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)

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that regulates genes involved in lipid and glucose metabolism, may contribute to the onset of metabolic disorders such as diabetes and the accompanying dyslipidemia. Fat-derived tumor necrosis factor alpha (TNF-alpha) and the acute-phase response protein, C-reactive protein (CRP), may also have a role in the development of obesity-related insulin resistance and type 2 diabetes mellitus. In this study, a group of 14 naturally occurring, insulin-requiring, type 2 diabetic cynomolgus monkeys were used to evaluate the effects of the PPAR-gamma agonist, rosiglitazone, on glycemic and lipid parameters and serum levels of TNF-alpha and CRP. The animals were randomized into 2 groups of 7. One group was treated with 0.5 mg/kg rosiglitazone orally once a day for 7 weeks. Blood was collected for evaluation at baseline, at 2 and 7 weeks during the treatment period, and at 7 and 13 weeks after treatment. Daily insulin requirements were recorded during the entire study. Results showed daily exogenous insulin requirements were significantly reduced (P <.01) in those treated with rosiglitazone, while glycemic control was maintained. Plasma triglyceride concentrations were significantly lower (P <.01) whereas plasma cholesterol levels tended to be lower and high-density lipoprotein (HDL) concentrations tended to be higher after treatment. No significant differences were noted in TNF-alpha and CRP serum levels during the treatment period. Body weights remained steady in both groups during the study. These results suggest overall improvement in insulin regulation and lipid profiles during treatment with rosiglitazone.
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PMID:Rosiglitazone treatment improves insulin regulation and dyslipidemia in type 2 diabetic cynomolgus monkeys. 1533 71

The liver X receptors (LXRs), LXRalpha and LXRbeta, are ligand-activated transcription factors of the nuclear receptor superfamily that control the expression of genes involved in cholesterol and fatty acid metabolism. While the identification of small-molecule non-steroidal LXR agonists has validated the LXRs as potential drug targets for cardiovascular disease, recent reports from several research groups suggest that LXR ligands will be valuable therapeutic agents for the treatment of inflammation, diabetes and neurodegenerative diseases. This review focuses on the effects of LXR agonists on relevant signaling pathways, the recently reported ligand-bound LXR crystal structures, and recently disclosed LXR small-molecule templates.
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PMID:Therapeutic opportunities for liver X receptor modulators. 1550 71

Nuclear receptors are major targets for drug discovery and have key roles in development and homeostasis, as well as in many diseases such as obesity, diabetes and cancer. This review provides a general overview of the mechanism of action of nuclear receptors and explores the various factors that are instrumental in modulating their pharmacology. In most cases, the response of a given receptor to a particular ligand in a specific tissue will be dictated by the set of proteins with which the receptor is able to interact. One of the most promising aspects of nuclear receptor pharmacology is that it is now possible to develop ligands with a large spectrum of full, partial or inverse agonist or antagonist activities, but also compounds, called selective nuclear receptor modulators, that activate only a subset of the functions induced by the cognate ligand or that act in a cell-type-selective manner.
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PMID:Principles for modulation of the nuclear receptor superfamily. 1552 Aug 17

Atherosclerosis is an inflammatory process triggered by the presence of lipids in the vascular wall and encompasses a complex interaction between inflammatory cells, vascular elements and lipoproteins through the expression of several adhesion molecules and cytokines. Activation of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation in vitro as well as in animal and human studies. The tissue distribution of PPAR-alpha is extensive and it is abundantly present in the vascular wall where it may mediate many of anti-inflammatory and antiatherogenic effects. Major clinical trials, such as the Veterans Affairs High-Density Lipoprotein Intervention Trial, the Helsinki Heart Study and the Diabetes Atherosclerosis Intervention Study, have demonstrated the beneficial effects of synthetic agonists of PPAR-alpha, specifically fibric acid derivatives, on cardiovascular disease outcome. Although fibric acid trials have reported cardiovascular risk reduction in patients with dyslipidemia, the favorable alterations in plasma lipids can only partially explain the reduction in cardiovascular events in these studies. One common link among these trials was a cohort with a high prevalence of insulin resistance or diabetes, conditions associated with heightened systemic inflammation and increased risk for development and progression of atherosclerosis. In this paper, we will review the many antiatherogenic effects of PPAR-alpha ligands and evidence from fibric acid trials that individuals with insulin resistance or diabetes benefit the most from these drugs, consistent with their anti-inflammatory and antithrombotic properties.
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PMID:Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. 1552 94

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARgamma signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARgamma is observed in tumours compared to normal tissues and PPARgamma agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPARgamma antagonist GW9662 prevented activation of PPARgamma and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPARgamma activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPARgamma-independent pathways and question the central belief that PPARgamma ligands mediate their anticancer effects via activation of PPARgamma.
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PMID:GW9662, a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation. 1553 90

PPARgamma is a ligand-dependent nuclear receptor and regulates adipogenesis and associates with diabetes, obesity. Recently, relationship between PPARgamma and bone metabolism was investigated. Here, we report the molecular mechanism of PPARgamma transcriptional activity and the suppression of PPARgamma activity by cytokines in bone marrow-derived mesenchymal stem cells.
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PMID:[PPARgamma and bone metabolism]. 1557 83

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPARgamma can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPARgamma, regulating the transcription of genes in a variety of metabolic pathways. PPARgamma is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical consequences of PPARgamma polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPARgamma partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPARgamma function, allowing us to hypothesize a general mechanism of PPARgamma action and speculate on future trends in the use of PPARgamma as a target in the treatment of type II diabetes.
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PMID:Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology. 1558 22

Peroxisome proliferator activated receptors (PPARs) are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. On activation by endogenously secreted prostaglandins and fatty acids, they initiate transcription of an array of genes that are involved in energy homeostasis. So far, three major types have been identified, namely PPAR-alpha, PPAR-beta/delta and PPAR-gamma. PPAR-alpha and PPAR-gamma are crucial for lipid and glucose metabolism, respectively. Although limited information is available on PPAR-beta biological functions, recent studies have shown that PPAR-beta also regulates glucose metabolism and fatty acid oxidation. The discovery of PPAR-alpha agonists such as fibrates and PPAR-gamma agonists such as thiozolidinediones enables recognition of the mechanisms involved in ameliorating the adverse effects of chronic disorders such as atherosclerosis and diabetes. In addition, PPARs are also involved in the regulation of various types of tumours, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has instigated much research in this field. In this article, structural features of PPARs, their gene transcription mechanisms and recent developments in the discovery of their biological functions are reviewed.
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PMID:An overview on biological mechanisms of PPARs. 1562 53

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent nuclear receptor and regulates adipogenesis and fat metabolism. PPARgamma is activated by fatty acid derivatives and some synthetic compounds such as the thiazolidinediones. In addition, certain cytokines were known to affect the transactivation function of PPARgamma. However, the molecular mechanism of the functional interaction between PPARgamma and cytokine signaling remains unclear. We found that combined treatment of PPARgamma and cytokines (IL-1 or TNF-alpha) inhibited adipogenesis and induced osteoblastgenesis in bone marrow-derived mesenchymal stem cells. Furthermore, we showed that the ligand dependent transactivation function of PPARgamma was suppressed by IL-1 and TNF-alpha. This suppression was mediated through NF-kappaB activated by the TAK1/TAB1-NIK cascade, a downstream cascade triggered with IL-1 or TNF-alpha signaling. Thus, we have identified a molecular mechanism of functional cross-talk between PPARgamma and cytokine signaling that may provide a theoretical basis for development of novel therapeutical strategies and design of novel compounds for treatment of obesity, diabetes, and some other chronic diseases.
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PMID:Nuclear receptors as targets for drug development: crosstalk between peroxisome proliferator-activated receptor gamma and cytokines in bone marrow-derived mesenchymal stem cells. 2414 68

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARgamma forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARgamma agonists that have allowed the characterization of many genes regulated by PPARgamma. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARgamma. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARgamma by 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARgamma in regulating the inflammatory response and emphasizes the potential efficacy of PPARgamma ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury.
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PMID:Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation. 1583 3


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