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PubMed1997

Effect of troglitazone on blood insulin levels after pancreas transplantation with systemic venous drainage in rats.

BACKGROUND: Troglitazone is a new oral antidiabetic agent and has been reported to reduce insulin resistance and improve peripheral hyperinsulinemia in patients with noninsulin-dependent diabetes mellitus. To examine the effect of troglitazone on insulin regulation after pancreas transplantation with systemic venous drainage, we measured peripheral glucose and insulin levels and performed an intravenous glucose tolerance test. METHODS: We divided the rats into four groups: diabetic rats with a pancreas graft and administration of troglitazone at 40 mg/day orally (group P+T, n=4), rats with a pancreas graft only (group P, n=4), age-matched normal rats (group N, n=5), and diabetic rats (group DM, n=4). RESULTS: Fasting insulin levels in group P were relatively higher than those in group N, whereas the values in group P+T were normalized. In the intravenous glucose tolerance test, troglitazone clearly regulates sigma immunoreactive insulin levels of pancreas transplanted rats (P vs. P+T: 244+/-23 vs. 145+/-14 microU/ml, P<0.05). CONCLUSION: Hyperinsulinemia induced by systemic venous drainage, which may progress atherosclerosis, can be controlled with troglitazone treatment.

Animals↗
PubMed2004

Troglitazone inhibits cyclin D1 expression and cell cycling independently of PPARgamma in normal mouse skin keratinocytes.

Troglitazone is one of the thiazolidinedione (TZD) class of anti-diabetic drugs and a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma). Troglitazone and other PPARgamma ligands have been shown to inhibit cell proliferation and induce cell cycle arrest in a variety of cancer cells, and have been considered as potential tumor preventive and tumor therapeutic agents. Little is known, however, about how normal or initiated cells respond to these agents during mouse skin carcinogenesis. We report here that troglitazone and another TZD, ciglitazone, dramatically inhibited mitogen-induced cellular proliferation in normal mouse skin primary keratinocytes and in the C50 keratinocyte cell line. This was accompanied by induction of cell cycle G1 phase arrest and suppression of cyclin D1, cdk4, and cdk2 expression. Troglitazone suppressed cyclin D1 expression at multiple levels. In addition, we demonstrated that PPARgamma was not expressed at functional levels in cultured mouse skin keratinocytes, and that the inhibitory effects of troglitazone on cellular proliferation and cyclin D1 expression in these cells were PPARgamma-independent. Given the important role of keratinocyte proliferation in skin carcinogenesis, our data suggest that TZD may be useful tumor preventive agents in skin.

Animals↗
PubMed2001

Troglitazone, a ligand for peroxisome proliferator-activated receptor gamma, inhibits chemically-induced aberrant crypt foci in rats.

The biological roles of peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, have been highlighted recently. Although PPARgamma ligand is suspected to play an important role in carcinogenesis, its effects on colon tumorigenesis remain undetermined. The present time-course study was conducted to investigate possible modifying effects of a PPARgamma ligand, troglitazone, on the development and growth of aberrant crypt foci (ACF), putative precursor lesions for colon carcinoma, induced by azoxymethane (AOM) or dextran sodium sulfate (DSS) in male F344 rats. Oral troglitazone (10 or 30 mg / kg body weight (b.w.)) significantly reduced AOM (two weekly subcutaneous injections, 20 mg / kg b.w.)-induced ACF. Treatment with troglitazone increased apoptosis and decreased polyamine content and ornithine decarboxylase (ODC) activity in the colonic mucosa of rats treated with AOM. Gastric gavage of troglitazone also inhibited colitis and ACF induced by DSS (1% in drinking water), in conjunction with increased apoptosis and reduced colonic mucosal polyamine level and ODC activity. Our results suggest that troglitazone, a synthetic PPARgamma ligand, can inhibit the early stage of colon tumorigenesis with or without colitis.

Animals↗
PubMed2004

Beneficial effects of troglitazone on neutrophil dysfunction in multiple low-dose streptozotocin-induced diabetic mice.

Patients with poorly controlled diabetes are at high risk of acquiring bacterial infections. However, conflicting results have been reported on neutrophil function in diabetes. We periodically evaluated neutrophil dysfunction in multiple low-dose streptozotocin (STZ)-induced diabetic mice, and then evaluated the effects of troglitazone and other thiazolidinediones (TZDs) on the decline of neutrophil function. Zymosan was injected intraperitoneally and neutrophil infiltration and phagocytosis were evaluated. While phagocytosis of zymosan by peritoneal neutrophils was consistently reduced in diabetic mice, neutrophil infiltration was decreased on day 30, but increased on day 40 after STZ injection. The in vitro chemotactic and phagocytic activities of blood neutrophils in mice that did not receive zymosan were consistently reduced in diabetic mice. Phorbol myristate acetate (PMA)-stimulated superoxide production by zymosan-induced peritoneal neutrophils and the levels of zymosan-induced tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta in peritoneal exudate fluids were also reduced in the diabetic mice. Treatment of the diabetic mice with troglitazone beginning 2 weeks after STZ injection did not improve hyperglycaemia but did prevent the decline of zymosan-induced neutrophil infiltration on day 30, and additionally promoted the increased infiltration on day 40. Troglitazone also promoted the chemotactic activity of blood neutrophils isolated from normal mice in vitro. Rosiglitazone but not pioglitazone induced a similar effect. Neutrophil phagocytosis was not enhanced by troglitazone either in vivo or in vitro. Taken together, neutrophil function is impaired by STZ-induced diabetes, but inflammatory infiltration does not always vary with the chemotactic disability or cytokine levels. Furthermore, troglitazone and rosiglitazone were suggested to improve at least neutrophil chemotactic activity in these animals.

Animals↗
PubMed2002

Formation of a novel quinone epoxide metabolite of troglitazone with cytotoxicity to HepG2 cells.

Troglitazone, an oral antidiabetic drug, was reported to cause adverse hepatic effects in certain individuals, leading to its withdrawal from the market. After incubation of troglitazone (100 microM) with the human hepatoma cell line, HepG2 cells, and human primary hepatocytes for 48 to 72 h, an unknown peak was detected in the cell culture. The formation of this peak from troglitazone (100 microM) was also catalyzed by expressed CYP3A4, and further HPLC analysis revealed that there were three metabolites (metabolite A, B, and C) in the peak. The major metabolite, metabolite C (M-C) was identified as an epoxide of a quinone metabolite of troglitazone by comparison with a synthetic authentic standard using tandem mass spectrometry, (1)H NMR, and (13)C NMR analyses. The other two metabolites (M-A and M-B) were stereoisomers with the same molecular weight as M-C, probably produced from M-C by intramolecular rearrangement at the epoxide moiety. M-C showed a weak cytotoxicity in HepG2 cells at low concentrations, as assessed by the crystal violet-staining assay. Since epoxides are generally regarded as the chemically reactive species, M-C may play a role in idiosyncrasy of troglitazone hepatotoxicity via individual differences either in the formation or degradation of this metabolite.

Antineoplastic Agents↗
PubMed2003

Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells.

Plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherosclerosis in diabetic patients. PAI-1 is produced by endothelial cells stimulated with various inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF-alpha-induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF-alpha induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells (HUVECs). A specific inhibitor for p38 mitogen-activated protein kinase, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580), and a protein kinase C inhibitor, calphostin C, had no inhibitory effects on TNF-alpha-induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha-induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha-induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF-alpha-induced PAI-1 secretion, suggesting that both NF-kappaB-dependent and NF-kappaB-independent pathways are involved in TNF-alpha-induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK. Furthermore, we have shown that troglitazone inhibited both TNF-alpha-induced PAI-1 protein secretion and mRNA in HUVECs. Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF-alpha-induced PAI-1 secretion. These results indicate That ERK and NF-kappaB are possible targets of TNF-alpha and troglitazone in the regulation of PAI-1 production.

Blotting, Northern↗
PubMed2004

Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP channels and induce insulin secretion.

It is known that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic beta-cells, but the precise mechanisms are not clear. The effects of PPAR-alpha ligands on pancreatic beta-cells also remain unclear. We investigated the effects of PPAR-alpha ligands (fenofibrate and fenofibric acid), a PPAR-gamma ligand (troglitazone), and an endogenous ligand of PPAR-gamma [15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-Delta12,14-PGJ2)] on KATP channel activity in clonal hamster insulinoma cell line, HIT-T15 cells. As assessed by whole-cell patch clamp, fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 reduced the KATP channel currents, and inhibition continued after washout of these agents. The concentration-response curves of fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 showed half-maximal inhibition of KATP channel currents (IC50) at 3.26, 94, 2.1, and 7.3 micromol/l, respectively. Fenofibrate (> or = 10(-6) mol/l), 15-deoxy-Delta12,14-PGJ2 (> or = 5 x 10(-5) mol/l), and troglitazone (> or = 10(-6) mol/l) inhibited [3H]glibenclamide binding, but fenofibric acid did not. In addition, fenofibrate (> or = 10(-6) mol/l), fenofibric acid (10(-4) mol/l), troglitazone (10(-4) mol/l), and 15-deoxy-Delta12,14-PGJ2 (> or = 10(-5) mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR-alpha and -gamma ligands interact directly with the beta-cell membrane and stimulate insulin secretion.

Animals↗
PubMed2006

Troglitazone and 9cis,11trans,13trans-conjugated linolenic acid: comparison of their antiproliferative and apoptosis-inducing effects on different colon cancer cell lines.

BACKGROUND: We have previously reported that troglitazone, a synthetic ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), and bitter gourd seed oil rich in 9cis,11trans,13trans-conjugated linolenic acid (9c,11t,13t-CLN) prevent colon carcinogenesis. To evaluate the chemotherapeutic effect and potency of these compounds on colon cancer cells, we investigated their antiproliferative and apoptosis-inducing effects using different human colon cancer cell lines. METHODS: The antiproliferative and apoptosis-inducing effects of troglitazone and 9c,11t,13t-CLN were evaluated and compared using HT-29, DLD-1 and Caco-2 cells at different stages of enterocytic differentiation. RESULTS: Troglitazone and 9c,11t,13t-CLN decreased cell viability and induced apoptosis in three colon cancer cell lines. The susceptibility of HT-29, which expresses PPARgamma at high levels, to troglitazone and 9c,11t,13t-CLN was higher than that of Caco-2 cells with low levels of PPARgamma. CONCLUSION: Troglitazone and 9c,11t,13t-CLN exhibited more effective chemotherapeutic effects on HT-29 cells than on Caco-2 cells.

Antineoplastic Agents↗
PubMed2001

Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor expressed in all of the major cell types found in atherosclerotic lesions: monocytes/macrophages, endothelial cells, and smooth muscle cells. In vitro, PPARgamma ligands inhibit cell proliferation and migration, 2 processes critical for vascular lesion formation. In contrast to these putative antiatherogenic activities, PPARgamma has been shown in vitro to upregulate the CD36 scavenger receptor, which could promote foam cell formation. Thus, it is unclear what impact PPARgamma activation will have on the development and progression of atherosclerosis. This issue is important because thiazolidinediones, which are ligands for PPARgamma, have recently been approved for the treatment of type 2 diabetes, a state of accelerated atherosclerosis. We report herein that the PPARgamma ligand, troglitazone, inhibited lesion formation in male low density lipoprotein receptor-deficient mice fed either a high-fat diet, which also induces type 2 diabetes, or a high-fructose diet. Troglitazone decreased the accumulation of macrophages in intimal xanthomas, consistent with our in vitro observation that troglitazone and another thiazolidinedione, rosiglitazone, inhibited monocyte chemoattractant protein-1-directed transendothelial migration of monocytes. Although troglitazone had some beneficial effects on metabolic risk factors (in particular, a reduction of insulin levels in the diabetic model), none of the systemic cardiovascular risk factors was consistently improved in either model. These observations suggest that the inhibition of early atherosclerotic lesion formation by troglitazone may result, at least in part, from direct effects of PPARgamma activation in the artery wall.

Animals↗
PubMed2006

PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP-2.

Cholesterol synthesis in animal cells is regulated by sterol regulatory element-binding protein (SREBP)-2. The objective of this study was to investigate whether activation of peroxisome proliferator-activatedreceptor (PPAR)-gamma influences the SREBP-2 dependent cholesterol synthesis in liver and intestinal cells. Therefore, HepG2 and Caco-2 cells were incubated with and without 10 or 30 microM of troglitazone, a synthetic PPAR gamma agonist, for 4 hrs. Incubation with 10 or 30 microM of troglitazone caused a significant, dose-dependent reduction of cholesterol synthesis in both HepG2 and Caco-2 cells (P < 0.05). HepG2 and Caco-2 cells incubated with 10 or 30 microM of troglitazone had also lower mRNA concentrations and lower nuclear protein concentrations of SREBP-2 than untreated control cells (P < 0.05). mRNA concentrations of the SREBP-2 target genes HMG-CoA reductase and LDL receptor were also reduced in HepG2 and Caco-2 cells treated with 30 microM of troglitazone compared to control cells (P < 0.05). In conclusion, this study shows that PPAR gamma activation by troglitazone lowers the cholesterol synthesis in HepG2 and Caco-2 cells by reducing the concentration of nuclear SREBP-2 and successive downregulation of its target genes involved in cholesterol synthesis.

Blotting, Western↗
PubMed2000

Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pronounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-gamma activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-gamma in the liver.

Adipose Tissue↗
PubMed1998

Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes.

There is increasing evidence that insulin resistance may be causally related to atherosclerosis. The measurement of common carotid arterial intimal and medial complex thickness (IMT) by B-mode ultrasound technique has been recognized as a powerful and non-invasive method to evaluate early atherosclerotic lesions. We investigated the effect of treatment with troglitazone, an insulin sensitizer, on IMT in a total of 135 Japanese subjects with type 2 diabetes. Troglitazone (400 mg daily) was administered for 6 months in 57 patients. Compared to control group (n = 78), the group given troglitazone showed a significant decrease in IMT as early as 3 months after the administration (IMT change: -0.080[SE 0.016] mm vs. control 0.027[SE 0.007] mm, P < 0.001). The decrease in IMT was also found after 6 months, although further decrease was not observed. Both HbA1c and postprandial serum triglycerides were decreased after troglitazone, but there was no statistically significant relation between a decrease in IMT and those in HbA1c or postprandial triglycerides. These findings indicate that troglitazone has a potent inhibitory effect on progression of early atherosclerotic lesions probably through the decreased insulin resistance in type 2 diabetes.

Carotid Arteries↗
PubMed2000

Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells.

Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated. Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone (P = 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen activator was unaffected. The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).

Aorta↗
PubMed2000

Leptin production in adipocytes from morbidly obese subjects: stimulation by dexamethasone, inhibition with troglitazone, and influence of gender.

This study examined the regulation of leptin production by dexamethasone and troglitazone. Subcutaneous and omental adipose tissue was obtained during bariatric surgical procedures (30 women and 16 men; body mass index, 52.5 +/- 1.7 kg/m2, age, 39 +/- 2 yr), and adipocytes were cultured in suspension. Subcutaneous adipocytes from females released significantly more leptin than did omental cells from the same subject (P < 0.05), but basal leptin release was not different in adipocytes from these depots in males. Dexamethasone (0.1 micromol/L) significantly increased leptin release within 24 h from sc (135 +/- 13% of control) and omental (227 +/- 53%) adipocytes of females, but not males. Dexamethasone-stimulated leptin production at 48 h was significantly greater in the omental adipocytes of females (398 +/- 64% of control) than in sc adipocytes of females (207 +/- 21%) or the omental (211 +/- 33%) and sc (180 +/- 23%) adipocytes of males. Troglitazone (10 micromol/L; 48 h) significantly inhibited dexamethasone-stimulated leptin release in sc (57 +/- 10.7% inhibition) and omental adipocytes (134 +/- 26% inhibition). There was no gender-related difference in the effect of troglitazone to inhibit dexamethasone-stimulated leptin release. Troglitazone significantly inhibited basal leptin production from omental adipocytes by 15.0 +/- 5.2%. The effect of dexamethasone and troglitazone to regulate leptin release was mediated through changes in ob gene expression, but did not involve changes in glucose uptake or metabolism to lactate. The data suggest that adipocytes from females are more responsive to the stimulatory effect of dexamethasone in vitro than are adipocytes from males. If adipocytes from females are more responsive to relevant in vivo stimuli for leptin secretion such as insulin or glucose, this could contribute to the gender difference in serum leptin. The data also suggest that leptin release from omental adipocytes may be more responsive to hormonal and nutrient regulation in vivo than are sc adipocytes.

Adipocytes↗
PubMed2001

Troglitazone amplifies counterregulatory responses to hypoglycemia in nondiabetic subjects.

As insulin sensitizers, thiazolidinediones could affect the hormonal counterregulatory response to hypoglycemia via the modulatory effect of insulin on counterregulation. In addition, recent studies suggest that thiazolidinediones may influence key steps in glucose sensing and glucoregulatory hormone secretion. We therefore evaluated the effects of a short course of troglitazone on counterregulatory hormones in response to mild hypoglycemia in eight lean nondiabetic subjects. Subjects received either troglitazone (400 mg/day) or placebo for 7 days before stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/L target plasma glucose steps, 50 min each). The glycemic thresholds for secretion of epinephrine (3.77 +/- 0.05 mmol/L) and glucagon (3.83 +/- 0.11 mmol/L) were reset to a higher plasma glucose concentration after troglitazone [4.05 +/- 0.05 mmol/L (P = 0.003) and 4.10 +/- 0.05 mmol/L (P = 0.03), respectively]. In addition, the magnitude of the rise in epinephrine and glucagon concentrations was higher with troglitazone (28% and 11%, respectively; P < 0.05 for both), whereas plasma norepinephrine, GH, and cortisol were comparable in both sets of studies. Endogenous glucose production, measured with [3-(3)H]glucose, rose by 33% (P < 0.05) in the troglitazone studies compared with 17% (P = NS) after placebo. We conclude that thiazolidinediones may induce an amplification of the counterregulatory response to hypoglycemia characterized by a shift in the glycemic threshold for and an increase in the magnitude of glucagon and epinephrine secretion, and subsequent activation of glucose production.

Adult↗
PubMed2002

Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone.

The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71%. The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC(0-24) values were 27 to 102 micrograms.hr/ml of troglitazone, 401 to 2060 micrograms.hr/ml of its sulfate conjugate, and 34 to 312 micrograms.hr/ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.

Administration, Oral↗
PubMed1997

Troglitazone.

Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.

Animals↗
PubMed1994

Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts.

Troglitazone (CS045), a compound belonging to the thiazolidine diones, is being tested as a new oral antidiabetic agent. Evidence exists from animal studies and clinical trials with non-insulin-dependent diabetes mellitus patients that Troglitazone might reduce insulin resistance. The molecular mechanism of this effect is not understood. In this study, we investigated whether Troglitazone might interfere with the mechanism of glucose-induced insulin resistance. Several studies indicate that hyperglycemia reduces the kinase activity of the insulin receptor in different cell types. This effect is paralleled by translocation of several protein kinase C (PKC) isoforms, and it can be prevented by PKC inhibitors, which suggests that glucose-induced receptor desensitization is mediated by activation of PKC. We studied the effect of hyperglycemia on the insulin receptor kinase activity and its modulation by Troglitazone in rat-1 fibroblasts that stably overexpress the human insulin receptor. Before stimulation with insulin (10(-7) M), cells were acutely exposed to hyperglycemic conditions in the absence or presence of Troglitazone (0.01-2 micrograms/ml). The insulin receptor was solubilized from a plasma membrane fraction or whole cell lysates, and proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted against antiphosphotyrosine and anti-insulin receptor beta-subunit (CT 104) antibodies. Acute hyperglycemia (25 mM glucose) induced a significant inhibition of the insulin receptor kinase (IRK) activity within 30 min (inhibition to 30 +/- 12.5% of maximal insulin-stimulated beta-subunit phosphorylation, n = 9, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗