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PubMed2000

Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism.

There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.

Animals↗
PubMed1999

Troglitazone: a review of its use in the management of type 2 diabetes mellitus.

UNLABELLED: Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy. Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years' duration showed that glycaemic control is maintained with troglitazone on a long term basis. In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100,000. CONCLUSIONS: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity.

Adult↗
PubMed1999

Inhibition of LDL oxidation in vitro but not ex vivo by troglitazone.

Diabetic subjects are at increased risk for developing coronary artery disease, in part because of increased oxidation of LDL, which promotes atherogenesis. Troglitazone, a new antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia. Structurally, it contains a tocopherol moiety similar to vitamin E and has been shown to have antioxidant properties in vitro. Therefore, we evaluated whether troglitazone inhibited LDL oxidation both in vitro and in type 2 diabetic subjects ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'-azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at 1 micromol/l and 100% inhibition at 5-10 micromol/l troglitazone. The inhibition of LDL oxidation by troglitazone also was time dependent. In addition, troglitazone inhibited oxidation of 125I-labeled LDL and its subsequent uptake and degradation by macrophages. To determine whether troglitazone was incorporated into LDL particles or acted in the aqueous milieu, troglitazone was incubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation. After re-isolation, LDL that was incubated with troglitazone was no longer protected from oxidation, compared with probucol-treated LDL, which remained protected. Further, [14C]troglitazone did not get incorporated into LDL. This suggests that troglitazone exerts its antioxidant effect in the aqueous milieu of LDL. Consistent with this was the observation that the lag phases of copper-induced conjugated diene formation, a measure of the susceptibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 min, n = 9) to subjects not taking the drug (77 +/- 3 min, n = 11; NS). Thus, troglitazone may be of value as an aqueous-phase antioxidant in addition to its effect on glucose homeostasis.

Antioxidants↗
PubMed2000

The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures.

In primary human and porcine hepatocyte cultures, we investigated the relationship between metabolism and cytotoxicity of troglitazone. Treatment of human hepatocytes for 2 h with 10, 20, 25, 35, and 50 microM troglitazone in protein-free medium resulted in concentration-dependent decreases in total protein synthesis. Decreases at 10 and 20 microM were reversible by 24 h, however protein synthesis did not recover at concentrations >/=25 microM. Troglitazone at 50 microM caused cellular death. In porcine hepatocytes, 100 microM troglitazone was lethal, whereas at 50 microM, protein synthesis completely recovered by 24 h. Recovery in protein synthesis was associated with metabolism of parent drug, whereas toxicity correlated (r(2) = 0.82) with accumulation of unmetabolized troglitazone. By 1 h, in human hepatocytes, troglitazone was metabolized to similar amounts of sulfate and quinone metabolites with little glucuronide detected. In contrast, porcine hepatocytes metabolized troglitazone to the similar amounts of glucuronide and the quinone metabolites with little sulfate detected. Exposure of human hepatocytes to a combination of 10 microM troglitazone and 10 microM 2,4-dichloro-4-nitrophenol resulted in a 70% decrease in protein synthesis, associated with 90% inhibition in the formation of troglitazone sulfate, a 4-fold increase in unmetabolized troglitazone, and no effect on formation of the quinone metabolite. Treatment with a combination of acetaminophen or phenobarbital with 20 microM troglitazone resulted in sustained decrease in protein synthesis associated with inhibition of sulfation and accumulation of troglitazone. These results suggest that inhibition of troglitazone sulfation may result in increased hepatotoxicity due to exposure to parent drug, or increased metabolism by alternate pathways.

Acetaminophen↗
PubMed2005

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells.

AIMS/HYPOTHESIS: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor gamma receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. METHODS: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK alpha1/alpha2 siRNA. RESULTS: Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5- and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. CONCLUSIONS/INTERPRETATION: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.

AMP-Activated Protein Kinases↗
PubMed2003

Effects of troglitazone on intracellular cholesterol distribution and cholesterol-dependent cell functions in MA-10 Leydig tumor cells.

Troglitazone treatment of MA-10 Leydig tumor cells resulted in cellular cholesteryl esters decreasing and cell free cholesterol increasing. This was not an effect unique to this chemical entity; rosiglitazone and pioglitazone caused these changes also. The excess free cholesterol was recovered largely in the cholesterol oxidase susceptible, plasma membrane cholesterol pool. This effect of troglitazone probably is not mediated by activation of peroxisome proliferator activated receptors since it immediately reversed with washing and did not occur at all in cells treated with the peroxisome proliferator activated receptor agonist, 15-deoxy Delta 12,14 prostaglandin J-2. Plasma membrane cholesterol esterification was inhibited by troglitazone in a dose-dependent manner. Plasma membrane cholesterol esterification was inhibited half-maximally by 14 microM troglitazone and by more than 90% by 40 microM troglitazone. This effect was not unique for MA-10 cells. Similar results were found using fibroblasts. Troglitazone was not simply inhibiting internalization of plasma membrane cholesterol. Dibutyryl-cAMP stimulation of troglitazone-treated cells resulted in more progesterone synthesis than in stimulated control cells; moreover, radioactive plasma membrane cholesterol was readily converted into progesterone in troglitazone-treated cells. Studies of LDL uptake in troglitazone-treated cells indicated that intracellular membranes were cholesterol replete. Troglitazone inhibited plasma membrane cholesterol esterification with kinetics similar to 58-035, a known inhibitor of the acyl coenzyme A: cholesterol acyltranserase (ACAT) enzyme. It is not likely an ACAT inhibitor since troglitazone did not block incorporation of exogenous free fatty acids into cholesteryl esters. Thus, it appears that troglitazone prevented presentation of free fatty acid to the ACAT enzyme.

Cell Membrane↗
PubMed2002

Troglitazone inhibits growth and improves insulin signaling by suppression of angiotensin II action in vascular smooth muscle cells from spontaneously hypertensive rats.

Troglitazone, a thiazolizidinedione, has recently been reported to possess anti-arteriosclerotic properties. To evaluate mechanisms underlying the anti-arteriosclerotic effects of troglitazone, we examined the effect of troglitazone on growth, expression of growth factors, and insulin signaling in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) which produce angiotensin II (Ang II) in a homogeneous culture. Troglitazone inhibited basal and serum-stimulated DNA synthesis and inhibited increases in the number of VSMC from SHR and normotensive Wistar-Kyoto (WKY) rats. Its inhibition was greater in VSMC from SHR. Troglitazone abolished DNA synthesis in response to Ang II in VSMC from both rat strains and markedly inhibited DNA synthesis in response to epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-AA in VSMC from SHR. Troglitazone did not alter the expression of transforming growth factor (TGF)-beta1, PDGF A-chain, or basic fibroblast growth factor (bFGF) mRNAs in VSMC from WKY rats, but it markedly decreased expression of these growth factor mRNAs in VSMC from SHR. Troglitazone markedly decreased basal and Ang II-stimulated expression of extracellular signal-regulated kinase proteins in VSMC from both rat strains. Troglitazone abolished Ang II-induced suppression of phosphatidilinositol 3-kinase (PI3-kinase) activity, insulin receptor substrate-1 (IRS-1) associated tyrosine phosphorylation, and IRS-1 associated p85 levels in VSMC from WKY rats. Basal PI3-kinase activity, tyrosine phosphorylation of IRS-1, and IRS-1 associated p85 levels were lower in VSMC from SHR than in cells from WKY rats. Troglitazone significantly increased PI3-kinase activity, IRS-1 associated tyrosine phosphorylation, and IRS-1 associated p85 levels in VSMC from SHR. These results indicate that troglitazone produce its anti-arteriosclerotic effects through suppression of the action of growth-promoting factors including Ang II, and that troglitazone inhibits Ang II-induced suppression of insulin signaling in VSMC from SHR, suggesting that tissue Ang II may lead to insulin resistance and to arteriosclerosis in hypertension. Troglitazone may be useful in the treatment of insulin resistance as well as of hypertensive vascular diseases.

Angiotensin II↗
PubMed1998

Troglitazone, a new antidiabetic agent possessing radical scavenging ability, improved decreased skin blood flow in diabetic rats.

Troglitazone is a new class of antidiabetic agent possessing radical scavenging ability similar to vitamin E. Because of this ability, it is expected to improve decreased nutritive capillary blood flow in diabetes. In the present study, we investigated the effects of troglitazone on skin blood flow(SBF) in normal and streptozotocin(STZ)-induced diabetic rats. Effects of troglitazone on vasodilation, PGI2 and PGE2 production were also assessed in perfused hindlimb, isolated rat aorta rings and 3T6 fibroblasts, respectively. SBF at the base of the tail was decreased in STZ diabetic rats (2.1+/-0.2 ml/min/100 g) compared with normal rats (3.8+/-0.2 ml/min/100 g). This decrease of SBF was significantly improved (2.9+/-0.2 ml/min/100 g) by troglitazone treatment (approximately 220 mg/kg/day) for 7 days in STZ diabetic rats without alleviating hyperglycemia. Similar troglitazone treatment (approximately 160 mg/kg/day for 7 days) tended to increase SBF (approximately 30%) even in normal rats. In normal rats, subcutaneous administration of troglitazone (60 mg/kg) acutely increased SBF and, this increase was suppressed by 70% with pretreatment (10 mg/kg s.c.) of indomethacin, cyclooxygenase inhibitor, suggesting that troglitazone increases skin blood flow predominantly by increasing PGI2 and PGE2 production. In hindlimb perfusion under fixed flow rate, troglitazone infusion (20 microM) significantly decreased perfusion pressure by 13%, which reflects vasodilation of blood vessels. This decrease of perfusion pressure was inhibited by concomitant infusion of indomethacin but not N-monomethyl-L-arginine, inhibitor of nitric oxide synthase. In vitro studies, using isolated rat aorta rings, revealed that troglitazone (4.5 to 45 microM) increases PGI2 production by 31 and 70%, respectively. In 3T6 fibroblast (a component of skin tissue), troglitazone at a low dose of 0.3 microM increased PGI2 and PGE2 by 200% and 25%, respectively. Overall all, these results suggest that troglitazone increases nutritive SBF probably by virtue of its radical scavenging thus the resulting in an increase in PGI2 and PGE2 production in blood vessels and fibroblast. Troglitazone may alleviate impaired microcirculation in diabetic patients through these effects.

Animals↗
PubMed2000

Troglitazone prevents and reverses dexamethasone induced insulin resistance on glycogen synthesis in 3T3 adipocytes.

Troglitazone lowers blood glucose levels in Type II diabetic patients. To evaluate the insulin sensitizing action of troglitazone on glycogen synthesis we have used dexamethasone-treated 3T3 adipocytes as an in vitro model. Differentiated 3T3 adipocytes were incubated with 100 nM dexamethasone for 6 days. Troglitazone (1.0 microM) or metformin (1.0 mM) with or without 200 nM insulin was added during the last 4 days. At the end, insulin (100 nM) stimulated glycogen synthesis was determined using (14)C-glucose. Dexamethasone caused a 50% reduction in glycogen synthesis. Troglitazone caused an approximately 3 fold increase in glycogen synthesis from 43.9+/-3.4 to 120+/-16.2 nmols h(-1). Under identical conditions metformin had no significant effect. When cells were incubated with troglitazone and dexamethasone simultaneously for 6 days, troglitazone but not metformin completely prevented dexamethasone-induced insulin resistance. RU 486 (1.0 microM) also completely prevented the insulin resistance. Chronic incubation with dexamethasone and insulin resulted in a 73% reduction in glycogen synthesis. In these adipocytes, troglitazone was partially active with glycogen synthesis rising from 23.1+/-3.0 to 44.4+/-4.5 nmol h(-1), P<0.01 while metformin was inactive. Troglitazone stimulated 2-deoxyglucose uptake by 2 - 3 fold in dexamethasone-treated adipocytes. Metformin also increased glucose uptake significantly. Troglitazone did not affect insulin binding while a 2 fold increase was observed in normal adipocytes where it exhibited a modest effect. Since the effect of troglitazone was greater in dexamethasone-treated adipocytes, troglitazone is likely to act by preventing dexamethasone-induced alterations which may include (i) binding to glucocorticoid receptor and (ii) effect on glucose uptake. These data demonstrate the direct insulin sensitizing action of troglitazone on glycogen synthesis and suggest a pharmacological profile different from metformin.

3T3 Cells↗
PubMed2003

Troglitazone inhibits isolated cell proliferation, and induces apoptosis in isolated rat mesangial cells.

BACKGROUND/AIMS: Troglitazone is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria. There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function. We determined the effect of troglitazone on isolated rat mesangial cell proliferation. METHODS: We determined PPAR-gamma mRNA expression in isolated rat mesangial cells. Chronic effects of 10(-6) to 10(-4) mol/l troglitazone on mesangial cell proliferation and mitogen-activated protein (MAP) kinase activity were also determined. The effects of troglitazone on apoptosis were investigated in rat mesangial cells. RESULTS: Rat PPAR-gamma mRNA was detected in isolated rat mesangial cells. Living cell number, assessed by colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly decreased with 10(-4) mol/l troglitazone. The addition of 10(-6) to 10(-4) mol/l troglitazone dose-dependently inhibited 5-bromo-2'-deoxyuridine (BrdU) uptake into isolated rat mesangial cells. The addition of 10(-4) and 10(-5) mol/l troglitazone significantly reduced MAP kinase activity. Troglitazone at the concentrations of 10(-6) to 10(-4) mol/l dose-dependently increased DNA fragmentation rates, indicating that troglitazone may cause apoptosis in rat mesangial cells. Bax and Bcl-xL proteins were not changed, although Bcl-2 proteins increased with troglitazone. CONCLUSIONS: The present data demonstrated that troglitazone inhibits cell proliferation, and induces apoptosis in rat mesangial cells, raising a possibility that it directly affects renal function.

Animals↗
PubMed1999

Troglitazone inhibits voltage-dependent calcium currents in guinea pig cardiac myocytes.

BACKGROUND: It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca2+ currents were examined and compared with classic Ca2+ antagonists (verapamil and nifedipine). METHODS AND RESULTS: Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca2+ currents consisted of both T-type (ICa,T) and L-type (ICa,L) Ca2+ currents. Troglitazone effectively reduced the amplitude of ICa,L in a concentration-dependent manner. Troglitazone also suppressed ICa,T, but the effect of troglitazone on ICa,T was less potent than that on ICa,L. The current-voltage relationships for ICa,L and the reversal potential for ICa,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on ICa,L measured at a holding potential of -40 mV was 6.3 micromol/L, and 30 micromol/L troglitazone almost completely inhibited ICa,L. Troglitazone 10 micromol/L did not affect the time courses for inactivation of ICa,L and inhibited ICa,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced ICa,L. CONCLUSIONS: These results demonstrate that troglitazone inhibits voltage-dependent Ca2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca2+ overload and subsequent myocardial changes.

Animals↗
PubMed1999

Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells.

We investigated the effects of troglitazone on cytokine-stimulated nitric oxide (NO) production in cultured rat vascular smooth muscle cells (VSMC). The increase in NO formation caused by interleukin-1alpha (IL-1) was enhanced by troglitazone in a concentration-dependent manner. Bacterial lipopolysaccharide-stimulated NO synthesis was also increased by troglitazone. The combinations of IL-1, tumor necrosis factor-alpha, or lipopolysaccharide with interferon-gamma (IFN) were strong stimuli for induction of NO synthesis in VSMC, which were further potentiated by the presence of troglitazone. When troglitazone was added at increasing intervals after the stimulation of VSMC with IL-1, the enhancement in NO production decreased as the interval lengthened, suggesting that troglitazone alters NO synthase (NOS) expression by VSMC rather than having a direct affect on VSMC NOS activity. Troglitazone had no effect on IL-1-elicited or IL-1/IFN-elicited nuclear factor-kappaB activity in VSMC. Troglitazone inhibited the degradation of cytokine-induced NOS mRNA. Thus troglitazone appears to enhance IL-1-induced NOS mRNA levels by prolonging its half-life rather than activating its transcription, which is nuclear factor -kappaB-dependent. No expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) was detected in VSMC, and 15-deoxy-D12,14 prostaglandin J2, the natural ligand for the PPARgamma, did not resemble the effect of troglitazone on IL-1-induced NO synthesis. These results indicate that troglitazone upregulates cytokine-stimulated NO synthesis in VSMC through PPARgamma-independent mechanisms. Considering its inhibitory effects on the action of numerous growth factors on VSMC, the direct vascular effects of troglitazone shown in this study may have important implications for prevention of restenosis and possibly atherosclerosis.

Animals↗
PubMedDate not supplied

Troglitazone-induced heart and adipose tissue cell proliferation in mice.

Troglitazone, a thiazolidinedione, is a novel agent for the oral treatment of non-insulin-dependent (Type II) diabetes mellitus; it works by increasing cell sensitivity to available insulin. Previous studies have shown that rodents treated with high doses of troglitazone develop increased heart weight and increased interscapular brown fat. This study investigated cellular proliferation in heart and brown fat of troglitazone-treated mice as well as possible interactions with an angiotensin-converting enzyme inhibitor (quinipril). B6C3F1 female mice were treated daily with either vehicle control, 125 mg/kg quinipril, 1,200 mg/kg troglitazone, or troglitazone/quinipril combination per os for up to 14 days. Four days before necropsy, mice were dosed with bromodeoxyuridine (BrdU) using osmotic pumps. Cell proliferation in heart, brown fat, and retroperitoneal white fat was investigated by means of light microscopic anti-BrdU immunolabeling techniques. Immunoelectron microscopy was used to determine the cell phenotypes and cellular distribution of BrdU label in heart and brown fat. Treatment with troglitazone for 2 wk resulted in increased heart and brown fat weights but in decreased white fat weight. Combination treatment with troglitazone and quinipril also resulted in decreased white fat weight compared with controls. Histologically, brown fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had coalescent lipid vacuoles and increased eosinophilia of the cytoplasm. White fat adipocytes in troglitazone- and troglitazone/quinipril-treated mice had decreased cell size and increased cytoplasmic eosinophilia. BrdU labeling revealed increased cell proliferation in troglitazone-treated hearts after 1 wk but did not reveal increased cell proliferation in quinipril- or troglitazone/quinipril-treated animals. Brown fat BrdU labeling after 1 wk was increased in troglitazone- and troglitazone/quinipril-treated mice. Ultrastructural anti-BrdU immunogold labeling demonstrated that troglitazone-treated heart and brown fat had greater populations of BrdU-labeled cells that were identified as endothelial cells. These results demonstrated that troglitazone-induced increased cardiac weight in mice can be prevented by quinipril and that increased cardiac weight coincides with early increased endothelial cell proliferation.

Adipocytes↗
PubMed1998

Troglitazone upregulates LDL receptor activity in HepG2 cells.

The aim of this in vitro study was to investigate the effect of troglitazone, a new oral antidiabetic agent, on LDL catabolism. HepG2 cells, which are cells from a well-differentiated cell line of hepatoma cells, were cultured and used to study LDL catabolism. Different concentrations of troglitazone, all within the therapeutic range for humans, were incubated in culture medium with 125I-labeled LDL to measure cell-associated and degraded 125I-LDL. Troglitazone increased cell-associated and degraded 125I-LDL by approximately 30%. We also investigated if this effect occurred through a LDL receptor-mediated pathway or a non-LDL receptor pathway. By using dextran sulfate, a substance known to release bound LDL from its receptor, we found that troglitazone upregulated LDL receptor activity by approximately 35%. In addition, we found that troglitazone increased the expression of the LDL receptor mRNA. The effect of troglitazone was comparable with that of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, with troglitazone having an upregulatory effect similar to that of fluvastatin. Insulin within human physiological concentrations also increased LDL receptor activity. We found that troglitazone and insulin had an additive effect on LDL catabolism. Also, the effect of troglitazone on LDL catabolism was studied in the presence of cyclosporine, an immunosuppressant drug that reduces LDL catabolism mainly by decreasing LDL receptor activity. The results showed that troglitazone can compensate for the reduced LDL receptor activity induced by cyclosporine, but that cyclosporine had a residual effect on the action of troglitazone. Thus troglitazone enhanced LDL binding, cell association, and degradation by increasing LDL receptor mRNA expression, with a subsequent increase in LDL receptor activity.

Chromans↗
PubMed2002

Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin.

Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 +/- 11 years, BMI 31 +/- 6.1 kg/m(2)) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4-6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P = 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P = 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be established. However, the data suggest that glucocorticoids and thiazolidinediones exert fundamentally antagonistic effects on human metabolism in both adipose and muscle tissues. By preventing or reversing insulin resistance, troglitazone may prove to be a valuable therapeutic agent in the difficult clinical task of controlling diabetes in patients receiving glucocorticoids.

Adult↗
PubMed2005

Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program.

The Diabetes Prevention Program (DPP) was a randomized clinical trial of prevention of type 2 diabetes in high-risk people. Troglitazone, an insulin-sensitizing agent, was used initially but was discontinued during the trial. Troglitazone therapy was compared with other DPP interventions, considering both the short-term "in-trial" results and the longer-term results after troglitazone were discontinued. From 1996 to 1998, participants were randomly assigned to treatment with metformin (n = 587), troglitazone (n = 585), double placebo (n = 582), or intensive lifestyle intervention (ILS) (n = 589). Because of concern regarding its liver toxicity, the troglitazone arm was discontinued in June 1998, after which follow-up of all participants continued. During the mean 0.9 year (range 0.5-1.5 years) of troglitazone treatment, the diabetes incidence rate was 3.0 cases/100 person-years, compared with 12.0, 6.7, and 5.1 cases/100 person-years in the placebo, metformin, and ILS participants (P < 0.001, troglitazone vs. placebo; P = 0.02, troglitazone vs. metformin; P = 0.18, troglitazone vs. ILS). This effect of troglitazone was in part due to improved insulin sensitivity with maintenance of insulin secretion. During the 3 years after troglitazone withdrawal, the diabetes incidence rate was almost identical to that of the placebo group. Troglitazone, therefore, markedly reduced the incidence of diabetes during its limited period of use, but this action did not persist. Whether other thiazolidinedione drugs used for longer periods can safely prevent diabetes remains to be determined.

Chromans↗
PubMed2000

Long-term effects of troglitazone: open-label extension studies in type 2 diabetic patients.

OBJECTIVE: To determine the long-term effects of troglitazone as monotherapy or in combination with sulfonylureas or insulin regarding glycemic and lipid measures. RESEARCH DESIGN AND METHODS: Patients who completed one of three double-blind studies (a 6-month troglitazone monotherapy study, a 52-week study of troglitazone in combination with micronized glyburide, or a 6-month study of troglitazone in combination with insulin) were allowed to enter open-label extensions of their respective double-blind studies. Troglitazone dose titrations were allowed to a maximum of 600 mg in response to inadequate glycemic control during the open-label phases of troglitazone monotherapy or sulfonylurea combination therapy but not with insulin combination therapy. This article focuses on the effectiveness of the highest dose of troglitazone used in these studies (600 mg daily). Safety data from all patients studied at all doses are also presented. RESULTS: For patients who received a fixed dose of 600 mg troglitazone, mean changes in fasting serum glucose and HbA1c levels from baseline to the end of the open-label phase were -57 mg/dl and -0.4%, respectively (monotherapy); -49 mg/dl and -1.8%, respectively (sulfonylurea combination); and -31 mg/dl and -1.0%, respectively (insulin combination). The proportion of patients achieving an HbA1c level of < or =8% from the combined cohort of all three studies was 54% versus only 19% at baseline. The mean decrease in triglycerides from baseline to the end of the open-label phase was 18% among all patients in the three studies who received a fixed dose of 600 mg troglitazone. Troglitazone was well tolerated in these three open-label studies; a total of 758 patients completed a total exposure of 16,264 patient-months to troglitazone in these three studies with minimal adverse events. CONCLUSIONS: Long-term use of troglitazone alone or in combination with sulfonylureas or insulin is safe and effective in sustaining glycemic control and in reducing hypertriglyceridemia in type 2 diabetic patients.

Blood Glucose↗
PubMed2001

The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats.

We investigated whether lack of the canalicular multispecific organic anion transporter in transport-deficient (TR-) rats would result in plasma and urinary accumulation of troglitazone or its major metabolites and whether any accumulation would be associated with increased levels of bilirubin or bile acids. Administration of a single oral dose of troglitazone (200 mg/kg) to TR- rats resulted in 2- and 50-fold increases in plasma levels and 30- and 500-fold increases in urinary amounts of troglitazone sulfate and troglitazone glucuronide, respectively, compared with normal rats. No changes were found in the plasma concentrations and urinary amounts of troglitazone or troglitazone-quinone. Accumulation of troglitazone metabolites in plasma was accompanied by a 2-fold increase in the serum level of conjugated bilirubin in TR- rats, whereas no changes were observed in normal animals. Bile acids were detected in the urine of both TR- and normal rats, with an average 3-fold greater level found in the urine of TR- animals. Biliary metabolic profiles revealed a delay in the secretion of troglitazone sulfate and troglitazone glucuronide in TR- rats over the first 2- and 4-h periods, respectively. These results demonstrate the role of multidrug resistant associated protein-2 in biliary secretion of troglitazone glucuronide and troglitazone sulfate and suggest the presence of compensatory mechanisms responsible for transport of troglitazone metabolites and bilirubin-glucuronide at the basolateral and canalicular sites of hepatocytes.

Animals↗