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 361 records · Page 20Linked to original sources
PubMed2006

Connective tissue growth factor and fibronectin secretion in renal tubular epithelial cells induced by TGF-beta1: suppressive effects of troglitazone.

Although some studies have suggested that troglitazone could retard the progression of glomerulosclerosis, its effects on renal tubulointerstitial fibrosis have not been completely clarified. The aim of this study was to investigate the effects of troglitazone on the secretion of connective tissue growth factor (CTGF) and fibronectin (FN) in human renal proximal tubular epithelial (HK-2) cells induced by transforming growth factor-beta1 (TGF-beta1). The mRNA of CTGF and FN were measured by semi-quantitative RT-PCR. CTGF and FN protein were detected by Western blot and ELISA, respectively. Our results revealed that troglitazone could inhibit CTGF and FN expression in a dose-dependent manner in human renal proximal tubular epithelial cells induced by TGF-beta1, which may be one of the mechanisms of troglitazone contributing to retard the progression of renal tubulointerstitial fibrosis.

Cells, Cultured↗
PubMed2005

Troglitazone reverses the inhibition of nitric oxide production by high glucose in cultured bovine retinal pericytes.

In the retinal microcirculation, there is a basal release of nitric oxide (NO) which maintains the retinal blood flow. The proportions of endothelial cells and pericytes in the retinal capillaries are almost equal, so pericytes appear to play a important role in the regulation of microcirculatory hemodynamics in the retina. It has been suggested that the pathogenesis of early diabetic retinopathy may involve a reduced bioavailability or diminished production of NO. In this study, we investigated the role of troglitazone, a potent agonist of peroxisome proliferator activated receptor-gamma (PPARgamma) used for the treatment of diabetes, on the NO release and the effect of exposure to high glucose on the production of NO in cultured bovine retinal pericytes. Troglitazone significantly increased NO production and iNOS expression after 24hr in a dose-and PPARgamma-dependent manner. Elevation of D-glucose, but not L-glucose, from 5.5 to 30 mm for 24 hr decreased NO production, but co-treatment with troglitazone reversed high glucose-induced inhibition of NO production as well as iNOS expression. In conclusion, high glucose inhibits iNOS expression and subsequently NO synthesis in cultured bovine retinal pericytes, and troglitazone restores the NO production.

Animals↗
PubMedDate not supplied

The thiazolidinedione drug troglitazone up-regulates nitric oxide synthase expression in vascular endothelial cells.

Endothelial dysfunction is a phenomenon often observed in diabetic patients, which is a cause for vascular complications of diabetes mellitus. Endothelium-derived nitric oxide (NO) is responsible for vasodilatation, and NO-dependent vasodilatation is diminished in diabetic patients. In the present study, we evaluated the effects of thiazolidinediones (TZDs), antidiabetic drugs known to improve insulin resistance and to have vasodilating properties, on endothelial NO synthase (eNOS) expression in cultured vascular endothelial cells. Human umbilical vein endothelial cells were treated with the TZDs troglitazone and pioglitazone, or the peroxisome proliferator-activated receptor (PPAR) gamma activator 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-dPGJ2). The expression of eNOS protein and its mRNA was determined by Western and Northern blot analyses, respectively. The effect of alpha-tocopherol that possesses structural similarity to troglitazone was also examined. Troglitazone up-regulated eNOS protein and its mRNA levels, whereas pioglitazone and 15-dPGJ2 failed to increase their levels. By contrast, alpha-tocopherol also increased in eNOS protein and mRNA. These results suggest that troglitazone up-regulates eNOS expression probably through its 6-hydroxychromanes structure but not activating PPARgamma.

Analysis of Variance↗
PubMed2002

Effects of leptin, troglitazone, and dietary fat on stearoyl CoA desaturase.

Leptin, troglitazone, and high fat feeding profoundly influence the lipid content of various tissues. To determine if they affect the expression of stearoyl CoA desaturase (SCD)-1 and -2, their mRNA was measured in livers of normal, hyperleptinemic, troglitazone-treated, and fat-fed rats. Hyperleptinemia, which reduces tissue TG by downregulating lipogenic enzymes and upregulating fatty acid oxidation, lowered SCD-1 96% below controls and reduced SCD-2 slightly. By contrast, hepatic SCD-1 mRNA of leptin-resistant fa/fa rats was five times wild-type controls, but SCD-2 mRNA was 66% lower. High fat feeding lowered SCD-1 by 80%, possibly by inducing hyperleptinemia. Troglitazone treatment, which reduces nonadipose tissue TG of fa/fa rats without downregulating lipogenic enzymes, raised SCD-2 13-fold but lowered SCD-1 by 25%. The findings suggest that leptin controls SCD-1 expression and that troglitazone's antilipotoxic action may involve SCD-2 upregulation.

Adenoviridae↗
PubMed2001

Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone: a peroxisome proliferator-activated receptor-gamma (PPARgamma)-independent, antioxidant-related mechanism.

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis. Enhanced expression of the PEPCK gene in liver is present in most models of diabetes, and is thought to contribute to the increased hepatic glucose output seen in this disease. Recently, we showed that troglitazone, the first thiazolidinedione (TZD) used clinically, inhibits expression of the PEPCK gene in isolated hepatocytes. We have pursued the molecular mechanism whereby troglitazone exerts this inhibition. TZDs are known to bind and activate peroxisome proliferator-activated receptor-gamma (PPARgamma), a nuclear receptor, which regulates expression of target genes. Initially, we examined the abilities of three other TZDs (rosiglitazone, englitazone, and ciglitazone) to inhibit expression of the PEPCK gene. Despite the fact that these agents are ligands for PPARgamma, they displayed little if any inhibitory activity on the expression of this gene. GW1929 [N-(2-benzoyl phenyl)-l-tyrosine], another potent PPARgamma ligand that is unrelated structurally to TZDs, had no inhibitory effect on PEPCK gene expression, while a natural PPARgamma ligand, the prostaglandin metabolite 15-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2), displayed only modest inhibitory activity. Treatment of hepatocytes with ligands for other isoforms of PPAR also had no significant effect on PEPCK gene expression. Troglitazone has an alpha-tocopherol (vitamin E) moiety that is not present in other TZDs, and treatment of hepatocytes with vitamin E led to an inhibition of PEPCK gene expression. These observations support the conclusion that troglitazone inhibits the expression of the PEPCK gene by a PPARgamma-independent, antioxidant-related mechanism.

Animals↗
PubMed1997

Troglitazone inhibits type 2KATP channel activity and depolarises tolbutamide-sensitive neurones in the rat ventromedial hypothalamus.

Patch-clamp recording techniques were used to examine the effect of troglitazone upon visually identified neurones contained in slices from the rat ventromedial hypothalamus. Bath application of 1-50 microM troglitazone depolarised tolbutamide-sensitive neurones in a poorly reversible manner. In outside-out patches, troglitazone inhibited KATP channel activity when added to the bath solution. It is concluded that troglitazone is a novel modulator of the type 2 KATP channel.

Adenosine Triphosphate↗
PubMed2002

Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors.

We report here our studies on troglitazone and rosiglitazone cytotoxicity in human hepatocytes isolated from multiple donors to investigate factors responsible for individual differences in sensitivity to the known hepatotoxicity of these antidiabetic drugs. Using cellular adenosine triphosphate (ATP) content as an endpoint, cytotoxicity of both drugs was evaluated in cryopreserved human hepatocytes from 37 donors. We confirmed reports of others that troglitazone was cytotoxic to human hepatocytes using cellular ATP content as an endpoint. In addition, we found that rosiglitazone, although less toxic in the study population, was cytotoxic to hepatocytes in some donors (EC(50)<100 microM). ATP content, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) metabolism, depletion of intracellular glutathione, Alamar Blue metabolism, and neutral red uptake were used as endpoints in a single donor study using freshly isolated human hepatocytes. Troglitazone appeared to be more toxic than rosiglitazone by all endpoints. From the demographic data provided to us for each donor, we were able to establish no direct correlation between cytotoxicity (expressed as EC(50) values) and age, sex, smoking status, or alcohol consumption. We conclude that troglitazone and rosiglitazone are differentially toxic to human hepatocytes, and that toxicity may be independent of age, sex, tobacco use, and alcohol use.

Adenosine Triphosphate↗
PubMed2002

Troglitazone suppresses cell growth of KU812 cells independently of PPARgamma.

We examined the effects of troglitazone, one of thiazolidinedione derivatives on human basophilic leukemia cell line KU812. Troglitazone caused the suppression of cell growth, which was suggested to result from the decrease in cyclin E and the hyperphosphorylated form of retinoblastoma tumor suppressor gene product (pRb). In addition, troglitazone caused a decrease in histamine secretion due to the reduced expression of histidine decarboxylase mRNA. Peroxisome proliferator-activated receptor (PPAR)-gamma mRNA was undetectable by reverse transcription-polymerase chain reaction (RT-PCR) in KU812 cells. These findings suggested that troglitazone suppressed cell growth and histamine synthesis independently of PPARgamma.

Antineoplastic Agents↗
PubMed1999

Troglitazone but not pioglitazone affects ATP-sensitive K(+) channel activity.

We compared the effects of the two thiazolidinedione derivatives, troglitazone and pioglitazone, on ATP-sensitive K(+) (K(ATP)) channel activities. Pancreatic beta-cell type and cardiac type K(ATP) channels were reconstituted in COS-1 cells (SV 40-transformed African green monkey kidney (AGMK) cells) by heterologously expressing sulfonylurea receptor 1 (SUR1) plus Kir6.2 and sulfonylurea receptor 2A (SUR2A) plus Kir6.2, respectively. Troglitazone inhibited [86Rb(+)] efflux in both K(ATP) channel types in the presence of metabolic inhibitors, which was confirmed by electrophysiological techniques. The [86Rb(+)] efflux increased by the channel openers diazoxide and pinacidil was abolished by troglitazone. In contrast, pioglitazone did not affect these channel activities in either type K(ATP) channel. These results suggest that troglitazone modulates the various cellular functions including insulin secretion by inhibiting the K(ATP) channels, while pioglitazone has no effect on K(ATP) channel activity.

ATP-Binding Cassette Transporters↗
PubMed1999

Pregnancy after treatment with the insulin-sensitizing agent troglitazone in an obese woman with the hyperandrogenic, insulin-resistant acanthosis nigricans syndrome.

OBJECTIVE: To report a case of unassisted pregnancy after 5 months of troglitazone treatment in a severely hyperandrogenic, insulin-resistant woman with acanthosis nigricans (HAIR-AN) previously managed with depot leuprolide acetate (LA) plus oral contraceptive and dexamethasone therapy. DESIGN: Case report. SETTING: Private infertility clinic. PATIENT(S): A 28-year-old African-American woman with excessive obesity (body mass index = 42 kg/m2) and HAIR-AN syndrome. INTERVENTION(S): Androgen suppression with depot LA plus oral contraceptive and dexamethasone therapy, troglitazone treatment resulting in normalization of fasting insulin and testosterone, spontaneous menses, and an unassisted pregnancy. MAIN OUTCOME MEASURE(S): Luteinizing hormone and testosterone concentrations, fasting insulin and glucose levels, insulin-glucose ratios, hCG levels, and ultrasound examinations. RESULT(S): Spontaneous menses followed by an intrauterine pregnancy after 5 months of treatment with troglitazone, an insulin-sensitizing agent, in a woman with severe HAIR-AN syndrome whose hyperandrogenism previously could be normalized only with depot LA plus oral contraceptive therapy and dexamethasone. CONCLUSION(S): Troglitazone treatment resulted in attenuation of both hyperinsulinemia and hyperandrogenism in an obese woman with HAIR-AN and resulted in resumption of menses and a spontaneous pregnancy.

Acanthosis Nigricans↗
PubMed1999

Combination treatment with troglitazone, an insulin action enhancer, and pravastatin, an inhibitor of HMG-CoA reductase, shows a synergistic effect on atherosclerosis of WHHL rabbits.

We examined whether improving insulin resistance augments the antiatherosclerotic effect of LDL reduction. Since WHHL rabbits show hyperinsulinemia and insulin resistance, we administered troglitazone (100 mg/kg), an insulin action enhancer, pravastatin sodium (50 mg/kg), an HMG CoA reductase inhibitor, and a combination of both drugs to 2-month-old WHHL rabbits for 32 weeks. As compared to the control, total cholesterol levels in the plasma and LDL were decreased significantly by 20% in the pravastatin and combination groups. Basal immunoreactive insulin levels and insulin index were decreased significantly by approximately 50% in the troglitazone and combination groups. Surface lesion area of atherosclerosis on the thoracic aorta was decreased significantly by 36% in the combination group and was less in the troglitazone group. Coronary atherosclerosis was decreased significantly by 39% in the combination group and was less in the pravastatin and troglitazone groups. The collagen content in the plaques was decreased in the troglitezone and combination groups and the extracellular lipid deposits were decreased in the pravastatin and combination groups. The incidence and severity of xanthomata in the digital joints were also decreased significantly in the three treated groups. In conclusion, the antiatherogenic effect of the combination treatment is stronger than that of the monotherapy.

Animals↗
PubMed2000

Troglitazone inhibits the expression of inducible nitric oxide synthase in adipocytes in vitro and in vivo study in 3T3-L1 cells and Otsuka Long-Evans Tokushima Fatty rats.

The aim of this study was to determine the mechanism of troglitazone action on nitric oxide (NO) production via inducible NO synthase (iNOS) in adipocytes in vitro and in vivo. The treatment of 3T3-L1 adipocytes with the combination of lipopolysaccharide (LPS), tumor necrosis factor-alpha and interferon-gamma synergistically induced de novo iNOS expression leading to enhanced NO production. The NO production was inhibited by co-treatment with aminoguanidine or N-nitro-L-arginine methylester hydrochloride. Troglitazone inhibited the NO production in a dose dependent manner by the suppression of iNOS expression. In the 24 week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, the mean weight and the blood glucose were 21% and 30%, respectively, higher than in their lean counterparts. The serum nitrite concentration was increased after injection of LPS (4 mg/kg, i.p.), more markedly in OLETF rats than in the lean rats. The epididymal fats from LPS-injected groups, but not the ones from the non-injected groups, expressed mRNA and protein of iNOS. Troglitazone pre-treatment blocked the LPS-induced expression of iNOS in adipose tissue and the increase in serum nitrite concentration. These results suggest that troglitazone inhibits the cytokine-induced NO production in adipocytes by blocking iNOS expression both in vitro and in vivo.

3T3 Cells↗
PubMed2000

Troglitazone has no effect on K(ATP) channel opener induced-relaxations in rat aorta and in human saphenous veins from patients with type 2 diabetes.

Troglitazone, a thiazolidinedione derivative, is an oral antidiabetic agent that enhances insulin sensitivity in insulin-resistant states. K(ATP) channels, on the other hand, have important roles protecting cardiovascular system in ischemic and/or hypoxic states. They are also important in the control of vascular tone, and therefore of blood pressure. We tested whether troglitazone can directly affect vascular K(ATP) channel opener-induced relaxations in vitro. 1, 10 or 100 microM troglitazone incubations for 30 min did not alter cromakalim (a K(ATP) channel opener)--induced relaxations in endothelium-denuded aortas from rat, saphenous veins from type 2 diabetic and nondiabetic patients. In addition, we compared the sensitivity to cromakalim in diabetic saphenous veins with that of nondiabetic veins. The concentration-response curve for cromakalim was shifted to the right in diabetic vein. pD2 values for cromakalim were 6.85+/-0.08 vs. 6.61+/-0.04 (p<0.05) in nondiabetic (n:10) and diabetic (n:7) veins respectively. % maximum response of cromakalim was also significantly decreased by 24+/-3% in diabetic veins. However, responsiveness of veins to phenylephrine or sodium nitroprusside were similar in both groups. The results obtained may be clinically useful 1. suggesting that in ischaemic and/or hypoxic insults troglitazone may not worsen vascular dilatation, through K(ATP) channel, in diabetic patients who are more prone to these conditions than healthy people, 2. providing an evidence that diabetes causes an impaired dilatation of human saphenous vein through K(ATP) channels. This may partly be related with diabetes-induced vascular complications, such as vasospasm and even hypertension. Accordingly, since saphenous veins are used as conduit vessels in coronary by-pass graft surgery, the results also suggest that the defective dilatation through K(ATP) channels may play a role on the performance of saphenous vein grafts in type 2 diabetes.

Animals↗
PubMed1997

Quantification of the effects of troglitazone on insulin sensitivity and beta-cell function in Watanabe heritable hyperlipidemic rabbits: a minimal model analysis.

Troglitazone is a newly developed antidiabetic drug that has been shown to improve insulin resistance and hyperinsulinemia both in diabetic animal models and in patients with non-insulin-dependent diabetes mellitus. The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia, is characterized by hyperinsulinemia, which reflects insulin resistance. In this study to determine the effects of troglitazone on glucose and insulin metabolism in WHHL rabbits, we quantified the rate of glucose utilization (glucose tolerance index [Kg]), sensitivity of first-phase posthepatic insulin secretion to glucose (phi1), sensitivity of second-phase posthepatic insulin secretion to glucose (phi2), insulin sensitivity to glucose disposal ([Si] inversely related to insulin resistance), insulin-independent glucose disposal (glucose effectiveness [Sg]), and rate of insulin clearance (Ki) by incorporating our previously reported two-compartment model of a glucose/insulin system with the glucose disappearance model of Bergman. Galvin insulin sensitivity (GIS) was also computed for comparison with Bergman Si. When troglitazone was administered as a food admixture (24 mg/d per animal) for 6 months, it did not significantly affect beta-cell function as measured by phi2, glucose tolerance as measured by Kg, or Sg, but increased both Si and Ki and reduced phi1, leading to a decreased plasma insulin response during the intravenous glucose tolerance test (IVGTT). Si was strongly and significantly correlated with GIS. These data indicate that in WHHL rabbits, troglitazone improves insulin sensitivity and posthepatic insulin clearance without affecting beta-cell function or glucose tolerance.

Animals↗
PubMed1999

Relationships between apolipoprotein(a) phenotype and increase of lipoprotein(a) by troglitazone.

Troglitazone is a new oral hypoglycemic agent that reduces insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). However, this agent increases serum lipoprotein(a) [Lp(a)], which is known as an atherogenic lipoprotein. The relationships between the response of Lp(a) to troglitazone and the apolipoprotein(a) [apo(a)] phenotype were investigated in this study. Nineteen NIDDM patients were treated with troglitazone for 4 weeks. Lp(a) increased significantly from 20.1+/-16.5 mg/dL to 44.1+/-31.9 mg/dL (P<.001) in all study patients. Lp(a) increased from 25.7+/-34.2 mg/dL to 50.1+/-38.7 mg/dL (P = .03) in patients with smaller apo(a) phenotypes (S1S4 to S2S4). Lp(a) also increased from 17.5+/-12.0 mg/dL to 41.3+/-29.6 mg/dL (P<.01) in patients with larger apo(a) phenotypes (S3 to S4). Therefore, the increase of Lp(a) by troglitazone may be independent of the apo(a) phenotype.

Adult↗
PubMed1998

Troglitazone ameliorates insulin resistance in a diabetic patient with Prader-Willi syndrome.

We report a patient with Prader-Willi syndrome (PWS) complicated by diabetes mellitus. PWS is a genetic disorder characterized by obesity, mental retardation and hypogonadism. Glucose intolerance in this syndrome is thought to be secondary to insulin resistance associated with morbid obesity. Therapy was directed primarily at decreasing insulin resistance and thereby improving glucose intolerance by the administration of troglitazone, which increases insulin sensitivity. Changes in glucose disposal rate assessed by euglycemic hyperinsulinemic clamp test were measured, as well as glucose and insulin responses to a 75 g-OGTT before and after troglitazone therapy. Glucose disposal rate increased by 36% and plasma glucose responses to 75 g-OGTT decreased by about 50% during 12 weeks of troglitazone therapy despite slight weight gain. Thus, troglitazone has beneficial effects on glycemic control by improving insulin sensitivity in patients with PWS complicated by diabetes mellitus.

Adolescent↗
PubMed2000

Peroxisome proliferator-activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-gamma activator troglitazone.

This study was conducted to determine whether cultured human coronary artery and aorta vascular smooth muscle (VSM) cells express the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma); whether the thiazolidinedione troglitazone, a ligand for PPARgamma, would inhibit c-fos expression by these cells; and whether troglitazone would inhibit proliferation and migration induced in these cells by mitogenic growth factors. Using immunoblotting and reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, we show that both human aorta and coronary artery VSM cell lines expressed PPARgamma protein and mRNA for both PPARgamma isoforms, PPARgamma1 and PPARgamma2. Immunocytochemical staining localized the PPARgamma protein primarily within the nucleus. Troglitazone inhibited basic fibroblast growth factor and platelet-derived growth factor-BB induced DNA synthesis in a dose-dependent manner and downregulated the growth-factor-induced expression of c-fos. Troglitazone also inhibited the migration of coronary artery VSM cells along a platelet-derived growth factor-BB concentration gradient. These findings demonstrate for the first time the expression and nuclear localization of PPARgamma in human coronary artery and aorta VSM cells. The data also suggest that the downregulation of c-fos expression, growth-factor-induced proliferation, and migration by VSM may, in part, be mediated by activation of the PPARgamma receptor.

Blotting, Northern↗
PubMed2001

Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.

A 68-year-old woman, with type 2 diabetes mellitus, hypercholesterolemia, and prior long-term simvastatin therapy, self-resumed troglitazone after running out of metformin. She developed an acute severe hepatitis with microvesicular steatosis and mysositis. There was subsequent resolution of the myositis but progression of the hepatitis to symptomatic cirrhosis over a period of 12 weeks. Both troglitazone and simvastatin are metabolized by cytochrome P-450 3A4. Troglitazone typically induces metabolism of drugs metabolized by this cytochrome so that simple simvastatin toxicity seems less likely to have been involved. The association with myositis, the severity of the hepatitis with progression to cirrhosis, and the presence of microvesicular steatosis suggests altered mitochondrial metabolism, which has been described with each agent, as the underlying pathogenic mechanism. Although troglitazone (Rezulin) has been withdrawn from the market, other similar agents are available for therapy of type 2 diabetes mellitus. Increased awareness of a potential interaction between these two classes of drugs is warranted.

Aged↗