Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoprotein cholesterol (LDL-C), has been reported to impair nitric oxide production and endothelium-dependent vasorelaxation. The effects of troglitazone (CAS 97322-87-7), which is an antidiabetic agent with antioxidant properties, on serum levels of lysoPC and nitrite/nitrate (NOx) have been studied. Eight patients with Type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM) were studied (age: 61.5 +/- 2.8 years; diabetes duration: 10.2 +/- 1.6 years). They were additionally given troglitazone (200 mg once daily) since their fasting plasma glucose (FPG) and HbA1c levels had been increased in spite of conventional medications. Before and after 12 weeks of treatment with troglitazone their blood pressure, FPG, HbA1c, lipid profiles and NOx were measured. Troglitazone treatment had a slight depressor effect (decreasing the blood pressure from 133 +/- 5/72 +/- 3 to 127 +/- 4/68 +/- 1 mmHg; p < 0.05). FPG and HbA1c were significantly decreased with the therapy (181 +/- 10 to 160 +/- 10 mg/dl; p < 0.05 and 9.1 +/- 0.6 to 8.1 +/- 0.5%; p < 0.05, respectively). In contrast, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL-C were maintained within normal limits throughout the study. Although lysoPC and NOx levels were not altered, a negative correlation between lysoPC and NOx levels was observed. These results suggest that troglitazone is a beneficial agent improving FPG and HbA1c levels in NIDDM patients, while its effects on serum lysoPC and NOx levels, at least for 12 weeks, seem to be minimal.
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PMID:Effect of troglitazone on endothelial function in type 2 diabetic patients. 1183 72

Troglitazone, rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) class - antidiabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. All three agents are believed to mediate their effects via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma). Despite this common mechanism of action, they all have unique chemical structures and receptor-binding affinities, and consequently, in addition to the class effects (probably mediated through PPAR gamma), each TZD has a unique safety profile. Side effects have been categorized as unique to individual TZDs, or common to the class of drug. Of the unique effects, the best characterized is hepatotoxicity, which has been associated specifically with troglitazone to date. Studies with rosiglitazone and pioglitazone indicate that hepatotoxicity is not a class effect. Further differences in the safety profiles of these agents arise because the oxidative metabolism for each agent occurs by distinct cytochrome pathways: troglitazone and pioglitazone involve CYP 3A4 and CYP 2C8 whereas rosiglitazone is principally metabolized by CYP 2C8. CYP 3A4 is involved in the metabolism of over 150 drugs, hence the potential for drug interactions with troglitazone and pioglitazone is much greater than with rosiglitazone. Class effects include edema, slight reductions in hemoglobin and hematocrit (due to hemodilution), weight gain and alterations in plasma lipid profiles. This article considers safety data obtained from both clinical trials and clinical practice as a means of differentiating among troglitazone, rosiglitazone and pioglitazone.
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PMID:Differentiating members of the thiazolidinedione class: a focus on safety. 1192 35

Polycystic ovary syndrome (PCOS) is a common disorder. Its prevalence is 5 to 10% in women of reproductive age. PCOS is associated with hyperinsulinism and insulin resistance. The pathophysiological situations has lead many authors to study the action of insulin-sensitizing agents on menses, ovulation rate, and pregnancy in patients with PCOS. Metformin (a member of the biguanide family), is used for treatment of type II diabetes mellitus in obese patients. Although metformin restores cyclic pituitary- gonadal function and improves fertility, it can decrease levels of androgen and LH and increase levels of SHBG in women with PCOS. Trooglitazone (a member of the thiazolidinedione family) has been withdrawn from use because of its liver toxicity. Troglitazone improves ovulation and hisrsutism in women with PCOS without change in body mass index. Other similar drugs with less liver toxicity may be useful for the treatment of PCOS. D-chiro-inositol is a mediator of insulin action and improves ovulatory cycles. Most of the studies reported have not been randomized but the results appear to be quite promising. These drugs may provide a substantial advance in the treatment of women with polycystic ovary syndrome.
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PMID:[Polycystic ovary syndrome: treatment with insulin-sensitizing agents]. 1193 80

Troglitazone has been shown to improve peripheral insulin resistance in type 2 diabetic patients and animal models. We examined the effect of troglitazone on the expression of glucose transporter 4 (GLUT4) in muscle and adipose tissue from Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of obese type 2 diabetes mellitus. In addition, the effects of troglitazone on GLUT4 translocation and on glucose transport activity in adipocytes were also evaluated. Muscle and adipose tissues were isolated from 35-week-old male troglitazone-treated and untreated OLETF rats at a dose of 150 mg/kg per day for 14 days. In skeletal muscle, the protein and mRNA levels of GLUT4 were not significantly different between OLETF and control rats and they were not affected by troglitazone. On the other hand, GLUT4 protein and mRNA levels in adipose tissue from OLETF rats were significantly decreased (P<0.01) compared with control rats and they were significantly increased (1.5-fold, P<0.01) by troglitazone. Troglitazone had no major effect on GLUT4 translocation in adipocytes, but it significantly increased (1.4-fold, P<0.05) the basal and insulin-induced amounts of GLUT4 in plasma membrane (PM) in adipocytes from OLETF rats. Consistent with these results, the basal and insulin-induced glucose uptakes in adipocytes from troglitazone-treated OLETF rats were significantly increased (1.5-fold, P<0.05) compared with untreated OLETF rats. Our results suggest that troglitazone may exert beneficial effects on insulin resistance by increasing the expression of GLUT4 in adipose tissue.
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PMID:Troglitazone improves GLUT4 expression in adipose tissue in an animal model of obese type 2 diabetes mellitus. 1194 63

Troglitazone (T) and d-chiroinositol (DCI) have been reported to improve insulin resistance associated with obesity and NIDDM. We tested whether these compounds counteract the insulin antagonistic effects of recombinant human GH. Male Wistar rats were allocated to 4 different treatment groups, rhGH (n=8), rhGH+T (n=7), rhGH+DCI (n=8) and control (saline, n=8). rhGH (2 IU/100 g/day) was injected sc twice daily for 2 days. T and DCI were given (20 mg/day) po for 5 days preceding and 2 days along with rhGH. Euglycemic hyperinsulinemic clamp studies were done to assess the hepatic glucose output (HGO) and glucose disappearance rate (GDR). Fasting plasma glucose, insulin, serum FFA and basal HGO were similar in all 4 treatment groups. During the hyperinsulinemic clamp which raised plasma insulin levels to 7.2 +/- 0.4 ng/ml, HGO was suppressed in the control and rhGH+T treated rats but not in the rats treated with rhGH and rhGH+DCI. GDR decreased in the rats which received rhGH (18.1 +/- 5.8 vs 30.3 +/- 5.2 mg/kg/min) compared to the control rats. The rats given either T (24.7 +/- 2.7) or DCI (31.4 +/- 2.7) along with rhGH showed comparable GDR to the control rats. These results indicated that rhGH induced hepatic and peripheral insulin resistance. Troglitazone counteracted the insulin-antagonistic action of rhGH both in the liver and the peripheral tissues. DCI was effective in offsetting peripheral insulin resistance but without any effect on hepatic insulin resistance associated with rhGH treatment.
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PMID:Pharmacological treatments for GH-induced insulin resistance. 1205 20

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.
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PMID:Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. 1206 33

Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and gamma-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.
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PMID:Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone. 1214 28

Troglitazone (TGZ) is an antidiabetic agent of the thiazolidinedione (TZD) class that potentiates insulin action. In addition to its effects on insulin action, TGZ has an antiproliferative effect on vascular smooth muscle cells (VSMCs), of which proliferation is a prominent feature of retenosis after balloon injury, as well as atherosclerosis. Therefore, we investigated the effects of TGZ on intimal formation and blood flow after balloon injury in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats to see whether the decrease in insulin resistance could minimize VSMC proliferation and could maintain blood flow. OLETF rats, an animal model of type 2 diabetes, develop spontaneous hyperglycemia after the age of 24 weeks. Balloon injury was applied to the left common carotid arteries of the rats with a 2F Fogarty catheter. Two weeks after the balloon injury, blood flow velocity was measured with Doppler ultrasonography, and histomorphometric analyses of the common carotid arteries were performed. The neointimal formation caused by VSMC proliferation was inhibited by TGZ treatment by as much as 80% (0.197 +/- 0.013 mm(2) v 0.157 +/- 0.011 mm(2), P <.05). The ratio of neointimal to medial area also decreased by 22% with TGZ treatment (1.651 +/- 0.148 v 1.292 +/- 0.083, P <.05). These effects of TGZ in OLETF rats were accompanied by alterations in plasma insulin, triglyceride, and total cholesterol levels. To look into the relationship between VSMC proliferation and hyperinsulinemia, we used a [(3)H]-thymidine incorporation assay to investigate the effects of TGZ on VSMC proliferation. Insulin (at a concentration of 17.3 nmol/L) significantly stimulated DNA synthesis (236.6% +/- 7.4%, P <.001), and TGZ significantly inhibited the insulin-induced DNA synthesis in VSMCs (106.43% +/- 4.23%, P <.001) in a dose-dependent manner. In balloon-injured arteries of the untreated group, systolic blood flow velocity decreased by 61% compared with uninjured arteries (P <.05). However, there was no significant difference in systolic blood flow velocity between injured and uninjured arteries in the treated group (0.906 +/- 0.043 v 0.991 +/- 0.066 meters per second [m/s], P = not significant [NS]). The systolic blood flow of injured arteries was improved by 143% in the treated group (P <.01). These data suggest that TGZ is a potent inhibitor of VSMC proliferation both in vivo and in vitro through a direct effect on VSMCs, and that TZDs might be very useful in the treatment and prevention of restenosis after balloon injury.
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PMID:Troglitazone improves blood flow by inhibiting neointimal formation after balloon injury in Otsuka Long-Evans Tokushima fatty rats. 1214 72

Prior to the introduction of troglitazone, it had been more than 30 years since the last significant improvement in antidiabetic therapy. In view of the pressing need for more effective oral agents for the treatment of Type 2 diabetes mellitus, troglitazone was granted priority review by the FDA and was launched in the USA in 1997. The first of the thiazolidinedione insulin sensitizing agents, troglitazone was quickly followed by rosiglitazone and pioglitazone. The glitazones proved to be effective not only in lowering blood glucose, but also to have beneficial effects on cardiovascular risk. Troglitazone was subsequently withdrawn because of concerns about hepatotoxicity, which appears to be less of a problem with rosiglitazone and pioglitazone. Recent insights into the molecular mechanism of action of the glitazones, which are ligands for the peroxisome proliferator-activated receptors, open the prospect of designing more effective, selective and safer antidiabetic agents. This document will review the history of troglitazone from discovery through clinical development.
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PMID:Troglitazone: the discovery and development of a novel therapy for the treatment of Type 2 diabetes mellitus. 1239

Pioglitazone is the second thiazolidine derivative used clinically in the type 2 diabetes mellitus (DM). In the prediabetic stage, hyperinsulinemia or insulin resistance has been suggested to be closely associated with the oxidative stress. The first thiazolidine derivative used to treat DM, troglitazone, is chemically related to alpha-tocopherol, a known antioxidant. Troglitazone prevents tissue damage, but has been reported to produce hepatotoxicity. Pioglitazone strongly increases insulin sensitivity, improves glucose and lipid metabolism and showed no evidence of hepatotoxicity. The mechanism of the antidiabetic action of pioglitazone involves activation of insulin receptors and/or high affinity for peroxisome proliferator-activated receptor gamma (PPARgamma). Hydroxylation of the phenyl and pyridine rings in the chemical structure of pioglitazone may facilitate the scavenging of hydroxyl radicals. The direct antioxidant effect of pioglitazone may contribute to its effect on insulin resistance. The hypoglycemic and hypolipidemic effects of pioglitazone are likely to reduce the expression of TNFalpha. The reduction in the oxidative stress may lead to the suppression of TGFbeta and of collagen accumulation. A decrease in collagen content is likely to improve left ventricular diastolic function and distensibility of the aortic wall. Reduction in the oxidative stress may prevent the proliferation of vascular smooth muscle cells and contribute to the decrease in the aortic wall stiffness.
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PMID:Pioglitazone: cardiovascular effects in prediabetic patients. 1248 Dec 3


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