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PubMed1999

Troglitazone inhibits the capacitative Ca2+ entry in endothelial cells.

To investigate the effects of troglitazone on the capacitative Ca2+ entry, we monitored changes in cytosolic Ca2+ concentrations ([Ca2+]i) induced by thapsigargin in fura-2-loaded porcine endothelial cells in situ and in primary culture. In aortic valve endothelial cells in situ, thapsigargin induced sustained elevation of [Ca2+]i. Both troglitazone and SKF 96365 inhibited the steady state increase in [Ca2+]i in a concentration-dependent manner. At 30 microM, troglitazone and SKF 96365 inhibited the [Ca2+]i elevation to 19.4 +/- 3.6% and 43.9 +/- 4.5%, respectively. In aortic endothelial cells in primary culture, both troglitazone (10 microM) and SKF 96365 (100 microM) completely inhibited the thapsigargin-induced [Ca2+]i increase. The EC50 value of troglitazone (1.4 +/- 0.1 microM) was lower than that of SKF 96365 (10.0 +/- 3.3 microM). We suggest that troglitazone would be a useful tool to investigate the capacitative Ca2+ entry.

Adenosine Triphosphate↗
PubMed1999

Troglitazone inhibits angiotensin II-induced extracellular signal-regulated kinase 1/2 nuclear translocation and activation in vascular smooth muscle cells.

The thiazolidinedione troglitazone inhibits angiotensin II-induced extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activity in vascular smooth muscle cells. Activation of extracellular signal-regulated kinase 1/2 by angiotensin II is a multistep process involving both its phosphorylation by mitogen-activated protein kinase extracellular signal-regulated kinase kinase in the cytoplasm and a subsequent translocation to the nucleus. The cytoplasmic activation of extracellular signal-regulated kinase 1/2 in vascular smooth muscle cells proceeds through the protein kinase Czeta --> mitogen-activated protein kinase extracellular signal-regulated kinase kinase --> extracellular signal-regulated kinase pathway. Troglitazone did not affect the angiotensin II-induced activation of protein kinase Czeta or its downstream signaling kinases extracellular signal-regulated kinase 1/2 in the cytosol. In contrast, angiotensin II-induced activation of protein kinase Czeta and extracellular signal-regulated kinase 1/2 in the nucleus were both inhibited by troglitazone. Nuclear translocation of extracellular signal-regulated kinase 1/2 induced by angiotensin II was completely blocked by troglitazone. Protein kinase Czeta, however, did not translocate upon angiotensin II stimulation. Troglitazone, therefore, inhibits both angiotensin II-induced nuclear translocation of extracellular signal-regulated kinase 1/2 and the nuclear activity of its upstream signaling kinase protein kinase Czeta. Since extracellular signal-regulated kinase 1/2 nuclear translocation may be a critical signaling step for multiple growth factors that stimulate vascular smooth muscle cells proliferation and migration, troglitazone may provide a new therapeutical approach for the prevention and treatment of atherosclerosis and restenosis.

Angiotensin II↗
PubMed2003

Effect of troglitazone on vascular and glucose metabolic actions of insulin in high-sucrose-fed rats.

In rats, diets high in simple sugar induce insulin resistance and alter vascular reactivity. The present study was designed to evaluate the effects of 5 weeks treatment with troglitazone on insulin sensitivity, regional hemodynamics, and vascular responses to insulin in chow-fed and high-sucrose-fed rats. Male rats were randomly divided in 4 groups to receive a regular chow diet in the absence (group 1) or presence of troglitazone (0.2% in food; group 2), or a sucrose-enriched diet in the absence (group 3) or presence of troglitazone (group 4) for 5 weeks. The rats were instrumented with Doppler flow probes and intravascular catheters to determine blood pressure, heart rate, and regional blood flows. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Glucose transport activity was examined in isolated muscles. Sucrose feeding was found to induce insulin resistance and to impair the insulin-mediated skeletal muscle vasodilation. Treatment with troglitazone was found to increase whole-body insulin sensitivity in sucrose- and chow-fed rats, but had no effect on skeletal muscle glucose transport activity measured in isolated muscles from both dietary groups. Changes in regional hemodynamics were observed in both dietary cohorts treated with troglitazone, and the hindquarter vasoconstrictor response to insulin noted in sucrose-fed rats was abolished by the treatment. The vascular effects of troglitazone, and its insulin-related attenuating effects on contractile tone, could have contributed, in part, to improve insulin action on peripheral glucose disposal, presumably by improving blood flow distribution and glucose delivery.

Animals↗
PubMed1998

Effects of troglitazone on dexamethasone-induced insulin resistance in rats.

Troglitazone, a thiazolidinedione derivative, has been shown to counteract insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test its effects on dexamethasone-induced insulin resistance, we measured hepatic glucose production (HGP) and the insulin-stimulated glucose disposal rate (Rd) by a euglycemic-hyperinsulinemic glucose clamp technique coupled with 3-3H-glucose infusion in male Wistar rats treated with low-dose dexamethasone ([LoDex] 0.05 mg/kg/d, n = 7), high-dose dexamethasone ([HiDex] 0.1 mg/kg/d, n = 7), or dexamethasone plus troglitazone (LoDex + T, n = 8; HiDex + T, n = 6). Dexamethasone was injected subcutaneously for 4 days. Troglitazone was administered orally at 20 mg/d for 3 days before and for 4 days along with the dexamethasone treatment. The glucose clamp study was performed after an overnight fast in chronically catheterized conscious rats with a continuous insulin infusion of 57.4 pmol/kg/min. Basal HGP was comparable among the control (45.8 +/- 2.1 micromol/kg/min, n = 7), LoDex (47.9 +/- 4.7 micromol/kg/min), LoDex + T (46.0 +/- 2.6 micromol/kg/min), and HiDex + T (54.7 +/- 3.4 micromol/kg/min) groups. It increased about twofold in the HiDex group (80.1 +/- 5.2 micromol/kg/min, P < .05 v control). Under hyperinsulinemia, HGP was suppressed to a similar level in the control (11.3 +/- 8.8 micromol/kg/min), LoDex (10.2 +/- 8.4 micromol/kg/min), and LoDex + T (7.8 +/- 7.9 micromol/kg/min) groups. The suppressive effect of insulin on steady-state HGP during the clamp was impaired in HiDex (63.7 +/- 9.7 micromol/kg/min, P < .05) and HiDex + T (64.0 +/- 6.5 micromol/kg/min, P < .05). Rd decreased 27% in LoDex (81.5 +/- 5.8 micromol/kg/min, P < .05) and 36% in HiDex (71.3 +/- 9.4 micromol/kg/min, P < .05) compared with the controls (111.4 +/- 7.4 micromol/kg/min). Troglitazone prevented the decrease in Rd in LoDex + T (102.6 +/- 5.7 micromol/kg/min), but not in HiDex + T (67.0 +/- 6.4 micromol/kg/min). These results indicate that the development of peripheral insulin resistance was prevented by troglitazone in LoDex rats. Troglitazone may be a useful drug to treat steroid-induced diabetes.

Animals↗
PubMed2000

UCP3 gene expression does not correlate with muscle oxidation rates in troglitazone-treated Zucker fatty rats.

Uncoupling protein-3 (UCP3), a mitochondrial carrier protein predominantly expressed in muscle, has been suggested to release stored energy as heat. The insulin-sensitizing thiazolidinediones enhance glucose disposal in skeletal muscle and have been reported to increase the expression of uncoupling proteins in various experimental systems. We therefore studied the effect of troglitazone treatment on UCP3 gene expression in muscles from lean and obese Zucker rats. In comparison with obese littermates, basal UCP3 mRNA levels in lean Zucker rats tended to be higher in white and red gastrocnemius muscles, but were lower in soleus (P<0.001) muscle and heart (P<0.01). In lean rats, troglitazone significantly increased UCP3 gene expression in white and red gastrocnemius and heart muscles (all P<0.01). In contrast, the drug reduced UCP3 mRNA expression in red gastrocnemius and soleus muscles of obese littermates (all P<0.001). The troglitazone-dependent decrease in UCP3 gene expression was accompanied by an increased weight gain in obese rats, while no such effect was observed in lean rats. In obese rats, improvement of insulin resistance by troglitazone was associated with increased rates of basal and insulin-stimulated CO(2) production from glucose measured in soleus muscle. These studies demonstrate that effects of troglitazone on UCP3 gene expression depend on the phenotype of Zucker rats and that troglitazone-induced metabolic improvements are not related to increased uncoupling resulting from upregulation of UCP3 mRNA expression in muscle.

Animals↗
PubMed2002

Physical property of troglitazone, an equal mixture of four stereoisomers.

Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two chiral centers. In the present study, the physical property of troglitazone were investigated. The solid state of troglitazone drug substance is characterized as a simple physical mixture of two diastereomers, as shown by the two endothermic peaks caused by the melting of the RR/SS and the RS/SR forms by differential scanning calorimetry (DSC). In addition, the powder X-ray diffraction pattern includes peaks resulting from both the RR/SS and the RS/SR forms. The water adsorption of troglitazone drug substance is due to the presence of the RR/SS diastereomer, which adsorbs water as a monohydrate. The solubility of troglitazone and the diastereomers were increased and the solubility ratios of the stereoisomers were changed by quenching. Troglitazone was proved to be stable against heat and humidity by the ratio of the stereoisomers and from the solid state form indicated by the DSC results.

Chemistry, Pharmaceutical↗
PubMed2002

Troglitazone treatment of aging Brown Norway rats improves food intake and weight gain after fasting without increasing hypothalamic NPY gene expression.

Compared to younger animals, aged male Brown Norway (BN) rats demonstrate increased body fat and serum insulin, and lower prepro-neuropeptide Y (ppNPY) mRNA content in the arcuate nucleus (ARC), and blunted food intake (FI) and body weight (BW) gain in response to a 72 h fast. Since centrally administered insulin decreases FI and weight of young rats and inhibits fasting-induced increases of NPY gene expression, we hypothesized that hyperinsulinemia in old rats contributes to an age-related central dysregulation of energy balance. Young, middle-aged and old BN rats were fed chow with troglitazone (Trog; 200 mg/kg BW/d) or without drug for 75 d (Experiment 1) or 66 d (Experiment 2). Rats were then fasted for 72 h, refed for 2 weeks and sacrificed after an overnight fast (Experiment 1) or fasted for 72 h and sacrificed (Experiment 2). Serum insulin and leptin were measured from trunk blood and brains were analyzed for ppNPY mRNA by in situ hybridization. In Experiment 1, troglitazone treatment resulted in increased post-fast weight gain, rate of gain and FI in old rats. Troglitazone decreased serum insulin by 50% in old rats, while leptin levels decreased 20-30% in all age groups in Experiment 1. No differences in serum insulin or leptin were detectable with troglitazone treatment in Experiment 2, due to the extreme suppression caused by the 72 h fast. Troglitazone treatment did not increase ARC NPY gene expression either after a 72 h fast and re-feeding for 2 weeks (Experiment 1) or immediately after a 72 h fast (Experiment 2). These findings suggest that increased insulin levels may contribute to age-related impairments of FI and BW regulation. However, improvements in these defects in energy regulation induced by troglitazone do not appear to result from changes in NPY gene expression, and may be due to alterations in other hypothalamic neuropeptides that regulate energy balance.

Aging↗
PubMed1997

Troglitazone lowers blood pressure and enhances insulin sensitivity in Watanabe heritable hyperlipidemic rabbits.

Although an association has been demonstrated between insulin resistance and hypertension, the mechanism of this association is not clear. Clarification of this point is important in hyperinsulinemic Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia, as hypertension markedly stimulates atherosclerosis in WHHL rabbits. The purpose of the present study was to determine whether troglitazone, a new thiazolidinedione drug for insulin resistance, could reduce blood pressure (BP) by improving hyperinsulinemia in WHHL rabbits. The effects of troglitazone, administered as a food admixture (24 mg/day) for 6 months, on hyperinsulinemia and BP were examined in WHHL rabbits. Insulin sensitivity (IS) was measured by the minimal model method using an intravenous glucose tolerance test (IVGTT). Troglitazone significantly reduced fasting insulin levels and the area-under-the-curve of insulin IVGTT profiles, indicating improved hyperinsulinemia. Troglitazone also significantly increased IS and reduced BP and heart rate (HR). Due to a significant correlation between HR and BP, a covariance analysis was performed. When BP was considered as a covariance factor, the change in HR was significant in treated rabbits. However, when HR was considered as a covariance factor, the change in BP was not significant, suggesting that reduced BP may be partly associated with changes in the sympathetic nervous system activity. In conclusion, troglitazone increases insulin sensitivity and lowers blood pressure in WHHL rabbits. Due to its dual effects on insulin resistance and hypertension, troglitazone offers a new pharmacological approach for the treatment of insulin-resistance syndrome.

Animals↗
PubMed1999

Acute troglitazone action in isolated perfused rat liver.

1. The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. 2. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 microM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin- and/or glucagon-stimulated conditions in isolated perfused rat livers. 3. During BSA-free perfusion, high dose troglitazone increased basal (P < 0.01), but inhibited glucagon-stimulated incremental glucose production by approximately 75% (10.0 +/- 2.5 vs control: 40.0 +/- 7.2 micromol g liver(-1), P < 0.01). In parallel, incremental lactate release rose approximately 6 fold (13.1 +/- 5.9 vs control: 2.2 +/- 0.8 mmol g liver(-1), P < 0.05), while bile secretion declined by approximately 67% [0.23 +/- 0.02 vs control: 0.70 +/- 0.05 mg g liver(-1) min(-1)), P < 0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon-stimulated glucose production, but rapidly increased lactate release (P < 0.0005) and portal venous pressure (+0.17 +/- 0.07 vs +0.54 +/- 0.07 cm buffer height, P < 0.0001). 4. These results indicate that troglitazone exerts both insulin-like and non-insulin-like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.

Animals↗
PubMed1999

Troglitazone and pioglitazone attenuate agonist-dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells.

1. The effects of troglitazone and pioglitazone on agonist-induced Ca2+ mobilization and cell proliferation were studied using fluorescent Ca2+ indicator fura-2 AM and incorporation of [3H]-thymidine in rat aortic smooth muscle cells. The patch clamp techniques were also employed. 2. Vasopressin and platelet-derived growth factor-BB (PDGF) caused a transient elevation in [Ca2+]i by Ca2+ mobilization from intracellular stores, followed by a sustained rise due to Ca2+ entry. Nicardipine partly inhibited the sustained phase, but La3+ completely abolished it. 3. Troglitazone and pioglitazone did not significantly affect the transient rise elicited by these agonists, but preferentially inhibited the sustained phase of [Ca2+]i. 4. Under voltage clamp conditions, troglitazone and pioglitazone inhibited voltage-dependent L-type Ca2+ current (ICa.L). They also inhibited nonselective cation channels (Icat) elicited by vasopressin in a concentration-dependent manner. The half maximal inhibitory concentrations of troglitazone on ICa.L and Icat were 4.6 and 5.7 microM, respectively. On the other hand, nifedipine and nicardipine did not inhibit Icat. 5. Vasopressin and PDGF increased incorporation of [3H]-thymidine, and nifedipine and nicardipine partly suppressed it. However, the inhibitory effects of La3+ and exclusion of extracellular Ca2+ were more potent than the Ca2+ blocking agents. Troglitazone and pioglitazone also inhibited it concentration-dependently. 6. These results suggest that troglitazone and pioglitazone preferentially inhibited agonist (vasopressin and PDGF)-induced Ca2+ entry and proliferation in rat vascular smooth muscle cells, where the inhibitory effects of thiazolidinediones on ICa.L and Icat might be partly involved. Thus, thiazolidinediones may exert hypotensive and antiatherosclerotic effects.

Animals↗
PubMed2002

Enhanced inhibition of L-type calcium currents by troglitazone in streptozotocin-induced diabetic rat cardiac ventricular myocytes.

1. Troglitazone, an insulin-sensitizing agent shown to improve cardiac function in both experimental animals and patients with diabetes, inhibits voltage-dependent L-type Ca(2+) currents (I(Ca,L)) in cardiac myocytes, which may underlie its cardioprotective effects. However, inhibition by troglitazone of I(Ca,L) in diabetic cardiac myocytes has not been characterized. 2. Using whole-cell voltage-clamp techniques, I(Ca,L) was measured in ventricular myocytes isolated from 4-6 weeks streptozotocin (STZ)-induced diabetic rats and age-matched control rats. 3. Under control conditions with CsCl internal solution, diabetic myocytes did not differ from control myocytes in membrane capacitance, current density or voltage-dependent properties of I(Ca,L). 4. Troglitazone decreased amplitude of I(Ca,L) in both control and diabetic myocytes in a concentration-dependent manner. This inhibition was more potent in diabetic than in control myocytes; half-maximum inhibitory concentrations of troglitazone measured at a holding potential of -50 mV were 4.3 and 9.5 micromol l(-1), respectively. 5. Troglitazone at 5 micromol l(-1) did not significantly influence the voltage dependency of steady-state inactivation or the inactivation time course of I(Ca,L) in either control or diabetic myocytes. 6. Since troglitazone inhibits I(Ca,L) more effectively in STZ-induced diabetic ventricular myocytes, this agent may prevent cardiac dysfunction in diabetes.

Animals↗
PubMed2001

Effect of troglitazone on urinary albumin excretion and serum type IV collagen concentrations in Type 2 diabetic patients with microalbuminuria or macroalbuminuria.

AIMS: Troglitazone, a newly developed thiazolidinedione derivative, has been shown to ameliorate microalbuminuria in diabetic animal model and in human diabetic nephropathy in short-term studies. The aim of the present study was to determine whether troglitazone or sulphonylurea affect micro- albuminuria, macroalbuminuria, or serum type IV collagen concentrations in patients with diabetic nephropathy. METHODS: We studied 32 normotensive patients with type 2 diabetes mellitus associated with microalbuminuria (n = 16) or macroalbuminuria (n = 16) and 20 healthy controls. The patients were randomly assigned to one of two groups: those treated with glibenclamide (5.0 mg/day) (n = 8) and those treated with troglitazone (400 mg/day) (n = 8). They received the drug regimen for 12 months. Serum type IV collagen was measured with sandwich enzyme immunoassay. RESULTS: Type IV collagen concentrations in macroalbuminuric patients were higher than those in microalbuminuric patients (P < 0.05) and healthy controls (P < 0.01). Troglitazone reduced urinary albumin excretion (UAE) in micro-albuminuric patients from 126 microg/min (range 58--180 microg/min) to 42 microg/min (range 14--80 microg/min) (P < 0.01) and also reduced serum type IV collagen levels gradually at 3, 6 and 12 months after treatment (P < 0.05). However, glibenclamide did not affect UAE and type IV collagen levels in micro- albuminuric diabetes patients. In addition, neither troglitazone nor gliben- clamide changed UAE and type IV collagen levels in macroalbuminuric patients. CONCLUSIONS: These data suggest that troglitazone is an effective treatment for renal injury in patients with early diabetic nephropathy.

Albuminuria↗
PubMed2000

Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion.

BACKGROUND: Renal complications of long-term, poorly controlled type 2 diabetes mellitus include glomerulosclerosis and interstitial fibrosis. The onset and progression of these complications are influenced by underlying pathophysiologies such as hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Troglitazone, a thiazolidinedione, has been shown to ameliorate these metabolic defects. However, it was not known whether therapeutic intervention with troglitazone would prevent the onset and progression of glomerulosclerosis. METHODS: Sixty male ZDF/Gmitrade mark rats and 30 age-matched Zucker lean rats were in the study. The ZDF/Gmitrade mark rats were divided into two groups, one in which blood glucose levels were uncontrolled (30 animals) and another (30) in which blood glucose was controlled via dietary administration of troglitazone. Ten animals from each group were sacrificed at one, three, and six months into the study. The kidneys were harvested and processed for immunostaining with BM-CSPG, a marker for mesangial matrix. Images of 200 glomeruli per animal were captured using digital imaging microscopy, and the index of mesangial expansion (total area mesangium/total area of tuft) per glomerular section was measured. RESULTS: The administration of troglitazone ameliorated the metabolic defects associated with type 2 diabetes mellitus. Moreover, the glomeruli from tissue sections of animals given troglitazone showed no mesangial expansion when compared with normoglycemic control animals, whereas the uncontrolled diabetic animals showed significant mesangial expansion at all time intervals. CONCLUSIONS: Therapeutic intervention with the thiazolidinedione troglitazone halts the early onset and progression of mesangial expansion in the ZDF/Gmitrade mark rat, preventing the development of glomerulosclerosis in this animal model of type 2 diabetes mellitus.

Animals↗
PubMed2003

Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells.

Increasing evidence has confirmed that ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) exhibit antitumoral effects through inhibition of cell proliferation and induction of cell differentiation in several malignant neoplasms. Recently, we have documented the accumulation of a cyclin-dependent kinase inhibitor, p27(Kip1), as well as an unexpected accumulation in cyclin E in G1-arrested human hepatoma cells treated with the PPARgamma ligand troglitazone. Simultaneous accumulations in both p27(Kip1) and cyclin E are known to be characteristic phenotypes in cells derived from mice lacking Skp2, an F-box protein component of the SCF ubiquitin-ligase complex. Thus, the aim of the present study was to assess whether Skp2 might be involved in the down-regulation of p27(Kip1) in troglitazone-treated human hepatoma cells. A striking decrease in Skp2 expression and a reciprocal increase in p27(Kip1) expression were found in troglitazone-treated hepatoma cells but not in those cells treated with other PPARgamma ligands such as pioglitazone and ciglitazone. Quantitative real-time RT-PCR analysis showed that troglitazone down-regulated Skp2 at the mRNA levels. Consistently, ectopic overexpression in Skp2 brought resistance to troglitazone, resulting in a decreased population of arrested cells at the G1 phase compared with that in the mock-transfected cells. In surgically resected hepatocellular carcinoma (HCC) tissue, an increased expression in Skp2 was found in both the moderately differentiated HCCs and the poorly differentiated HCCs. In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27(Kip1) accumulation in human hepatoma cells. This therapeutic potential of the ligand may lead to new cell-cycle-based antitumor strategies for advanced HCCs.

Antineoplastic Agents↗
PubMed1999

Reduction of vascular tone by introduction of troglitazone to the canine coronary artery.

The insulin-sensitizing agent troglitazone ((+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy++ +)benzyl]-2,4- thiazolidinedione, CAS 97322-87-7), has been reported to reduce vascular tone in the rat tail artery. This study was designed to examine whether troglitazone could relax the precontracted canine coronary artery in vitro. Isometric tension of coronary arterial rings was measured, and analysis by Mann-Whitney U-test revealed that significant relaxation was induced even with 1 mumol/l troglitazone. This relaxation was not affected by blocking of NO synthase, cyclooxygenase, the large and intermediate conductance Ca(2+)-activated K+ channel, the ATP-sensitive K+ channel, or the Na(+)-K+ pump. The exact mechanism of the reduction of vascular tone by troglitazone remains unclear. However, the finding that troglitazone acts as a vasorelaxant in the coronary artery may be clinically useful, since troglitazone is mainly used for type II diabetic patients with insulin resistance, which is associated with increased risk for coronary artery disease.

Animals↗
PubMed2001

Effects of troglitazone and voluntary running on insulin resistance induced high fat diet in the rat.

It is well known that troglitazone and voluntary running have the capacity to improve insulin resistance. The purpose of this study was to evaluate the combination effect of troglitazone and voluntary running on insulin action. Female rats aged 7 weeks were divided into high-fat diet (HF), high-fat diet + troglitazone (0.3% in diet; Tg), high-fat diet + voluntary running (for 3 wks; Tr), high-fat diet + troglitazone + voluntary running (Tg-Tr), and control (C) groups. A sequential euglycemic clamp experiment with two different insulin infusion rates of 3.0 (L-clamp) and 30.0 mU/kg BW/min (H-clamp) was performed on these rats after an overnight fast. Blood glucose concentrations were kept at fasting levels by periodic adjustment of the intravenous glucose infusion rate during the clamp experiment. Glucose infusion rates (GIRs) calculated from 60 to 90, 150 to 180 min were regarded as an index of whole body insulin action. After the clamp experiment, we determined the amount of glycogen content in the gastrocnemius muscle. Fat feeding markedly reduced GIRs in both L- and H- clamp experiments compared with C. Troglitazone treatment did not improve high-fat induced insulin resistance. In both L- and H-clamp experiments, GIRs were increased by voluntary running compared with HF, and reached the same levels as in C. GIRs of Tg-Tr were not greater than those of Tr. Glycogen content in gastrocnemius muscle showed the same trend as the results for GIRs. Therefore, the combination effect of troglitazone and voluntary running on insulin action was not found, but the effect of voluntary running was shown in fat-induced insulin resistance.

Animals↗
PubMed2001

Effect of obesity and troglitazone on expression of two glutathione peroxidases: cellular and extracellular types in serum, kidney and adipose tissue.

To determine the effect of obesity on expression of cellular- (C-) and extracellular (EC-) glutathione peroxidase (GPX) in serum, kidney and adipose tissue, we measured GPX in serum, kidneys and adipose tissue of the obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat and its lean counterpart (LETO). We also investigated the effect of troglitazone. Five each of OLETF and LETO rats were fed diet with or without 0.2% troglitazone for 10 days. Final body weight, kidney weight, blood glucose and serum tumor necrosis factor-alpha (TNF-alpha) level were higher in OLETF rats than in LETO rats. Serum and kidney GPX activities were higher, but adipose tissue GPX activity was lower, in OLETF rats than in LETO rats. Troglitazone treatment decreased adipose tissue GPX activity and abolished overproduction of TNF-alpha in OLETF rats. Immunoblot analysis, for the first time, revealed that both obesity and troglitazone suppressed the protein signals for C-GPX and EC-GPX in adipose tissue. Serum protein carbonyl groups were increased in OLETF rats and troglitazone completely blocked this increase. Increased serum GPX activity in obese rat was due to the increased secretion of EC-GPX from the kidney. Troglitazone protected against the enhanced oxidative stress induced by obesity independently of the serum GPX concentration.

Adipose Tissue↗
PubMed2005

Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines.

Troglitazone is a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) that is a ligand-activated transcription factor regulating cell differentiation and growth. PPARgamma may play a role in thyroid carcinogenesis since PAX8-PPARgamma1 chromosomal translocations are commonly found in follicular thyroid cancers. We investigated the antiproliferative and redifferentiation effects of troglitazone in 6 human thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hürthle cell), and ARO82-1 (anaplastic) cell lines. PPARgamma was expressed variably in these cell lines. FTC-236 and FTC-238 had a rearranged chromosome at 3p25, possibly implicating the involvement of the PPARgamma encoding gene whereas the other cell lines did not. Troglitazone significantly inhibited cell growth by cell cycle arrest and apoptotic cell death. PPARgamma overexpression did not appear to be a prerequisite for a response to treatment with troglitazone. Troglitazone also downregulated surface expression of CD97, a novel dedifferentiation marker, in FTC-133 cells and upregulated sodium iodide symporter (NIS) mRNA in TPC-1 and FTC-133 cells. Our investigations document that human thyroid cancer cell lines commonly express PPARgamma, but chromosomal translocations involving PPARgamma are uncommon. Troglitazone, a PPARgamma agonist, induced antiproliferation and redifferentiation in thyroid cancer cell lines. PPARgamma agonists may therefore be effective therapeutic agents for the treatment of patients with thyroid cancer that fails to respond to traditional treatments.

Adenocarcinoma, Follicular↗