Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
 ...
PMID:Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. 1578 56

Abstract Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob / ob and db / db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob / ob and db / db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob / ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions.
 ...
PMID:Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. 1598 91

Inflammation is a central component of several chronic human diseases, including atherosclerosis and type 2 diabetes. Several nuclear receptors repress inflammatory responses, but their molecular mechanisms remain poorly understood. The nuclear receptor superfamily is composed of transcription factors that have emerged as key regulators of inflammation and lipid homeostasis. These include the glucocorticoid receptor, which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. In addition, peroxisome proliferator-activated receptors and liverXreceptors, in response to endogenous eicosanoids and oxysterols, respectively, modulate transcriptional pathways involved in inflammatory responses and lipid homeostasis.
 ...
PMID:PPARs and other nuclear receptors in inflammation. 1677 82

Recent epidemiological studies demonstrated a beneficial effect of coffee consumption for the prevention of type 2 diabetes, however, the underlying mechanisms remained unknown. We demonstrate that coffee extract, corresponding to an Italian Espresso, inhibits recombinant and endogenous 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. The inhibitory component is heat-stable with considerable polarity. Coffee extract blocked 11beta-HSD1-dependent cortisol formation, prevented the subsequent nuclear translocation of the glucocorticoid receptor and abolished glucocorticoid-induced expression of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. We suggest that at least part of the anti-diabetic effects of coffee consumption is due to inhibition of 11beta-HSD1-dependent glucocorticoid reactivation.
 ...
PMID:Coffee inhibits the reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee? 1681 82

The glucocorticoid receptor (GR) is a crucial target gene for glucocorticoid-induced insulin resistance and hepatic gluconeogenesis linked to the development of type 2 diabetes. The liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of the metabolic gene linked to carbohydrate homeostasis. To assess the tissue-specific interaction of LXR with GR in the development of type 2 diabetes, we examined the possible effect of LXR agonist T0901317 on GR gene expression in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). Chronic ligand activation of LXR by a synthetic LXR T0901317 markedly decreased the expression of both GR mRNA and its protein in liver and improved the phenotype of type 2 diabetes in obese db/db mice. Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase mRNA and 11beta-hydroxysteroid dehydrogenase type 1-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver. Treatment of db/db mouse primary hepatocytes with T0901317 resulted in dramatic suppression of GR mRNA and required ongoing protein synthesis. Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11beta-hydroxysteroid dehydrogenase type 1 and phosphoenolpyruvate carboxykinase. These findings suggest that some of antidiabetic actions of LXR agonist T0901317 may be mediated, at least in part, through the suppression of hepatic GR gene expression.
 ...
PMID:Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice. 1687 40

Excess body fat, obesity, is one of the most common disorders in clinical practice. Obese individuals are at increased risk for physical ailments, such as type 2 diabetes, coronary heart disease, hypertension, and several types of cancer. The location of the body fat is a major determinant of the degree of excess morbidity and mortality due to obesity. More specifically, the amount of subcutaneous truncal or abdominal fat, and the amount of visceral fat located in the abdominal cavity independently predicts obesity-related adverse health outcomes. The obesity gene map shows putative loci on all chromosomes except Y. More than 300 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. These genes can be divided into two broad categories: (a) rare gene variants that have a strong influence, and (b) common gene variants that have a weaker influence on obesity phenotypes. Studies in humans have suggested a positive association between obesity, hypertension, and insulin resistance, with alleles at the glucocorticoid receptor gene. In this article, we will estimate the risk by which such gene polymorphism mediates a role in obesity.
 ...
PMID:A brief update of glucocorticoid receptor variants and obesity risk. 1714 38

It is unclear how hepatic glucocorticoid receptor (GR) function and hypothalamic-pituitary-adrenal axis tone contribute to the diabetic state and in particular whole-body glucose fluxes. We have previously demonstrated that long-term exposure to hepatic GR inhibition lowers glucose levels in ob/ob mice (J Pharmacol Exp Ther 2005;314:191). The purpose of this study was to determine the effects of a novel GR antagonist (A-348441) on whole-body glucose fluxes in a model of insulin resistance, the Zucker fatty (fa/fa) rat. After an overnight fast, euglycemic-hyperinsulinemic clamp studies were performed 2 hours after single oral dosing as follows: (1) A-348441 at 100 mg/kg or (2) vehicle. Furthermore, effects of 1 week of treatment with either vehicle or A-348441 (3, 10, 30, or 100 mg/kg PO, once per day) were investigated in separate groups of rats fasted overnight and given a final dose of their respective compound, followed 2 hours later by a euglycemic-hyperinsulinemic clamp. One week after catheter implantation, body weight returned to presurgery levels, with no difference between groups. A single, 100-mg/kg dose of A-348441 significantly increased glucose infusion rate 4-fold (P < .05) and reduced endogenous glucose production by 37% (P < .05) but did not change glucose disposal. After 1 week of sub-long-term dosing, fasting glucose levels were reduced dose-dependently with A-348441 vs vehicle (-8%, not significant; -14%, -20%, and -25%, P < .05, at 3, 10, 30, and 100 mg/kg, respectively) with no observed hypoglycemia or change in fasting insulin levels. A-348441 increased the glucose infusion rates after 1-week treatment by 1.3-, 5.7-, 7.3-, and 6.4-fold (P < .05). Endogenous glucose production was decreased (-25%, -44%, -50%, and -61%, P < .05), whereas glucose disposal was increased (29% and 13%, not significant; 23% and 34%, P < .05), with A-348441. In summary, single-dose treatment with the liver-selective GR antagonist A-348441 decreases glucose production with no effect on glucose disposal or fasting glucose levels. After 1 week of treatment with A-348441, (1) there was no effect on body weight, (2) fasting glucose levels decreased, (3) both glucose disposal and glucose infusion rate increased during clamping, and (4) endogenous glucose production was greatly reduced. In addition, hepatic glucose production was highly correlated with fasting glucose levels (r = 0.97). In conclusion, these results indicate that A-348441 increases insulin sensitivity at both the liver and peripheral tissues, leading toward a normalization of the insulin resistant state. Furthermore, with 1-week vs single-dose liver-selective glucocorticoid antagonism, we have determined that the peripheral effect is secondary to the primary event of reduced hepatic glucose production. The approach of inhibiting the hepatic GR may be an advantageous treatment paradigm for individuals with type 2 diabetes mellitus.
 ...
PMID:Liver-selective glucocorticoid receptor antagonism decreases glucose production and increases glucose disposal, ameliorating insulin resistance. 1729 27

The major glucocorticoid in man, cortisol, plays important roles in regulating fuel metabolism, energy partitioning and body fat distribution. In addition to the control of cortisol levels in blood by the hypothalamic-pituitary-adrenal axis, intracellular cortisol levels within target tissues can be controlled by local enzymes. 11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the regeneration of active cortisol from inert cortisone, thereby amplifying cortisol levels and glucocorticoid receptor activation in adipose tissue, liver and other tissues. 11Beta-HSD1 is under complex tissue-specific regulation and there is evidence that it adjusts local cortisol concentrations independently of the plasma cortisol concentrations, e.g. in response to changes in diet. In obesity 11beta-HSD1 mRNA and activity in adipose tissue are increased. The mechanism of this up-regulation remains uncertain; polymorphisms in the HSD11B1 gene have been associated with metabolic complications of obesity, including hypertension and type 2 diabetes, but not with obesity per se. Extensive data have been obtained in mice with transgenic over-expression of 11beta-HSD1 in liver and adipocytes, targeted deletion of 11beta-HSD1, and using novel selective 11beta-HSD1 inhibitors; these data support the use of 11beta-HSD1 inhibitors to lower intracellular glucocorticoid levels and treat both obesity and its metabolic complications. Moreover, in human subjects the non-selective 'prototype' inhibitor carbenoxolone enhances insulin sensitivity. Results of clinical studies with novel potent selective 11beta-HSD1 inhibitors are therefore eagerly awaited. The present article focuses on the physiological role of glucocorticoids in regulating energy partitioning, and the evidence that this process is modulated by 11beta-HSD1 in human subjects.
 ...
PMID:Extra-adrenal regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning. 1734 66

Intrauterine growth retardation (IUGR) has been linked to later development of type 2 diabetes in adulthood. An abnormal metabolic intrauterine milieu affects the development of the fetus by permanently modifying gene expression of susceptible cells. Altered gene expression persists after birth, suggesting that an epigenetic mechanism may be responsible for changes in transcription. Uteroplacental insufficiency (IUGR) is associated with hypomethylation and hyperacetylation of genomic DNA in brain and liver of IUGR fetal and juvenile rats. These findings are associated with zinc deficiency that often accompanies fetal growth retardation. Studies in the IUGR rat also demonstrate that an abnormal intrauterine environment induces epigenetic modifications of key genes regulating beta-cell development and experiments directly link chromatin remodeling to suppression of transcription. Dietary protein restriction of pregnant rats causes fetal growth retardation and is associated with hypomethylation of the glucocorticoid receptor (GR) and PPARgamma genes in liver of the offspring. It is postulated that these epigenetic changes result in the observed increase in gene expression of GR and PPARgamma. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring.
 ...
PMID:Developmental origins of beta-cell failure in type 2 diabetes: the role of epigenetic mechanisms. 1741 45

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.
 ...
PMID:The role of genes in growth and later health. 1819 45


<< Previous 1 2 3 4 5 6 7 Next >>