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PubMed1998

Troglitazone inhibits progesterone production in porcine granulosa cells.

Troglitazone (a thiazolidinedione that improves insulin resistance) lowers elevated androgen concentrations in women with polycystic ovarian syndrome. In this study, we assessed the direct effects of troglitazone on steroidogenesis in porcine granulosa cells. Troglitazone inhibited progesterone production in a dose- and time-dependent manner (earliest effects at 4 h, maximum at 24 h) without affecting cell viability. Progesterone production was also inhibited by troglitazone in the presence of 25-hydroxycholesterol, indicating that the drug does not affect intracellular cholesterol transport. Troglitazone also inhibited FSH- and forskolin-stimulated progesterone secretion. The reduced progesterone production was accompanied by marked elevations of pregnenolone concentrations, suggesting inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). The activity of 3beta-HSD in troglitazone-treated granulosa cells was decreased by more than 60%, compared with controls after 24 h. Troglitazone did not affect aromatase activity in porcine granulosa cells. In summary, troglitazone has direct effects on porcine granulosa cell steroidogenesis. The drug specifically inhibits 3beta-HSD activity, resulting in impaired progesterone production. The clinical relevance of this direct in vitro effect on steroidogenesis needs further investigation.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Troglitazone effects on gene expression in human skeletal muscle of type II diabetes involve up-regulation of peroxisome proliferator-activated receptor-gamma.

Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). To determine whether troglitazone might enhance insulin action by stimulation of PPARgamma gene expression in muscle, total PPARgamma messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days +/- troglitazone, 11.5 microM). Troglitazone treatment increased PPARgamma mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 +/- 63 to 630 +/- 100 x 10(3) copies/microg total RNA, P = 0.003) and in nondiabetic control subjects (200 +/- 42 to 490 +/- 81, P = 0.003). PPARgamma protein levels in both diabetic (4.7 +/- 1.6 to 13.6 +/- 3.0 AU/10 microg protein, P < 0.02) and nondiabetic cells (7.4 +/- 1.0 to 12.7 +/- 1.8, P < 0.05) were also upregulated by troglitazone treatment. Increased PPARgamma was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARdelta, myogenin, uncoupling protein-2, or sarcomeric alpha-actin protein. In summary, we showed that troglitazone markedly induces PPARgamma, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARgamma protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.

Adult↗
PubMed1996

Effect of troglitazone on leptin production. Studies in vitro and in human subjects.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulin-sensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/l troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40-50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.

Adipocytes↗
PubMed1999

A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients.

Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels. We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients. To avoid the confounding effect of improved glycemic control on insulin action and secretion, patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10); euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII, and 3) after CSII plus either troglitazone or metformin. The 24-h glucose, insulin, and C-peptide profiles were performed on the day before the second and third glucose clamps. Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/-0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53% with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P < 0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The 24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone. Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII alone) and was then 45% higher than in the CSII plus metformin patients (P < 0.005). In conclusion, metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes. Troglitazone (600 mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII-treated euglycemic patients. This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone.

Blood Glucose↗
PubMed1997

Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone.

OBJECTIVE: The primary purpose of this study was to assess the effects of 12 weeks of treatment with either troglitazone, an investigational thiazolidinedione that acts as an insulin-action enhancer, or placebo in patients with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A total of 51 subjects with IGT between 24 and 77 years of age were enrolled in this multicenter, double-blind, placebo-controlled, parallel group study (troglitazone, 25 patients; placebo, 26 patients). Patients were randomly assigned to receive either 400 mg troglitazone (every morning [QAM]) or placebo (QAM). The main outcome measure was the oral glucose tolerance test (OGTT) assessing glucose, insulin, and C-peptide levels in the fasting state and every 30 min up to 2 h after ingesting the glucose load. Fasting serum levels of HbA1c, fructosamine, lipids, and blood pressure were also measured. RESULTS: A total of 46 patients completed the study. The glucose, insulin, and C-peptide responses after a glucose load were significantly reduced at 6 and 12 weeks in the troglitazone treatment group. After 6 weeks of treatment, 75% (n = 18) of those taking troglitazone had improved to normal glucose tolerance, whereas only 38% (n = 9) of those of placebo showed improvement (P = 0.008). After 12 weeks of treatment, 80% (n = 16) of the troglitazone treatment group had normalized their glucose tolerance, while only 48% (n = 10) of those on placebo had converted to normal (P = 0.016). Fasting triglyceride levels in the troglitazone treatment group had decreased by 40 mg/dl (0.45 mmol/l) (P = 0.0016). Other lipid measurements, blood pressure, glycosylated hemoglobin, and fructosamine were normal at baseline for both treatment groups and remained normal throughout the study. CONCLUSIONS: The glycemic response after a glucose load is statistically and clinically significantly improved for patients with IGT treated with troglitazone.

Adult↗
PubMed1998

Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients.

OBJECTIVE: Troglitazone, which improves peripheral insulin resistance of experimental diabetic animals and diabetic patients, affects ob gene expression in the adipose tissue of rodents. The present study was undertaken to examine a hypothesis that clinical administration of troglitazone may reduce circulating leptin levels and affect eating behavior in NIDDM patients. RESEARCH DESIGN AND METHODS: Troglitazone was administered at a dosage of 200 mg twice daily for 12 weeks in 20 poorly controlled NIDDM patients. Chronological changes in glycemic control, serum lipids, immunoreactive leptin (IRL) levels, and BMI were measured. Body fat weight was also assessed by bioelectric impedance. RESULTS: Troglitazone significantly decreased fasting plasma glucose, serum immunoreactive insulin, and HbA1c levels. Serum levels of IRL and triglyceride were significantly reduced by troglitazone administered for 4, 8, and 12 weeks. Troglitazone administration significantly increased the BMI in NIDDM patients, and two-thirds of the patients complained of increased hunger after the start of troglitazone administration. CONCLUSIONS: Troglitazone significantly reduces circulating leptin levels at clinical doses. It may affect the eating behavior of poorly controlled NIDDM patients through the improvement of glycemic control and/or the reduction of circulating leptin.

Blood Glucose↗
PubMed1999

Effect of troglitazone on body fat distribution in type 2 diabetic patients.

OBJECTIVE: Troglitazone was recently reported to specifically promote the differentiation of pre-adipocytes into adipocytes in vitro in subcutaneous fat only, indicating a relation to insulin-resistance-improving action of troglitazone. To expand on this finding, we investigated at the clinical level how long-term administration of troglitazone influences the body fat distribution in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Troglitazone (400 mg/day) was administered for 6 months to 30 type 2 diabetic patients whose glycemic control was poor. A total of 18 patients received diet therapy alone (in the single-treatment group, BMI 26.0 +/- 4.6, HbA1c 8.2 +/- 1.7%), and 12 patients concomitantly received glibenclamide (1.25-7.5 mg/day) (in the concomitant sulfonylurea group, BMI 25.4 +/- 4.7, HbA1c 9.2 +/- 1.2%). BMI, HbA1c, serum lipid level, and body fat distribution, which were determined by computed tomography (CT) scan at the umbilical level, were measured and compared before and after troglitazone treatment. RESULTS: During the 6-month troglitazone treatment, HbA1c levels decreased and BMI increased in both groups. As for body fat distribution in the single-treatment group, visceral fat area (VFA) decreased (from 118.3 +/- 54.3 to 101.1 +/- 50.8 cm2; P < 0.001), and subcutaneous fat area (SFA) increased (from 189.7 +/- 93.3 to 221.6 +/- 101.6 cm2; P < 0.001), resulting in a decrease in visceral/subcutaneous (V/S) ratio (from 0.74 +/- 0.48 to 0.50 +/- 0.32; P < 0.001). In the concomitant sulfonylurea group, VFA was unchanged (from 108.1 +/- 53.5 to 112.5 +/- 59.9 cm2), while SFA increased (from 144.6 +/- 122.0 to 180.5 +/- 143.5 cm2; P < 0.01), thereby decreasing the V/S ratio (from 0.91 +/- 0.46 to 0.77 +/- 0.44; P < 0.01). The serum triglyceride level and the area under glucose curve during the 75-g oral glucose tolerance test decreased significantly in the single-treatment group. CONCLUSIONS: According to our data, troglitazone appears to promote fat accumulation in the subcutaneous adipose tissue rather than in the visceral adipose tissue in mildly obese Japanese people with type 2 diabetes. This shift of energy accumulation from the visceral to subcutaneous adipose tissue may greatly contribute to the troglitazone-mediated amelioration of insulin resistance.

Abdomen↗
PubMed2000

Efficacy of troglitazone on body fat distribution in type 2 diabetes.

OBJECTIVE: The insulin-sensitizing action of troglitazone may be mediated through the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the promotion of preadipocyte differentiation in adipose tissue on which troglitazone has depot-specific effects. We investigated the relationship between efficacy of the drug and body fat distribution. Changes in body fat distribution were also investigated by long-term administration of the drug. RESEARCH DESIGN AND METHODS: Troglitazone was given at a dose of 400 mg/day to 20 patients with type 2 diabetes whose diet and sulfonylurea therapy produced unsatisfactory glycemic control (HbA(1c) >7.8%) and whose insulin secretory capacity was found to be preserved (postprandial C-peptide >3 ng/ml). HbA(1c) values, serum lipid levels, and body weight were measured monthly Body fat distribution was evaluated in subcutaneous (SC) and visceral fat using a computed tomography scan at umbilical levels before and after troglitazone therapy RESULTS: During the 1-year troglitazone treatment, HbA(1c) was significantly decreased (from 9.2 +/- 0.2 to 7.1 +/- 0.2%, P < 0.01), showing lowest values at 4-6 months, whereas body weight was significantly increased (BMI 24.6 +/- 0.6 to 25.7 +/- 0.6 kg/m2, P < 0.01). Reduction of HbA(1c) (deltaHbA(1c)) from the baseline value during treatment was significantly greater in obese patients (BMI >26 kg/m2) than in nonobese patients (-3.2 +/- 0.4 vs. -2.1 +/- 0.3%, P < 0.05) and was more significant in women than in men (-3.2 +/- 0.2 vs. - 1.4 +/- 0.2%, P < 0.01). The level of deltaHbA(1c) during treatment showed a significant negative correlation with SC fat area (r = -0.742, P < 0.01) but not with visceral fat area. Weight gain during troglitazone treatment resulted in increased accumulation of SC fat without a change in visceral fat area and, consequently. in a significant decrease in the visceral-to-SC fat ratio. CONCLUSIONS: Predominant accumulation of SC fat for the visceral fat tissue was an important predictor of the efficacy of troglitazone therapy in patients with type 2 diabetes. Greater efficacy of troglitazone was observed in women who were characterized by more accumulation of SC adipose tissue than men. Long-term administration of the drug resulted in weight gain with increased accumulation of SC adipose tissue, probably because of the activation of PPAR-gamma in the region.

Adipose Tissue↗
PubMed2004

Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes.

OBJECTIVE: Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes. We therefore treated young, glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity, glucose metabolism, and glycogen synthase activity. RESEARCH DESIGN AND METHODS: Relatives were randomized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo. Before and after treatment, an oral glucose tolerance test (OGTT) and a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) were performed, including 3-(3)H glucose infusion, glycolytic flux calculations, indirect calorimetry, and muscle biopsies. RESULTS: Twelve relatives received troglitazone and 12 placebo (aged 30.8 +/- 2.0 vs. 30.3 +/- 1.6 years, BMI 29.6 +/- 0.8 vs. 30.5 +/- 1.3 kg/m(2); means +/- SE). Area under the curve (AUC) for plasma glucose at the second OGTT was unchanged after troglitazone. In contrast, troglitazone reduced fasting (from 70.3 +/- 6.9 to 52.2 +/- 5.8 vs. 73.6 +/- 11.0 to 73.3 +/- 6.5 pmol/l, P < 0.02) and AUC plasma insulin (mean [CI] from 335.7 [230.9-488.1] to 277.4 [179.4-428.8] vs. 313.8 [218.2-451.2] to 353.9 [208.3-601.3] pmol/l, P < 0.05). Additionally, fasting plasma triglycerides were reduced by troglitazone (from 1.86 +/- 0.33 to 1.38 +/- 0.27 vs. 2.22 +/- 0.44 to 2.35 +/- 0.46 mmol/l, P < 0.01). Insulin-stimulated glucose disposal increased in the troglitazone group (from 208.3 +/- 23.7 to 263.5 +/- 30.4 vs. 197.1 +/- 20.0 to 200.8 +/- 20.8 mg. m(-2). min(-1), P < 0.02) mainly due to increased glucose storage (from 99.9 +/- 17.9 to 146.0 +/- 25.3 vs. 87.1 +/- 16.7 to 87.9 +/- 15.7 mg. m(-2). min(-1), P < 0.02), which took place without altering insulin-stimulated glycogen synthase activity. CONCLUSIONS: In glucose-tolerant first-degree relatives, treatment with troglitazone improved insulin sensitivity almost 50%, primarily due to increased glucose storage. It is suggested that the use of insulin action enhancers can be especially valuable in this group of subjects with a known high risk for developing type 2 diabetes.

Blood Glucose↗
PubMed2001

Comparison of the metabolic effects of metformin and troglitazone on fructose-induced insulin resistance in male Sprague-Dawley rats.

BACKGROUND AND PURPOSE: Insulin resistance is a hallmark of the development of type 2 diabetes. Metformin and troglitazone are oral antidiabetic agents used to reduce insulin resistance. The aim of this study was to compare the metabolic effects of these two drugs in fructose-induced insulin-resistant rodents. METHODS: Male Sprague-Dawley rats were allocated to receive one of the following four treatments for 6 weeks: normal rat chow (control group, n = 7), high-fructose diet (fructose group, n = 7), high-fructose diet plus metformin (metformin group, n = 8), or high-fructose diet plus troglitazone (troglitazone group, n = 8). Systolic blood pressure (SBP), insulin, free fatty acid (FFA), and triglyceride concentrations were measured as parameters of insulin resistance. Leptin concentration was also measured in the four groups. RESULTS: The fructose group developed significantly elevated SBP, hyperinsulinemia, and hypertriglyceridemia without significant change in body weight or leptin concentration compared with the control group. The metformin group had significantly reduced body weight (397.9 +/- 40.9 vs 470.1 +/- 59.6 g, p < 0.05), insulin concentration (14.8 +/- 10.5 vs 48.4 +/- 15.2 microU/mL, p < 0.05), triglyceride concentration (75.3 +/- 65.5 vs 250.1 +/- 95.7 mg/dL, p < 0.05), and leptin concentration (3.1 +/- 1.5 vs 6.9 +/- 2.0 ng/mL, p < 0.05) without significant change in SBP (147.8 +/- 5.8 vs 152.4 +/- 13.0 mm Hg, p > 0.05) compared with the fructose group. The troglitazone group had significantly reduced SBP (137.8 +/- 9.2 vs 152.4 +/- 13.0 mm Hg, p < 0.05), insulin concentration (15.0 +/- 13.6 vs 48.4 +/- 15.2 microU/mL, p < 0.05), FFA concentration (38.9 +/- 22.7 vs 78.7 +/- 24.6 mg/dL, p < 0.05), triglyceride concentration (67.6 +/- 32.4 vs 250.1 +/- 95.7 mg/dL, p < 0.05), and leptin concentration (4.4 +/- 2.0 vs 6.9 +/- 2.0 ng/mL, p < 0.05) without significant change in body weight (452.5 +/- 32.8 vs 470.1 +/- 59.6 g, p > 0.05) compared with the fructose group. The metabolic effects of metformin and troglitazone on insulin, FFA, triglyceride, and leptin concentrations were not significantly different. However, metformin treatment resulted in significantly lower body weight (397.9 +/- 40.9 vs 452.5 +/- 32.8 g) and troglitazone treatment in significantly lower SBP (137.8 +/- 9.2 vs 147.8 +/- 5.8 mm Hg) compared to the fructose group, after adjusting for basal values (p < 0.05). CONCLUSIONS: Both metformin and troglitazone were comparably effective in reducing insulin resistance. Metformin treatment caused body weight reduction but was not effective in reducing SBP. Troglitazone treatment lowered SBP but did not reduce body weight.

Animals↗
PubMedDate not supplied

Troglitazone: a possible modulator of ovarian steroidogenesis.

OBJECTIVE: Troglitazone increases insulin sensitivity. When used to treat women with insulin-resistant polycystic ovary syndrome (PCOS), troglitazone lowers androgen concentrations and improves ovulatory, endocrine, and metabolic disturbances. However, it is not known whether these effects are due to increased peripheral insulin sensitivity only or to direct effects on steroidogenesis. To determine whether troglitazone has a direct effect on ovarian steroidogenesis, we studied the effect of troglitazone on androgen production in cultured rat theca interstitial cells (rTICs) and on progesterone production in cultured human granulosa lutein cells (hGLCs). METHODS: Primary cell cultures of rTICs were isolated from the ovaries of hypophysectomized immature Sprague-Dawley rats, and hGLCs was obtained from women who had in vitro fertilization-embryo transfer. Treatments included troglitazone, insulin, LH, hCG, and combinations of these agents. Media were collected and assayed for androsterone and progesterone. RESULTS: Troglitazone decreased both basal and insulin-, LH-, and hCG-stimulated androsterone production by TIC and progesterone production by hGLCs in a dose-dependent manner. CONCLUSION: We found a direct effect of troglitazone on the production of androsterone by rTICs and progesterone by hGLCs. These results suggest that the beneficial effects of troglitazone in PCOS may not be due solely to improvement of peripheral insulin resistance and hyperinsulinemia, but also to a possible direct effect on ovarian steroidogenesis.

Adult↗
PubMed2002

Peroxisome proliferator-activated receptor gamma ligand troglitazone induces cell cycle arrest and apoptosis of hepatocellular carcinoma cell lines.

BACKGROUND: Ligand activation of peroxisome proliferator-activated receptor gamma (PPARgamma) results in the inhibition of proliferation of various cancer cells. The aim of this study is to investigate the mechanisms of cell growth inhibition of hepatocellular carcinoma (HCC) cell lines by the PPARgamma ligand, troglitazone. METHODS: Six HCC cell lines were used to study the effects of troglitazone on cell growth by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, on cell cycle by flow cytometry, and on the cell cycle-regulating factors of late G1 phase by Western blotting. Apoptosis assays were performed by flow cytometry using membrane, nuclear, cytoplasmic, and mitochondrial markers. Caspase inhibitors were used to analyze the mechanisms of apoptosis induced by troglitazone. RESULTS: Troglitazone showed a potent dose-dependent effect on the growth inhibition of all six HCC cell lines, which were suppressed to under 50% of control at the concentration of 10 micromol/L. The growth inhibition was linked to the G1 phase cell cycle arrest through the up-expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins, and the hypophosphorylation of retinoblastoma protein. Troglitazone induced apoptosis by caspase-dependent (mitchondrial transmembrane potential decrease, cleavage of poly [adenosine diphosphate ribose] polymerase, 7A6 antigen exposure, Bcl-2 decrease, and activation of caspase 3) and caspase-independent (phosphatidylserine externalization) mechanisms. CONCLUSIONS: Our data suggest that ligand activation of PPARgamma by troglitazone or modified analogs of the thiazolidinedione class of drugs is a novel target for effective therapy against HCC, because of the significant antiproliferative and programmed cell death induction capabilities demonstrated by troglitazone.

Antineoplastic Agents↗
PubMed1997

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells.

Trolitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu(++)-induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu(++) were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HUVEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu(++)- and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu(++)-induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu(++)- and HUVEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation.

Arteriosclerosis↗
PubMed1997

Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers.

The oxidative modification of low density lipoprotein is of importance in atherogenesis. Antioxidant supplementation has been shown, in published work, to increase low density lipoprotein resistance to oxidation in both healthy subjects and diabetic subjects; in animal studies a contemporary reduction in atherogenesis has been demonstrated. Troglitazone is a novel oral antidiabetic drug which has similarities in structure with vitamin E. The present study assessed the effect of troglitazone 400 mg twice daily for 2 weeks on the resistance of low density lipoprotein to oxidation in healthy male subjects. Ten subjects received troglitazone and ten received placebo in a randomised, placebo-controlled, parallel-group design. The lag phase (a measure of the resistance of low density lipoprotein to oxidation) was determined by measurement of fluorescence development during copper-catalysed oxidative modification of low density lipoprotein. The lag phase was increased by 27 % (p < 0.001) at week 1 and by 24% (p < 0.001) at week 2 in the troglitazone treated group compared with the placebo group. A number of variables known to influence the resistance of low density lipoprotein to oxidation were measured. They included macronutrient consumption, plasma and lipoprotein lipid profile, alpha-tocopherol, beta-carotene levels in low density lipoprotein, low density lipoprotein particle size, mono and polyunsaturated fatty acid content of low density lipoprotein and pre-formed low density lipoprotein hydroperoxide levels in low density lipoprotein. Troglitazone was associated with a significant reduction in the amount of pre-formed low density lipoprotein lipid hydroperoxides. At weeks 1 and 2, the low density lipoprotein hydroperoxide content was 17% (p < 0.05) and 18% (p < 0.05) lower in the troglitazone group compared to placebo, respectively. In summary the increase in lag phase duration in the troglitazone group appeared to be due to the compound's activity as an antioxidant and to its ability to reduce the amount of preformed low density lipoprotein lipid hydroperoxides. This antioxidant activity could provide considerable benefit to diabetic patients where atherosclerosis accounts for the majority of total mortality.

Administration, Oral↗
PubMed1998

Inhibitory effect of troglitazone on diabetic neuropathy in streptozotocin-induced diabetic rats.

Free-radical scavengers and inhibitors of tumour necrosis factor-alpha (TNF-alpha) such as N-acetylcysteine and pentoxifylline have been shown to inhibit the development of peripheral neuropathy in streptozotocin(STZ)-induced diabetic rats. In this study we examined the effect of troglitazone, an anti-diabetic thiazolidinedione, on diabetic neuropathy, since it also is a free-radical scavenger and a TNF-alpha inhibitor. Rats were fed powder chow mixed with troglitazone at 0.5% and 0.125% ad libitum. Although blood glucose concentrations were remarkably higher and body weight lower in diabetic than in nondiabetic rats, troglitazone had no effect on these throughout the 24-week experiment. Serum lipoperoxide concentrations, tibial nerve lipoperoxide content and serum TNF-alpha activity induced by lipopolysaccharide was increased in diabetic rats, but inhibited in troglitazone-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve slowed in diabetic rats, compared with that in nondiabetic rats. On the other hand, the slowed MNCV was (p < 0.05-0.01) inhibited after weeks 12 and 16 of the experiment in diabetic rats treated with high and low doses of troglitazone, respectively. Morphometric analysis showed that troglitazone suppressed the decrease of the myelinated fibre area (p < 0.05), axon/myelin ratio (p < 0.01) and fascicular area (p < 0.05) and suppressed the increase of myelinated fibre density (p < 0.001) in diabetic rats. These results indicate that troglitazone has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats irrespective of blood glucose concentrations.

Animals↗
PubMed2002

Concentration-dependent stimulatory and inhibitory effect of troglitazone on insulin-induced fatty acid synthase expression and protein kinase B activity in 3T3-L1 adipocytes.

In order to study the effect of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone on the insulin-induced expression of fatty acid synthase (FAS) in adipocytes, we generated a 3T3-L1 cell line stably expressing a FAS reporter gene construct. In this cell line, a low concentration of troglitazone (250 nM) increased the effect of insulin on the FAS promoter activity and the expression of FAS protein about 1.5- to 2-fold. Since the effect of insulin on the expression of FAS is believed to be mediated by activation of protein kinase B (PKB), we investigated the effect of troglitazone on the regulation of PKB. Troglitazone (250 nM) increased the maximal effect of insulin on PKB activity about twofold without significantly affecting its EC(50) (1.4+/-0.5 nM vs. 2.2+/-0.6 nM in controls). Higher concentrations of troglitazone (> or =1 microM) inhibited both insulin-stimulated PKB activity and expression of FAS. In summary, our data indicate a dual effect of troglitazone on the insulin-induced FAS gene expression in 3T3-L1 cells. The therapeutic, stimulatory effect is produced by low concentrations of troglitazone (250 nM), and is presumably mediated by enhanced activation of PKB.

3T3 Cells↗
PubMed2001

Troglitazone treatment increases bone marrow adipose tissue volume but does not affect trabecular bone volume in mice.

Aging is associated with decreased trabecular bone mass and increased adipocyte formation in bone marrow. As osteoblasts and adipocytes share common precursor cells present in the bone marrow stroma, it has been proposed that an inverse relationship exists between adipocyte and osteoblast differentiation. In order to test this hypothesis, we studied mice treated with troglitazone (n = 9) given as a 0.2% of food admixture (2.0 g troglitazone per kg food) for 10 months and control mice (n = 9). Troglitazone is a potent stimulator of adipogenesis acting at the nuclear receptor: peroxisome proliferator activated receptor-gamma (PPARgamma). Histomorphometric analysis of proximal tibia was performed in order to quantitate the amount of trabecular bone volume per total volume (BV/TV %), adipose tissue volume per total volume (AV/TV %), and hematopoietic marrow volume per total volume (HV/TV %) using the point-counting technique. Bone size did not differ between the two groups. In troglitazone-treated mice, AV/TV was significantly higher than in control mice (4.7+/-2.1% vs. 0.2+/-0.3%, respectively, mean +/- SD, P < 0.001). BV/TV was similar in the two groups (16.9+/-5.6% for troglitazone-treated group vs. 14.9+/-4.7% for control group) as well as ash weight of the vertebrae. HV/TV was reduced in troglitazone-treated mice compared with control mice (78.4+/-6.8% vs. 84.9+/-4.7%, respectively, P < 0.05) and the presence of vascular sinusoids was reduced (7.3+/-1.7% vs. 16.1+/-5.6%, respectively, P < 0.05). Our data demonstrate that adipogenesis and osteogenesis can be regulated independently. Troglitazone-induced adipogenesis in the bone marrow may be caused by changes in the bone marrow vascularity.

Adipocytes↗
PubMed2002

Decreased synthesis of matrix metalloproteinase-7 and adhesion to the extracellular matrix proteins of human colon cancer cells treated with troglitazone.

PURPOSE: In the present study, we investigated the effect of troglitazone, a selective ligand and agonist of PPAR-gamma, on the metastatic potential of human colon cancer cells. METHODS: High- and low-PPAR-gamma expression clones of the colon cancer cell line, HT29, namely clones 21 and 3 respectively, were used. We investigated the effect of troglitazone on the proliferation, on the adhesion to extracellular matrix proteins and on the synthesis of matrix metalloproteinases (MMPs) of colon cancer cells. RESULTS: Troglitazone inhibited the proliferation of both subclones, in a dose-dependent manner, and the inhibitory effect correlated with the level of PPAR-gamma expression. Troglitazone strongly inhibited the production of MMP-7, an enzyme associated with invasiveness of cancer cells, by both subclones. In addition, troglitazone caused a strong decrease in the adhesion of clone 21 to extracellular matrix (ECM) proteins, laminin and type IV collagen. This effect was independent of beta1-integrins expression CONCLUSION: In addition to inhibition of cancer cell growth, troglitazone had an inhibitory effect on two important events associated with the metastatic potential of cancer cells, production of MMPs and adhesion to ECM proteins. Consequently, troglitazone is a promising agent for the treatment and prevention of colon cancer metastasis.

Antineoplastic Agents↗