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PubMed2004

Decrease in serum C-reactive protein levels by troglitazone is associated with pretreatment insulin resistance, but independent of its effect on glycemia, in type 2 diabetic subjects.

Insulin-sensitizing thiazolidinediones (TZDs) decrease inflammatory markers such as high-sensitive C-reactive protein (hsCRP) in sera in addition to their hypoglycemic effects. However, factors associated with the decrease in serum hsCRP concentrations are unclear. In the present study, an effect of troglitazone on serum hsCRP levels was investigated and compared with its effect on glycemia. A total of 34 subjects with type 2 diabetes (17 men and 17 women, aged 54+/-2 years and body mass index (BMI) 26.7+/-0.6 kg/m(2), mean+/-S.E.) were studied. Nineteen out of the 34 subjects was treated with troglitazone 400mg daily for 12 weeks. The remaining 15 subjects were treated with metformin 750 mg daily as a control group. Baseline hsCRP levels were comparable between the two groups, and those were positively associated with fasting insulin levels. After treatment, glycemic control assessed by HbA1c and fasting glucose levels improved in both groups, whereas insulin sensitivity index estimated by homeostasis model assessment (HOMA-R) decreased only in the troglitazone-treated group. Serum levels of hsCRP significantly decreased from 916+/-210 ng/ml to 569+/-123 ng/ml (P<0.05) in the troglitazone-treated group, whereas the levels remained unchanged in the metformin-treated group (from 1087+/-248 ng/ml to 1152+/-301 ng/ml). In the troglitazone-treated group, there was no difference in the absolute and percent change in serum hsCRP levels between responders, who displayed the decrease in HbA1c greater than 0.6% (n=12), and the remaining non-responders (n=7). The decrease in serum hsCRP concentrations was negatively related to baseline levels of serum hsCRP and insulin and HOMA-R. In conclusion, troglitazone, but not metformin, reduced serum hsCRP levels in type 2 diabetic patients. The decrease in serum hsCRP concentrations by troglitazone was associated with the pretreatment levels of hsCRP and insulin resistance, but independent of the changes in glycemia.

Blood Glucose↗
PubMed2004

Attenuation by 4-aminopyridine of delayed vasorelaxation by troglitazone.

Troglitazone and other thiazolidinediones (TZDs) are thought to relax arterial smooth muscle by directly inhibiting calcium channels in smooth muscle cell membranes. However, until recently such inhibition was only examined acutely, ie, within only seconds or minutes after administration of these agents to arterial smooth muscle preparations. Recently, a novel experiment was reported in which troglitazone caused a 2-phase relaxation of perfused resistance arteries, namely, an acute relaxation (within the first 20 minutes of treatment), which was blocked by a nonselective calcium channel blocker and a delayed relaxation (after 2 hours), which was not. We sought to determine if any of the 4 major potassium (K) channels in vascular smooth muscle play a role in the delayed relaxation. We incubated vascular contractile rings prepared from ventral tail arteries of rats with physiological buffer containing either 0 or 4 micromol/L troglitazone for 3 hours (4 micromol/L is typical of plasma levels from diabetic patients). Different K channel inhibitors (1 mmol/L 4-aminopyridine [4AP]; 1 mmol/L tetraethylammonium [TEA]; 5 micromol/L glyburide; 20 micromol/L barium) were coadministered with each level of troglitazone in additional preparations. Then these arterial rings were contracted with either norepinephrine (NE), arginine vasopressin (AVP), or high-K buffer. All contractions were significantly relaxed by troglitazone (P <.05). Only 4AP significantly attenuated troglitazone's relaxation of NE and AVP contractions (P <.05), though not high-K-induced contractions. TEA, glyburide, and barium had no such influence. Thus, for both adrenergic (NE) and nonadrenergic (AVP) contractions, the delayed arterial vasorelaxation by troglitazone may be mediated at least in part by activation of 4AP-sensitive K channels. Furthermore, the specific subtype of the channels involved is most likely those bound in the outer cell membrane where their effectiveness in terms of mediating relaxation would depend on an intact transmembrane K ion gradient.

4-Aminopyridine↗
PubMed1998

Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse.

Troglitazone has recently been introduced in the treatment of Type 2 diabetes. In addition to its anti-diabetic effects it acts as a perixosome proliferator activated receptor-gamma (PPAR-gamma) agonist and has anti-inflammatory properties by inhibiting macrophage tumour necrosis factor-alpha (TNF-alpha) secretion. It also inhibits the production of endothelial selectin (e-selectin). Troglitazone also reduces interleukin-1alpha induced nitric oxide production in pancreatic beta-cells, which may be relevant in preventing nitric oxide mediated damage to these cells in the Type 1 diabetes process. We tested troglitazone in the spontaneous model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, to determine its effect on the disease process. When administered by gavage from weaning at a dose of 400 mg/kg body weight (n = 32), troglitazone reduced the incidence of diabetes by 16 weeks compared to controls (n = 32) in a pattern that was maintained up to the conclusion of the experiment at 31 weeks of age (p < 0.05). Insulitis was unaltered (index = 1.05 +/- 0.71 vs. 1.13 +/- 0.82, treated vs. controls, p = 0.78). The study was repeated using troglitazone in the diet of NOD mice (n = 24) to give a dose of approximately 200 mg/kg body weight in order to provide a more consistent level of troglitazone during the time course of the experiment. There was a reduction of diabetes incidence in this group but it did not reach significance. Insulin levels were reduced in gavage treated mice although such reduction did not reach significance (p < 0.07). We conclude that, in view of its effect on this model of autoimmune diabetes and because of its known function as an insulin sensitiser, troglitazone might be considered for potential use in those patients with Type 1 masquerading as Type 2 diabetes.

Age Factors↗
PubMed1999

Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes.

Insulin-sensitizing thiazolidinediones such as troglitazone and pioglitazone have been shown to lower blood pressure in vivo and cause vasorelaxation in vitro. Rosiglitazone (BRL 49653) is a novel thiazolidinedione which has been reported not to cause vasoleraxation. We therefore compared the effects of troglitazone and rosiglitazone on Ca2+ and K+ currents in rat aorta and pulmonary artery smooth muscle cells. Currents were recorded with the conventional whole cell patch clamp technique. Both drugs reduced the voltage-gated (L-type) Ca2+ current in rat aorta cells, with half-maximal current inhibition by troglitazone and rosiglitazone at 2 and 10 microM, respectively. Troglitazone, 2 microM and rosiglitazone, 20 microM caused a similar hyperpolarizing shift of 12 mV in the potential-dependence of Ca2+ current availability. Troglitazone (20 microM) produced a marked block of the tetraethylammonium- and paxilline-sensitive Ca2+ activated K+ current, while rosiglitazone (20 microM and 60 microM) slightly enhanced this current. Rat pulmonary artery smooth muscle cells have a prominent delayed rectifier K+ current. Troglitazone produced a potent block of this current (half-maximal inhibition at <1 microM), while rosiglitazone caused a smaller inhibition at 10 and 60 microM. These results show that troglitazone has relatively potent blocking effects on a wide variety of ion currents in vascular smooth muscle cells. Rosiglitazone exerts less potent, but similar effects on the Ca2+ current and delayed rectifier K+ current, but it enhances the Ca2+ activated K+ current. reserved.

Animals↗
PubMed1999

Troglitazone inhibits alpha1-adrenoceptor-induced DNA synthesis in vascular smooth muscle cells.

While vascular smooth muscle cell proliferation is important in hypertension, relatively little is known about the contribution of catecholamines. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit angiotensin II-, basic fibroblast growth factor (FGF)-induced growth of vascular smooth muscle cells. We hypothesize that these agents might also inhibit the effect of the stimulation of alpha1-adrenoreceptors on the proliferation of vascular smooth muscle cells. Troglitazone (1-20 microM), a member of the thiazolidinediones, significantly inhibited the stimulation of alpha1-adrenoreceptor-induced DNA synthesis, c-fos induction and mitogen-activated protein (MAP)-kinase activation. This effect was associated with inhibition by troglitazone of the transactivation of the serum response element (SRE), which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via blockade of the upstream of MAP kinase activation in vascular smooth muscle cells. At this dose, troglitazone inhibited the ternary complex factor (TCF)-dependent activation, which is regulated by MAP kinase activation, but did not inhibit the TCF-independent SRE activation. Besides, the degree of the inhibitory effect of troglitazone on MAP kinase activation, DNA synthesis, c-fos expression differs. This may show that troglitazone work on multiple sites. These results suggest that troglitazone is a potent inhibitor of vascular smooth muscle cells proliferation through the downregulation of c-fos expression and may be a useful agent for prevention of atherosclerosis which is a result of hypertension.

Animals↗
PubMed2000

Troglitazone does not initiate hypertrophy but can sensitise cardiomyocytes to growth effects of serum.

Chronic administration of troglitazone might predispose to cardiac hypertrophy. The aims of the study were to determine if troglitazone could (i) initiate a trophic response directly in ventricular cardiomyocytes and (ii) modify responses to other trophic stimuli. After 24 h, troglitazone (10 nM-10 microM) (i) did not increase cellular protein mass and decreased incorporation of [14C]phenylalanine, a marker of protein synthesis, (ii) interacted with serum (10% v/v) and insulin-like growth factor-1 (10 nM) to produce small trophic responses, (iii) increased cellular protein mass but not protein synthesis with insulin (1 unit/ml). Troglitazone (1 microM) attenuated responses to phorbol-12-myristate-13-acetate (PMA) (100 nM), and noradrenaline (5 microM) and endothelin-1 (100 nM), which also activate protein kinase C. In summary, troglitazone does not initiate cardiomyocyte growth directly in vitro, and can inhibit protein kinase C-mediated growth mechanisms. However, the interaction of troglitazone with serum growth factors may contribute modestly to the development of hypertrophy. As troglitazone produced a moderate hypertrophic effect per se in re-differentiated cardiomyocytes, it may directly increase the severity of established hypertrophy.

Animals↗
PubMed1999

Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome.

OBJECTIVE: To investigate the effect of troglitazone, a new antidiabetic agent that improves insulin resistance, on endocrine, metabolic, and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome (PCOS). DESIGN: Prospective clinical study. SETTING: Infertility outpatient clinic, Niigata University Hospital, Niigata, Japan. PATIENT(S): Thirteen women with PCOS and insulin resistance. INTERVENTION(S): Troglitazone (400 mg/d) was administered for 12 weeks. MAIN OUTCOME MEASURE(S): Insulin and other hormone (gonadotropins, androgens) levels; various parameters relating to glucose and lipid metabolism before, during, and after troglitazone administration; and ovulation rate. RESULT(S): The mean (+/-SD) fasting insulin concentration was significantly reduced, from 18.3+/-8.9 to 10.5+/-7.1 microU/mL. The LH level was reduced from 9.7+/-3.4 to 4.8+/-3.9 mIU/mL and the testosterone level was reduced from 0.9+/-0.5 to 0.5+/-0.3 ng/mL in accordance. Atherosclerotic lipid levels also were normalized. Before troglitazone administration, the ovulation rate during clomiphene citrate therapy was 34.9% per cycle (15/43). This increased significantly to 72.7% (8/11) during troglitazone coadministration. Further, an ovulation rate of 42.3% (11/26) was achieved with troglitazone alone. CONCLUSION(S): In women with PCOS and insulin resistance, the reduction of hyperinsulinemia that is produced by troglitazone improves the hyperandrogenism that characterizes PCOS, restoring ovulation.

Adult↗
PubMed1999

Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice.

Recent investigations suggest that cytotoxic cytokines such as tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta or free radicals play an essential role in destruction of pancreatic beta cells in Type 1 diabetes and that, therefore, anti-oxidant or anti-TNF alpha and IL-1beta therapy could prevent the development of Type I diabetes. Troglitazone belongs to a novel class of antidiabetic agent possessing the ability to enhance insulin action provably through activating PPAR gamma and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the development of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)-injected mice. In addition, effects of troglitazone on cytokine-induced pancreatic beta cell damage were examined in vitro. Type 1 diabetes was induced by MLDSTZ injection to DBA/2 mice (40 mg/kg/day for 5 days). Troglitazone was administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from the start of or immediately after STZ injection. MLDSTZ injection elevated plasma glucose to 615 +/- 8 mg/dl 4 weeks after final STZ injection and was accompanied by infiltration of leukocytes to pancreatic islets (insulitis). Troglitazone treatment with MLDSTZ injection prevented hyperglycemia (230 +/- 30 mg/dl) and, suppressed insulitis and TNF alpha production from intraperitoneal exudate cells. TNF alpha (10 pg/ml) and IL-1beta (1 pg/ml) addition to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0.03 to approximately 3 microM) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that troglitazone prevents the development of Type 1 diabetes in the MLDSTZ model by suppressing insulitis associated with decreasing TNF alpha production from intraperitoneal exudate cells and the subsequent TNF alpha and IL-1beta-induced beta cell damage.

Animals↗
PubMed2000

Troglitazone enhances glycolysis and improves intracellular glucose metabolism in rat mesangial cells.

To clarify the action of the new antidiabetic agent, troglitazone, on rat mesangial cells, we assessed its effect on the uptake and intracellular metabolism of glucose. Troglitazone increased the uptake of 2-deoxyglucose (2DOG) in a dose-dependent manner with an upregulation of glucose transporter 1 (GLUT1) mRNA, whereas it had no effect on the uptake of alpha-methyl glucoside (AMG). This troglitazone-induced glucose uptake was not suppressed by phlorizin. In 5 mmol/L glucose, 2 microg/mL (4.5 micromol/L) troglitazone increased glucose consumption 2.9-fold, similar to that in 20 mmol/L glucose. Troglitazone increased the production of pyruvate and lactate as a consequence of the increase in glycolysis, but did not increase the cellular ATP content. Troglitazone improved the high-glucose-induced accumulation of intracellular sorbitol and fructose and elevation of the cellular redox potential. These data suggest that troglitazone enhances glucose uptake through GLUT1 with an acceleration of glycolysis, and improves the abnormal intracellular glucose metabolism under high-glucose conditions in rat mesangial cells.

Adenosine Triphosphate↗
PubMed1998

Effects of troglitazone on hepatic and peripheral insulin resistance induced by growth hormone excess in rats.

It is well known that short-term growth hormone (GH) administration in humans and animals induces insulin resistance and glucose intolerance. The purpose of the present study was to clarify whether troglitazone, a new insulin-sensitizing drug of the thiazolidinedione class, counteracts the insulin antagonistic effects of recombinant human (rh) GH on glucose metabolism in rats. Male Wistar rats weighing 184 to 226 g were treated either with rhGH (n = 8) or rhGH plus troglitazone (n = 8). rhGH (20 IU/kg body weight/d) was given by subcutaneous injection twice daily for 2 days. Troglitazone was given at 100 mg/kg/d orally for 5 days before and 2 days during rhGH. Saline was injected to the control rats (n = 7). Euglycemic clamp studies with an insulin infusion rate of 8 mU/kg/min were performed in these rats after an overnight fast. Hepatic glucose output (HGO), glucose infusion rate (GIR), and glucose disappearance rate (GDR) were measured. Fasting levels of plasma glucose (6.6 +/- 0.1, 6.1 +/- 0.3, 6.5 +/- 0.2 mmol/L), insulin (187.5 +/- 24.1, 206.4 +/- 24.1, 182.3 +/- 31.0 pmol/L), and serum free fatty acid (FFA) (1.58 +/- 0.18, 1.43 +/- 0.16, 1.61 +/- 0.25 mEq/L) were comparable among rats treated with rhGH, rhGH plus troglitazone, and controls, respectively. Basal HGO was also comparable among the three treatment groups. HGO was suppressed significantly during the hyperinsulinemic glucose clamp in control rats, but not in rhGH rats. When troglitazone was coadministered with rhGH, suppressibility of HGO during the glucose clamp was comparable to that of controls. GIR (13.5 +/- 4.5 v 24.1 +/- 4.1 mg/kg/min) and GDR (18.1 +/- 5.8 v 30.3 +/- 5.2 mg/kg/min) were decreased by rhGH treatment compared with control values. They returned to normal levels in rats treated with both rhGH and troglitazone (GIR, 22.4 +/- 5.9; GDR, 24.7 +/- 7.1). From these results, it is evident that rhGH treatment impaired insulin's ability to suppress HGO and stimulate peripheral glucose utilization. Troglitazone could block the insulin antagonistic effects of GH on hepatic glucose output and peripheral glucose utilization.

Administration, Oral↗
PubMed1999

Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats.

Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by either potentiating or mimicking insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of glucosamine on insulin action that may play an important role in hyperglycemia-induced insulin resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp was performed during the last 120 minutes. Pretreatment with troglitazone or D-chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic insulin resistance. In contrast, HGO failed to increase during glucosamine infusion in rats pretreated with troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic insulin resistance. D-Chiroinositol pretreatment had no effect on the glucosamine-induced increase in HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR, indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats, glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D-chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol, partially blocked the glucosamine-induced hepatic insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to hexosamine-induced peripheral insulin resistance.

Animals↗
PubMed2000

Inhibitory effect of troglitazone on TNF-alpha-induced expression of monocyte chemoattractant protein-1 (MCP-1) in human endothelial cells.

Insulin resistance is one of the risk factors for the progression of atherosclerosis. Recently, the new oral insulin-sensitizing drug troglitazone is thought to offer potential in the treatment of diabetes. If adopted for such use, this drug might be helpful in protecting against the development of atherosclerosis and microvascular complications via its improvement of insulin resistance. However, it has not yet been clarified whether troglitazone acts directly on the vascular cells and inhibits the progression of atherosclerosis. Meanwhile, Monocyte chemoattractant protein-1 (MCP-1) is known to play an important role in the pathogenesis of atherosclerosis by inducing monocyte migration. Therefore, we investigated the effect of troglitazone on the expression of MCP-1 in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with or without troglitazone (1 or 10 microM) in the presence or absence of various concentrations of tumor necrosis factor-alpha (TNF-alpha) (5, 50 or 500 ng/ml), and then the amounts of MCP-1 secreted from the HUVECs were measured. We found that TNF-alpha increased the secretions of MCP-1 119-fold vs. control, and that troglitazone significantly inhibited this TNF-alpha-induced increase in MCP-1 secretions (19.4%). Moreover, Northern blot analysis revealed that troglitazone decreased the MCP-1 mRNA level in HUVECs. Our present studies indicated that troglitazone may prevent the progression of atherosclerosis by inhibiting MCP-1 expression in endothelial cells.

Cells, Cultured↗
PubMed2001

Serum leptin level as an indicator to predict the clinical efficacy of troglitazone in patients with type 2 diabetes mellitus.

Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.

Biomarkers↗
PubMedDate not supplied

Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus.

The objective of this study was to determine if treatment of non-insulin-dependent diabetes mellitus (NIDDM) patients with the "insulin sensitizer" troglitazone, both as monotherapy and in combination with insulin, corrects the impaired fibrinolysis and activated coagulation associated with NIDDM. Patients participating in two clinical trials comparing troglitazone and placebo in patients with NIDDM were studied at the time of randomization and after 26 weeks of treatment. Eighteen patients were treated with troglitazone (ten in combination with insulin and eight as monotherapy) and eight were treated with placebo (four in each trial). Plasma concentrations of plasminogen activator inhibitor (PAI-1), prothrombin fragment F1+2, fibrinogen, and von Willebrand Factor (vWF) activity were measured. Plasma PAI-1 concentrations fell significantly from a mean of 68.8 +/- 32.3 ng/mL to 40.4 +/- 20.4 in the troglitazone treated group, but did not change significantly in the placebo treated group. Plasma PAI-1 concentrations were elevated in 15 patients treated with troglitazone and fell to normal in eight of them. There was no significant change in plasma F1+2, vWF, and fibrinogen, but plasma C-peptide and triglyceride concentrations fell significantly with troglitazone. This study demonstrates that troglitazone treatment is associated with a significant fall in plasma PAI-1 antigen concentrations in patients with NIDDM and, therefore, may have a beneficial effect on fibrinolysis.

Adult↗
PubMed2000

Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group.

The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.

Chromans↗
PubMed1997

Acute non-insulin-like stimulation of rat muscle glucose metabolism by troglitazone in vitro.

1. The direct short-term effects of troglitazone on parameters of glucose metabolism were investigated in rat soleus muscle strips. 2. In muscle strips from Sprague-Dawley rats, troglitazone (3.25 micromol l(-1)) increased basal and insulin-stimulated glucose transport by 24% and 41%, respectively (P<0.01 each). 3. In the presence of 5 nmol l(-1) insulin, stimulation of glucose transport by 3.25 micromol l(-1) troglitazone was accompanied by a 36% decrease in glycogen synthesis, while glycolysis was increased (112% increase in lactate production) suggesting a catabolic response of intracellular glucose handling. 4. Whereas insulin retained its stimulant effect on [3H]-2-deoxy-glucose transport in hypoxia-stimulated muscle (by 44%; c.p.m. mg(-1) h(-1): 852+/-77 vs 1229+/-75, P<0.01), 3.25 micromol l(-1) troglitazone failed to increase glucose transport under hypoxic conditions (789+/-40 vs 815+/-28, NS) suggesting that hypoxia and troglitazone address a similar, non-insulin-like mechanism. 5. No differences between troglitazone and hypoxia were identified in respective interactions with insulin. 6. Troglitazone acutely stimulated muscle glucose metabolism in a hypoxia/contraction-like manner, but it remains to be elucidated whether this contributes to the long-term antidiabetic and insulin enhancing potential in vivo or is to be regarded as an independent pharmacological effect.

Animals↗
PubMed2000

Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells.

1. The effect of troglitazone, an anti-diabetic drug with insulin-sensitizing action, on antigen-induced production of leukotriene (LT) B(4), C(4) and E(4) and prostaglandin D(2) (PGD(2)) was examined in dinitrophenol (DNP)-specific immunoglobulin E (IgE)-sensitized RBL-2H3 mast cells following stimulation by the antigen, DNP-conjugated human serum albumin. Levels of LTB(4), C(4) and E(4) and PGD(2) in the conditioned medium were enzyme-immunoassayed. 2. Troglitazone inhibited the antigen-induced production of LTB(4), C(4) and E(4) and the potency of the inhibition was comparable to that of zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX) and a clinically used anti-asthmatic drug. Neither troglitazone nor zileuton affected antigen-induced production of PGD(2), arachidonic acid release from membrane phospholipids and degranulation. 3. Troglitazone inhibited LTB(4) production by the supernatant fraction of RBL-2H3 cell lysate with similar potency to zileuton, suggesting that troglitazone inhibits LT production by direct inhibition of 5-LOX activity. 4. Furthermore, it was shown that troglitazone as well as zileuton inhibited LTB(4) production in A23187-stimulated rat peritoneal neutrophils. 5. These findings suggest that troglitazone inhibits antigen-induced LT production in the IgE-sensitized RBL-2H3 cells and A23187-stimulated rat peritoneal neutrophils by direct inhibition of 5-LOX activity.

Animals↗
PubMed2003

Differences in troglitazone action on glucose metabolism in freshly isolated vs long-term incubated rat skeletal muscle.

1. Exposure of isolated skeletal muscle to troglitazone has resulted in inconsistent findings ranging from inhibition to stimulation of fuel oxidation and the glycogenic pathway. To better understand such variation in outcome, the present study used isolated rat soleus muscle strips to examine the interdependent influences of prolonged maintenance in vitro and of troglitazone exposure. 2. If freshly isolated muscle strips were exposed to troglitazone (1 micro mol l(-1)) for 24 h, glucose oxidation was markedly reduced (-26+/-1%, P<0.0001), whereas glycogen synthesis remained unaffected (+9+/-7%, n.s.). 3. In contrast, extended exposure to troglitazone for 72 h increased both glucose oxidation (+65+/-28%, P<0.05) and glycogen synthesis (+46+/-11%, P<0.005), and a similar stimulatory effect was also observed in muscles exposed to troglitazone only during the last 24 h of their 72 h preincubation period (glucose oxidation: +61+/-15%, P<0.001; glycogen synthesis: +43+/-15%, P<0.01). 4. Troglitazone thus stimulated glucose utilization in long-term incubated muscle independent of the duration of exposure (24 or 72 h), whereas it inhibited glucose utilization in freshly isolated muscle. 5. The observed differences in troglitazone action on freshly isolated vs long-term incubated muscle suggest that findings on muscle tissue subject to prolonged maintenance in vitro cannot be extrapolated to native muscle in vivo.

Animals↗