Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Troglitazone”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 757 records · Page 42Linked to original sources
PubMed1999

A novel method for analysis of nuclear receptor function at natural promoters: peroxisome proliferator-activated receptor gamma agonist actions on aP2 gene expression detected using branched DNA messenger RNA quantitation.

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor superfamily, plays an essential role in the mediation of the actions of antidiabetic drugs known as thiazolidinediones (TZDs). PPARgamma activates many target genes involved in lipid anabolism including the adipocyte fatty acid binding protein (aP2). In this study, induction of aP2 gene expression by PPARgamma agonists was examined in both cultured cells and diabetic mice using branched DNA (bDNA)-mediated mRNA quantitation. bDNA technology allows for the direct measurement of a particular mRNA directly within cellular lysate using a 96-well plate format in a time frame comparable to a reporter gene assay. In cultured human subcutaneous preadipocytes, the TZDs, troglitazone and BRL-49653, both rapidly induced aP2 mRNA as detected with the bDNA method. In these cells, the effect of BRL-49653 on aP2 mRNA levels was detectable as early as 30 min after treatment (47% increase) and was maximal after 24 h of treatment (12-fold increase). The effects of troglitazone on aP2 mRNA induction were similar to those of BRL-49653 except that the maximal level of induction was consistently lower (e.g. 24 h treatment = 4-fold increase). Dose-response relationships for both of the TZDs were also determined using the 24-h treatment time point. EC50s for both BRL-49653 and troglitazone were estimated to be 80 nM and 690 nM, respectively. A natural PPARgamma ligand, 15-deoxy-delta12,14-PGJ2, was also active in this assay with a maximal induction of aP2 mRNA of approximately 5-fold when tested at 1 microM. Since the PPARgamma:retinoid X receptor (RXR) heterodimer has been characterized as a permissive heterodimer with respect to RXR ligands, the ability of 9-cis-retinoic acid (9-cis-RA) to induce aP2 mRNA was examined. Although 9-cis-RA had very low efficacy (2-fold induction), the maximal effect was reached at 100 nM. No synergism or additivity in aP2 mRNA induction was detected when 9-cis-RA was included with either of the TZDs used in this study. Significant induction of aP2 mRNA in bone marrow of db/db mice treated with either troglitazone or BRL-49653 was also detected, indicating that the bDNA assay may be a simple method to monitor nuclear receptor target gene induction in vivo.

Adipocytes↗
PubMed2005

Thiazolidinediones for treatment of polycystic ovary syndrome.

OBJECTIVE: To review the pathophysiology and treatment of polycystic ovary syndrome (PCOS) and the evidence for use of thiazolidinediones in the treatment of this syndrome. DATA SOURCES: We conducted a MEDLINE database search for English-language literature published from January 1966-July 2004. Key terms used were thiazolidinediones, troglitazone, rosiglitazone, pioglitazone, polycystic ovary syndrome, and PCOS. Bibliographies in the relevant articles were reviewed for additional references. SELECTION: All clinical trials were reviewed. DATA SYNTHESIS: Troglitazone has been evaluated in numerous clinical trials of women with PCOS. These trials provided a body of evidence supporting the efficacy of troglitazone for management of PCOS complications, such as insulin resistance, hyperandrogenism, and anovulation. Due to safety concerns, however, troglitazone is no longer marketed in the United States. Clinical data are emerging regarding the utility of newer, safer thiazolidinediones, such as pioglitazone and rosiglitazone, for this patient population. The available literature provides evidence that these newer agents improve insulin sensitivity, glycemic control, hormone responsiveness, menstrual regularity, and ovulation rates. Pioglitazone and rosiglitazone have been well tolerated in clinical studies and have an improved safety profile in terms of liver toxicity. CONCLUSION: Pioglitazone and rosiglitazone should be considered a second-line treatment alternative to metformin for management of women with PCOS who are resistant to insulin or who are obese.

Adult↗
PubMed2005

Action of thiazolidinediones on differentiation, proliferation and apoptosis of normal and transformed thyrocytes in culture.

Differentiating drugs may be able to re-sensitize thyroid carcinomas to radioiodine therapy. Substituted thiazolidinediones (TZDs) belong to the group of oral anti-diabetic drugs that also possess anti-proliferative and pro-apoptotic effects and, potentially, differentiating effects on several cancer cell lines. Some of the effects are mediated via the peroxisome proliferator-activated receptor gamma (PPAR-gamma). We investigated the effect of troglitazone, rosiglitazone and pioglitazone on differentiation in normal porcine thyrocytes and in the follicular carcinoma cell lines FTC 133 and FTC 238. Differentiation was investigated by measuring 125I uptake and the expression of sodium-iodide symporter and thyroglobulin proteins. The TZDs were tested in the presence of retinol and retinoic acid. Additionally, proliferation was evaluated by [3H]thymidine uptake and cell number and apoptosis by annexin V-labeling. Controls included tocopherol and unsubstituted thiazolidinedione and co-incubation of the TZDs with the PPAR-gamma antagonist GW9662. PPAR-gamma and retinol X receptor (RXR)-alpha were investigated by immunocytochemistry, Western blot and RT-PCR. Cells derived from the metastasis showed greater responses than cells derived from the primary tumor. Troglitazone showed greater effects than the other TZDs. Troglitazone significantly increased 125I uptake and apoptosis and decreased [3H]thymidine uptake and cell number. The amount of the sodium iodide-symporter in the membrane fraction was significantly increased, while that of thyroglobulin was not influenced by the treatment. Inclusion of antagonist did not abolish these effects. No synergistic effect with any retinoid was detected. All transformed cells expressed PPAR-gamma and RXR-alpha but TZDs did not change their expression. Troglitazone appears to be suited for the re-differentiation treatment of dedifferentiated thyroid carcinoma because its action is twofold. On the one hand it increases differentiation and on the other hand it inhibits proliferation.

Adenocarcinoma, Follicular↗
PubMed2005

Insulin resistance contributes to obesity-related proteinuria.

OBJECTIVE: Proteinuria is a recognized complication of obesity, but the pathogenesis remains unclear. We undertook the present study to clarify the factors contributing to proteinuria associated with obesity. METHODS: We studied 12 obese patients with proteinuria. Twenty-seven age-matched obese subjects without proteinuria served as controls. A glucose tolerance test and renal biopsy were performed in all patients. Fasting serum insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were regarded as reflecting insulin resistance. To delineate the relation between insulin resistance and proteinuria, troglitazone, which acts an insulin sensitizer was given to 6 of 12 patients with a regular diet for 8 weeks. The 6 others were observed without receiving troglitazone. RESULTS: The 12 patients showed the presence of a cluster of insulin resistance factors: higher blood pressure, higher body mass index, higher fasting plasma glucose, higher fasting serum insulin, and higher HOMA-IR than controls. The renal biopsy specimens exhibited no histological abnormalities in 7, focal segmental glomerulosclerosis in 3 and benign nephrosclerosis in 2. Troglitazone attenuated HOMA-IR and ameliorated proteinuria, but did not affect body weight, creatinine clearance, or blood pressure. In contrast, the parameters in the patients not given troglitazone did not change. CONCLUSION: Insulin resistance is a factor contributing to obesity-related proteinuria. The role of insulin resistance as a factor reducing proteinuria remains to be clarified.

Adult↗
PubMed1999

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

Animals↗
PubMed2000

Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat.

Thiazolidinediones and exercise are both known to improve insulin action independently. Therefore, we determined whether combined therapy could normalize insulin action in the Zucker fatty (ZF) rat. Rats were fed troglitazone as a 0.2% food admixture over a 3-week exercise training period (treadmill running 5 days/week, 20 m/min, 0% grade, 60 min/day). Subsequent to drug and/or exercise therapy, animals were chronically cannulated in the carotid artery (sampling) and jugular vein (infusion). After a 4-day recovery from surgery, animals were exposed to a hyperinsulinemic (40 mU x kg(-1) x min(-1)) euglycemic clamp (8.5 +/- 0.12 mmol/l; P = 0.45 between groups). Independently, exercise (n = 7) and troglitazone (n = 7) improved the glucose disposal rate 20% (P = 0.04) and 76% (P = 0.001), respectively, when compared with untreated ZF controls (n = 11). In combination, exercise and troglitazone therapy (n = 6) produced significant increments in the following: tracer-determined glucose disposal rate (combined therapy, 52.4 +/- 2.9 mg x kg(-1) x min(-1), vs. untreated ZF, 25.8 +/- 0.8 mg x kg(-1) x min(-1); P = 0.0001), total GLUT4 protein (twofold increase; P = 0.001), insulin receptor substrate (IRS)-1 protein (fourfold increase; P = 0.0001), and Akt phosphorylation (2.9-fold increase; P = 0.002). In conclusion, 1) exercise and troglitazone therapy each improved insulin action in the ZF rat, whereas the combination of the two led to complete normalization of insulin sensitivity, and 2) combination treatment also resulted in normalization of GLUT4 total protein, IRS-1 protein, and Akt phosphorylation compared with lean littermates.

Animals↗
PubMed2000

Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter.

We identified the peroxisomal proliferator response element (PPRE) in the +68/+89 region of the rat GLUT2 gene. To identify whether the putative PPRE in the GLUT2 gene (GLUT2-PPRE) is functional, GLUT2 promoter-luciferase reporter constructs were transfected into CV-1 cells. Promoter activities were increased by coexpression of peroxisomal proliferator-activated receptor (PPAR)-gamma, retinoid X receptor (RXR)-alpha, and treatment of their ligands; troglitazone and 9-cis retinoic acid potentiated the transactivational effects. Introduction of mutations in GLUT2-PPRE resulted in loss of transactivational effects of the PPAR-gamma/RXR-alpha heterodimer. Electrophoretic mobility shift assay using nuclear extracts of CV-1 cells, which were transfected with various combinations of PPARs or RXR-alpha expression plasmids, revealed that heterodimers of PPAR-gamma and RXR-alpha preferentially bound to GLUT2-PPRE. In HIT-T15 cells, promoter activity of the rat GLUT2 gene was increased by troglitazone and 9-cis retinoic acid, and mutations of GLUT2-PPRE resulted in reduction of promoter activity. In addition, we observed increased GLUT2 transcription by troglitazone and 9-cis retinoic acid in isolated rat primary islets. These results suggested that the GLUT2-PPRE is functional and plays a significant role in gene expression of GLUT2 in pancreatic beta-cells. This is the first report identifying PPRE in a gene involved in glucose homeostasis, linking the effect of troglitazone on the regulation of insulin secretion.

Alitretinoin↗
PubMed2002

Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.

Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of beta-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.

Adult↗
PubMed2000

[The development of thiazolidinedione drugs as anti-diabetic agents].

Thiazolidinedione drugs which increase insulin sensitivity are attracting attention of diabetologists. The first drug, ciglitazone ameliorated hyperglycemia in animal models of obese type 2 diabetes such as KKAy mice, but the effect was too weak for clinical application. The first clinical drug troglitazone was approved and marketed in 1997, and the second drug pioglitazone in 1999. Troglitazone was designed to combine tocopherol, anti-peroxidant, and thiazolidinedione. Plasma glucose is lowered in type 2 diabetic patients by troglitazone or pioglitazone alone or in combination with sulfonylureas. The decrease in glycemia is accompanied with the decrease in plasma insulin, suggesting that the effect is mediated by the improvement of insulin sensitivity. Other new thiazolidinedione drugs such as rosiglitazone are in development. Rare but severe hepatic injury occasionally leading to death has been noticed after several months of clinical application of troglitazone. Monthly examination of liver enzymes reduced the number of severe hepatotoxicity. The ultimate evaluation of thiazolidinediones awaits more clinical experiences.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor gamma ligands inhibit estrogen biosynthesis in human breast adipose tissue: possible implications for breast cancer therapy.

Estrogen biosynthesis is catalyzed by aromatase cytochrome P-450 (the product of the CYP19 gene). Adipose tissue is the major site of estrogen biosynthesis in postmenopausal women, with the local production of estrogen in breast adipose tissue implicated in the development of breast cancer. In human adipose tissue, aromatase is primarily expressed in the mesenchymal stromal cells and is a marker of the undifferentiated preadipocyte phenotype. Aromatase expression in adipose tissue is regulated via the distal promoter I.4, under the control of glucocorticoids and class I cytokines such as oncostatin M, interleukin 6, and interleukin 11, as well as tumor necrosis factor alpha. These cytokines, which are expressed in adipose, also inhibit adipocyte differentiation. Therefore, we hypothesized that factors which stimulate adipocyte differentiation should inhibit aromatase expression. These factors include synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands such as thiazolidinediones, e.g., troglitazone and rosiglitazone (BRL49653) and the endogenous PPARgamma ligand 15-deoxy-delta12,14-prostaglandin J2. We have demonstrated by measurement of aromatase activity and by reverse transcription-PCR/Southern blotting that these PPARgamma ligands inhibit aromatase expression in cultured breast adipose stromal cells stimulated with oncostatin M or tumor necrosis factor alpha plus dexamethasone in a concentration-dependent manner, whereas a metabolite of troglitazone that does not activate PPARgamma has no effect. We have also shown that troglitazone inhibits luciferase activity of reporter constructs containing various lengths of the upstream region of promoter I.4 transfected into mouse 3T3-L1 preadipocyte mesenchymal cells, whereas the troglitazone metabolite does not. Because local estrogen production in breast fat is implicated in breast cancer development in postmenopausal women, the actions of PPARgamma ligands suggest that they may have potential therapeutic benefit in the treatment and management of breast cancer.

Adipose Tissue↗
PubMed2000

Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

Animals↗
PubMed2002

Nuclear receptor agonists as potential differentiation therapy agents for human osteosarcoma.

PURPOSE: This study was designed to investigate whether nuclear receptor agonists can be used as potential differentiation therapy agents for human osteosarcoma. EXPERIMENTAL DESIGN: Four osteosarcoma cell lines (143B, MNNG/HOS, MG-63, and TE-85) were treated with proliferator-activated receptor (PPAR)gamma agonists, troglitazone and ciglitazone, and a retinoid X receptor (RXR) ligand, 9-cis retinoic acid. The proliferation and induction of apoptosis in the treated cells were assessed, as was the induction of alkaline phosphatase, a differentiation marker of osteoblasts. RESULTS: The expression of PPARgamma was readily detected in all tested osteosarcoma lines. On treatment with the PPARgamma and RXR ligands, all four osteosarcoma lines exhibited a significantly reduced proliferation rate and cell viability. Among the four lines, 143B and MNNG/HOS were shown to be more sensitive to ligand-induced apoptosis, as demonstrated by the Crystal Violet and Hoechst staining assays. Of the three tested ligands, troglitazone was shown to be the most effective in inducing cell death, followed by 9-cis retinoic acid. Moreover, a strong synergistic effect on the induction of cell death was observed when both troglitazone and 9-cis retinoic acid or ciglitazone and 9-cis retinoic acid were administered to osteosarcoma cells. Troglitazone was shown to effectively induce alkaline phosphatase activity, a well-characterized hallmark for osteoblastic differentiation. CONCLUSIONS: Our findings suggest that PPARgamma and/or RXR ligands may be used as efficacious adjuvant therapeutic agents for primary osteosarcoma, as well as potential chemopreventive agents for preventing the recurrence and metastasis of osteosarcoma after the surgical removal of the primary tumors.

Alitretinoin↗
PubMedDate not supplied

The ligands of peroxisome proliferator-activated receptor (PPAR) gamma inhibit growth of human esophageal carcinoma cells through induction of apoptosis and cell cycle arrest.

In the present study, we examined the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the growth-inhibitory effects of Troglitazone and Pioglitazone, selective ligands for PPARgamma, using a series of human esophageal carcinoma cell lines (TE-1, -3, -7, -8, -12 and -13). PPARgamma expression was detected in all six human esophageal carcinoma cell lines. The esophageal carcinoma cell line TE-13 showed marked growth inhibition in response to Troglitazone and Pioglitazone. Flow cytometry performed on TE-13 cells exposed to Troglitazone showed that the cell cycle was arrested at the G1-phase. This result was confirmed by the finding of reduced cyclin D and cyclin E expression by Western blot analysis. DNA ladder formation was also detected, as was the induction of apoptosis-related proteins. Our results suggested that Troglitazone inhibited the growth of human esophageal carcinoma cell lines via G1 arrest and apoptosis and that PPARgamma ligands should be considered as possible target molecules in the treatment of human esophageal carcinomas.

Antineoplastic Agents↗
PubMed1998

Inhibitory action of insulin-sensitizing agents on calcium channels in smooth muscle cells from resistance arteries of guinea-pig.

1. The actions of troglitazone, pioglitazone, metformin and bezafibrate, agents that improve insulin-resistance, on voltage-dependent Ca2+ channels in arterial smooth muscle cells were examined by use of the conventional and nystatin-perforated whole-cell clamp methods. Single cells were freshly isolated from resistance mesenteric arteries of guinea-pigs. The actions of these agents on 77 mM K+-induced contraction of the isolated arteries were also examined with the use of isometric tension recording. 2. The thiazolidinedione derivatives, troglitazone and pioglitazone, inhibited whole-cell Ca2+ currents in a dose-dependent manner with dissociation constants of 3.0 microM and 44.9 microM and Hill coefficients of 0.61 and 0.68, respectively. These two agents inhibited the 77 mM K+-induced contraction with similar potencies as those inhibiting the Ca2+ currents. Metformin and bezafibrate had no apparent effects on the Ca2+ current or high K+-induced contraction. 3. The inhibitory action of troglitazone on Ca2+ currents was not affected by the command potential, the holding potential, or the stimulation frequency, suggesting that its mode of the action differs from that of known organic Ca2+ channel antagonists. 4. The inhibitory action of troglitazone on Ca2+ currents was not affected by the addition of insulin to, or the removal of glucose from, the solutions. 5. In conclusion, the thiazolidinedione derivatives directly inhibited the voltage-dependent Ca2+ channels in a different manner from that of organic Ca2+ channel antagonists. This inhibitory action on Ca2+ channels was not a common feature of insulin-sensitizing agents.

Animals↗
PubMed2001

A role for C/EBPbeta in regulating peroxisome proliferator-activated receptor gamma activity during adipogenesis in 3T3-L1 preadipocytes.

The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin. In this study, we demonstrate that exposure of 3T3-L1 preadipocytes to DEX and insulin fails to induce adipogenesis as indicated by a lack of C/EBPalpha, PPARgamma2, and adipose protein 2/fatty acid-binding protein expression; however, PPARgamma1 is expressed. Treatment of these MIX-deficient cells with a PPARgamma ligand, troglitazone, induces C/EBPalpha expression and rescues the block in adipogenesis. In this regard, we also show that induction of C/EBPalpha gene expression by troglitazone in C3H10T1/2 cells ectopically expressing PPARgamma occurs in the absence of ongoing protein synthesis, suggesting a direct transactivation of the C/EBPalpha gene by PPARgamma. Furthermore, ectopic expression of a dominant negative isoform of C/EBPbeta (liver-enriched transcriptional inhibitory protein (LIP)) inhibits the induction of C/EBPalpha, PPARgamma2, and adipose protein 2/fatty acid-binding protein by DEX, MIX, and insulin in 3T3-L1 cells without affecting the induction of PPARgamma1 by DEX. Exposure of LIP-expressing preadipocytes to troglitazone along with DEX, MIX, and insulin induces differentiation into adipocytes. Additionally, we show that sustained expression of C/EBPalpha in these LIP-expressing adipocytes requires constant exposure to troglitazone. Taken together, these observations suggest that inhibition of C/EBPbeta activity not only blocks C/EBPalpha and PPARgamma2 expression, but it also renders the preadipocytes dependent on an exogenous PPARgamma ligand for their differentiation into adipocytes. We propose, therefore, an additional role for C/EBPbeta in regulating PPARgamma activity during adipogenesis, and we suggest an alternative means of inducing preadipocyte differentiation that relies on the dexamethasone-associated induction of PPARgamma1 expression.

3T3 Cells↗
PubMed2004

Peroxisome proliferator-activated receptor gamma-dependent and -independent growth inhibition of gastrointestinal tumour cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a ligand-activated transcription factor. Although ligand-induced cellular differentiation and growth inhibition have been mostly studied on human cancers expressing PPARgamma, it is unclear if the transcriptional activation of PPARgamma is the main mechanism of growth inhibition. In this study, we investigated whether there is a link between growth inhibitory effect and transcriptional activation of PPARgamma in several gastrointestinal tumour cell lines. The transcriptional activation potential of PPARgamma was assessed by reporter gene assay employing a PPRE-luciferase vector, and growth inhibitory effect of PPARgamma was investigated by (3)H-thymidine incorporation assay, in the presence or absence of thiazolidinedione ligands, rosiglitazone and troglitazone. As expected, in the case of cell lines positive for the transcriptional activation potential of PPARgamma (T.Tn, MKN-45 and LoVo), both the ligands induced growth inhibition. However, in case of some other cell lines negative for the transcriptional activation potential of PPARgamma (TT, AGS and HCT-15), troglitazone still showed a growth inhibitory effect. Administration of the PPARgamma antagonist GW9662 did not reverse this growth inhibitory activity of troglitazone. The introduction of dominant negative mutants of PPARgamma did not suppress the activity either. These observations suggest that while rosiglitazone inhibits cellular growth predominantly through transcriptional activation of PPARgamma, troglitazone can induce it both in PPARgamma-dependent and -independent pathways.

Base Sequence↗
PubMed2001

Factors associated with the risk of liver enzyme elevation in patients with type 2 diabetes treated with a thiazolidinedione.

STUDY OBJECTIVE: To characterize frequency of liver enzyme elevation in patients with type 2 diabetes mellitus receiving troglitazone. DESIGN: Retrospective study. SETTING: Hospital-affiliated medical center. PATIENTS: Two hundred ninety-one patients with type 2 diabetes mellitus. INTERVENTION: Data from patients with an average troglitazone exposure of 412.7 +/- 255.6 days were studied. MEASUREMENTS AND MAIN RESULTS: Enzyme elevations more than 1.5 times the upper limit of normal (ULN) occurred in 17 patients (5.8%) and more than 3-fold elevations in 6 (2.1%). The relationship among enzyme elevation events, demographic factors, duration of troglitazone exposure, frequency of monitoring, and concurrent drugs (limited to glucose and lipid-lowering agents) was assessed by multiple logistic regression. Age was an independent predictor of risk (p=0.009), and concurrent insulin therapy approached statistical significance (p=0.051) for 1.5-fold ULN elevation in liver enzymes. Age and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were the only significant predictors of 3-fold ULN elevations (p=0.03 and p=0.04, respectively). CONCLUSION: Several factors appear to increase the risk of enzyme elevation events in patients treated with troglitazone.

Adult↗
PubMed2002

Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction.

OBJECTIVE: Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. RESEARCH DESIGN AND METHODS: This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised > 6,000 patients aged 30-80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6- to 12-week intervals thereafter. Patients with at least one on-therapy ALT value >3 times the upper limit of the reference range were identified, and their case records examined in detail. RESULTS: At baseline, 5.6% of the patients with type 2 diabetes (mean HbA(1c) 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients ( approximately 83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value >3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulin-treated 0.40%. The respective rates of ALT values >3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64. CONCLUSIONS: No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 person-years. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-gamma agonist class effect. Poorly controlled patients with type 2 diabetes may have moderate elevations of serum ALT that will decrease with improved glycemic control during treatment with rosiglitazone or other antihyperglycemic agents.

Adult↗