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

Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.
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PMID:Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. 942 89

The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPARgamma protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPARgamma correlates well with the ability of ligands to activate this receptor. However, analyses of PPARgamma mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPARgamma and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPARgamma, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome.
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PMID:Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. 1074 14

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARgamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARgamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARgamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARgamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.
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PMID:Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. 1098 6

Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "insulin resistance syndrome" which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor. Although PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARgamma activation by PPARgamma agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes.
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PMID:Troglitazone and related compounds: therapeutic potential beyond diabetes. 1106 64

Patients with insulin resistance and/or type 2 diabetes have a 5-fold increase in cardiovascular mortality rate. Therefore, it is a current issue of discussion that arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity. Concerning a possible molecular link between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between lipid metabolism, insulin action, and obesity at a gene regulatory level. Alterations in the structure, function and regulation of transcription factors appear to be such signalling steps which might play an essential role in the pathogenesis and therapy of cardiovascular risk factors associated with insulin resistance, eg the so called metabolic syndrome. Recent examples are members of the nuclear hormone receptor superfamily, eg peroxisome proliferator-activated receptor (PPAR) isoforms and sterol regulatory element-binding proteins (SREBPs). Beside their regulation by different metabolites, these transcription factors are also targets of hormones, like insulin and leptin, growth factors, and inflammatory signals. Therefore, they appear to be a point of signalling convergence at a gene regulatory level. Major signalling pathways coupling receptors at the cell surface for hormones, growth factors as well as cytokines to gene regulatory events in the nucleus are the MAP-kinase cascades. We have recently defined different postreceptor defects in these pathways in patients with clinical phenotypes corresponding to congenital lipoatrophy. Therefore, these studies may identify novel pathways which play a role in the control of body weight, insulin sensitivity and cardiovascular risk.
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PMID:Insulin-regulated transcription factors: molecular link between insulin resistance and cardiovascular risk factors. 1146 84

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity. These include leptin, tumor necrosis factor alpha, Acrp30/adiponectin/adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor gamma, a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans.
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PMID:Resistin and obesity-associated insulin resistance. 1175 Aug 58

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. Since PPARs appear to be closely involved in the regulation of dietary fat storage and catabolism, they have been established as an important target for the treatment of type 2 diabetes and other disorders associated with the high intake of dietary fat. Thiazolidinediones (TZDs) were the first class of compounds to be identified as PPAR gamma-ligands, constituting a new class of antidiabetic drugs that have recently been introduced as therapeutic agents for the treatment of type 2 diabetes mellitus by acting as insulin sensitizers. These compounds improve insulin resistance by increasing cell sensitivity to insulin. In fact, PPAR gamma agonists increase peripheral insulin sensitivity by increasing the transcription of genes, which, in turn, increase glucose uptake, also improving insulin-stimulated glucose disposal in muscle. PPAR gamma agonists increase insulin signaling, reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus favoring the formation of smaller, more insulin-sensitive adipocytes. TZDs have been proven effective in different experimental models to evaluate their effectiveness as an antidiabetic agent, and the involvement of PPAR gamma in the pharmacological effects of these compounds has been supported by studies showing an excellent correlation between the hypoglycemic action of these drugs and their affinity for PPAR gamma. Despite this evidence, the site of action and the molecular mechanism of TZDs remain unclear. The aim of the present article was to review and discuss the most relevant pharmacological studies performed in the search for establishing the mechanism of action of antidiabetic TZDs and related compounds acting as PPAR gamma agonists, as well as to summarize those representative experimental approaches currently used to evaluate PPAR gamma agonists as therapeutic agents for the treatment of insulin-resistant type 2 diabetes mellitus.
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PMID:Experimental approaches to study PPAR gamma agonists as antidiabetic drugs. 1250 Apr 31

Adipogenesis is the process by which mature fat cells are formed from pre-adipocytes. Adipogenesis has come under increasing scrutiny not only because the availability of reliable in vitro models makes it an attractive choice for developmental studies, but also because adipocytes are increasingly recognized as major players in a variety of physiological and pathophysiological states, such as obesity and type 2 diabetes. Adipocytes develop from mesenchymal stem cell precursors that are characterized by multipotency. Under the influence of various cues, these cells become committed to the adipocyte lineage. Further hormonal stimulation recruits these pre-adipocytes to accumulate lipid, express fat-specific markers, and become sensitive to the metabolic effects of insulin. A complex transcriptional cascade regulates this process, involving several distinct classes of transcription factor. In particular, the role of the nuclear hormone receptor PPARgamma will be discussed, along with bZip family members C/EBPalpha, C/EBPbeta, and C/EBPdelta. The relationship of adipose depots to the lymphatic system will also be discussed.
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PMID:The molecular control of adipogenesis, with special reference to lymphatic pathology. 1254 24

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARgamma in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARgamma seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARgamma-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these 'adipogenic compounds' is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes.
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PMID:PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? 1258 94

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the nuclear hormone receptor superfamily. PPAR has three isoforms designated PPARalpha, PPARbeta/delta and PPARgamma. Although all three isoforms share similar protein sequence and structure, they differ in tissue distribution, ligand selectivity and biological actions. As ligand-activated transcription factors, PPARs participate in a broad spectrum of biological processes, including cell differentiation, energy balance, lipid metabolism, insulin sensitivity, bone formation, inflammation and tissue remodeling. PPARalpha is the molecular target of the hypolipidemic fibrates including benzafibrate and clofibrate. In general, PPARalpha is expressed in tissues with high mitochondrial and beta-oxidation activity corresponding to its role in regulating lipid metabolism. In contrast, PPARbeta/delta is ubiquitously expressed and has been suggested to be involved in bone formation, oocyte implantation and lipid catabolism. PPARbeta/delta ligands have been found to effectively improve lipid profile and insulin resistance. PPARgamma is a key player in adipogenesis and plays an important role in diverse cellular processes such as cell cycle regulation, cell differentiation and insulin sensitivity. Synthetic PPARgamma ligands, including thiazolidinediones and non-thiazolidinedione compounds, have been shown to increase insulin sensitivity and improve hyperglycemia in insulin resistance and noninsulin dependent diabetes mellitus. The biological effects of PPARs indicate that both agonists and antagonists for PPARs may provide new therapeutic options in a variety of human diseases. (c) 2002 Prous Science. All rights reserved.
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PMID:The Role of PPARs in the Transcriptional Control of Cellular Processes. 1267 57


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