitus. To identify putative physiological agents that activate NUC-1, we tested the ability of acetone extracts of various rat tissues to activate the transcription of an MMTV-luciferase reporter gene, via a GR/NUC-1 hybrid receptor. GR/NUC-1 contains the ligand binding region of the NUC-1 receptor and the DNA binding domain of the glucocorticoid receptor. Using this assay, we found stimulatory activity in the pancreas, which upon purification and characterization was identified as methyl-palmitate, known to be enriched in pancreatic lipids. In addition, we determined that ethyl esters of palmitic and oleic acids are also potent activators of this receptor. Thus, fatty acid ester formation may control the cellular concentrations of fatty acids, and acyl-ester formation may play a role in the control of metabolic pathways and the activation of the PPAR.
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PMID:Identification of fatty acid methyl ester as naturally occurring transcriptional regulators of the members of the peroxisome proliferator-activated receptor family. 893 43

The full-length human glucocorticoid receptor (hGR), overexpressed in Spodoptera frugiperda (Sf9) cells, associates with heat shock protein 90 (hsp90) and hsp70 and binds dexamethasone with high affinity. Baculovirus infection of Sf9 cells grown in TNM-FH medium results in the rapid depletion of glucose from the medium within 24 h. Noting a discrepancy between hGR protein levels and ligand binding capacity in such cultures, we hypothesized that the depletion of glucose from the medium could result in intracellular ATP depletion and consequently affect the ligand binding capacity of the recombinant hGR. Supplementation of the Sf9 culture medium with additional glucose resulted in a three-fold increase in intracellular ATP levels, and a three-fold increase in 3H-dexamethasone binding capacity, without altering the protein levels of hGR, hsp90 or hsp70. However, more hsp90 co-immunoprecipitated with hGR from cells grown in glucose supplemented medium. Our data support the hypothesis that high-affinity ligand binding by hGR requires the ATP-dependent formation of the hGR:hsp90 heterocomplex. Besides having practical consequences for the production of recombinant GR and other related proteins, our findings could ultimately have relevance in diseases such as diabetes mellitus.
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PMID:Optimal ligand binding by the recombinant human glucocorticoid receptor and assembly of the receptor complex with heat shock protein 90 correlate with high intracellular ATP levels in Spodoptera frugiperda cells. 918 52

Glucocorticoids have been used as anti-inflammatory, anti-allergic and immunosuppressive agents since the beginning of the 1940s, and during recent years the mechanisms by which they exert their anti-inflammatory effects have begun to be better understood. Inhibition of inflammatory response is primarily mediated via the glucocorticoid receptor and the two transcription factors, AP-1 and NF kappa B, which are of crucial importance for the expression of pro-inflammatory cytokines and other genes involved in the inflammatory process. Unfortunately, long-term treatment with glucocorticoids is associated with a series of adverse effects such as hypertension, bone fragility, diabetes, dermatrophy and personality changes. However, owing to advances in biotechnology and recent clarification of the molecular mechanisms involved, it is now becoming possible to develop new glucocorticoids with a more selective anti-inflammatory effect without serious side-effects.
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PMID:[New glucocorticoids are more selective. Current knowledge can eliminate serious adverse effects]. 923 45

Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production. Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter. Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates. Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice. These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids.
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PMID:Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. 932 75

The molecular mechanisms underlying increased hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription and gluconeogenesis in type II diabetes are largely unknown. To examine the involvement of glucocorticoids and the cis-acting insulin response sequence (IRS, -416/-407) in the genetically obese db/db mouse model, we generated crosses between C57BL/KsJ-db/+ mice and transgenic mice that express -460 or -2000 base pairs of the rat PEPCK gene promoter containing an intact or mutated IRS, linked to a reporter gene. Transgenic mice expressing the intact PEPCK(460)-CRP (C-reactive protein) transgene bred to near homozygosity at the db locus were obese, hyperinsulinemic, and developed fasting hyperglycemia (389 +/- 26 mg/100 ml) between 4 and 10 weeks of age. Levels of CRP reporter gene expression were increased 2-fold despite severe hyperinsulinemia compared with non-diabetic non-obese transgenic mice. Reporter gene expression was also increased 2-fold in transgenic obese diabetic db/db mice bearing a mutation in the IRS, -2000(IRS)-hGx, compared with non-obese non-diabetic transgenic 2000(IRS)-hGx mice. Treatment of obese diabetic db/db transgenic mice with the glucocorticoid receptor blocker RU 486 decreased plasma glucose by 50% and reduced PEPCK, GLUT2, glucose-6-phosphatase, tyrosine aminotransferase, CRP, and hGx reporter gene expression to levels similar to those of non-obese normoglycemic transgenic mice. Taken together, these results establish that -460 bp of 5'-flanking sequence is sufficient to mediate the induction of PEPCK gene transcription in genetically obese db/db mice during the development of hyperglycemia. The results further demonstrate that the mechanism underlying increased expression of gluconeogenic enzymes in the db/db mouse requires the action of glucocorticoids and occurs independently of factors acting through the PEPCK IRS (-416/-407) promoter binding site.
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PMID:Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hyperglycemia are regulated by glucocorticoids in genetically obese db/db transgenic mice. 939 82


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