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PubMed2001

Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-gamma-mediated changes in gene expression.

Thiazolidinediones (TZDs) are believed to induce insulin sensitization by modulating gene expression via agonistic stimulation of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We have shown earlier that the TZD troglitazone inhibits mitochondrial fuel oxidation in isolated rat skeletal muscle. In the present study, rat soleus muscle strips were exposed to TZDs to examine whether the inhibition of fuel oxidation is mediated by PPAR-gamma activation. Our findings consistently indicated direct, acute, and PPAR-gamma-independent TZD action on skeletal muscle fuel metabolism. Rapid stimulation of lactate release by 20 micromol/l troglitazone within 30 min suggested that direct TZD action on skeletal muscle in vitro does not rely on changes in gene expression rates (12.6 +/- 0.6 [control] vs. 16.0 +/- 0.8 micromol. g(-1). h(-1) [troglitazone]; P < 0.01). This conclusion was supported by the failure of actinomycin D and cycloheximide to block the effects of troglitazone. Mitochondrial fuel oxidation was consistently inhibited by six different TZDs (percent inhibition of CO(2) production from palmitate after 25 h: troglitazone, -61 +/- 2%; pioglitazone, -43 +/- 7%; rosiglitazone, -22 +/- 6%; BM13.1258, -47 +/- 9%; BM15.2054, -51 +/- 4%; and T-174, -59 +/- 4% [P < 0.005 each]), but not by PPAR-gamma agonistic compounds not belonging to the TZD class (JTT-501, -5 +/- 7% [NS]; prostaglandin J(2), 17 +/- 7% [P < 0.05]), which further argues against dependence on PPAR-gamma activation. In summary, our findings provided good evidence that direct inhibition of mitochondrial fuel oxidation in isolated skeletal muscle is a group-specific effect of TZDs and is independent of PPAR-gamma-mediated gene expression.

Animals↗
PubMedDate not supplied

The emerging role of thiazolidinediones in the treatment of diabetes-mellitus and related disorders.

Type II diabetes is a polygenic disorder, characterized in most cases by early onset of resistance to the action of insulin. Insulin sensitizers belonging to the thiazolidinedione class offer the first therapeutic option specifically targeting the underlying insulin resistance. Troglitazone is the prototype drug of this class and has been approved for marketing in several countries. Troglitazone offers several benefits over traditional oral hypoglycemic agents such as sulfonylureas and the biguanide metformin. Most of these advantages are related to better control of glycemic parameters with troglitazone alone or when added to existing treatment. In addition, it has interesting lipid lowering activity that may be of potential benefit in reducing morbidity from cardiovascular disease among diabetics. However, troglitazone may not be the ideal insulin sensitizer since 20-30% of diabetics do not respond to it. Also, it produces liver toxicity in 2% of patients, necessitating withdrawal of the drug. A number of second generation insulin sensitizers, belonging to the same chemical class as troglitazone, are in clinical development. The role of insulin sensitizers in the management of diabetes and other diseases in which insulin resistance is an underlying feature, is likely to undergo evolution as more information is obtained from clinical studies.

Animals↗
PubMed1999

[Insulin-sensitizing agent].

Troglitazone is a new oral insulin-sensitizing agent from the thiazolidinedione group of compounds that has been developed in Japan Thiazolidinediones improve the insulin sensitivity at muscle, adipose tissue and liver. The overall effectiveness of troglitazone seems to be less potent than is usually seen with sulfonylureas, however, there are good responders to troglitazone, in which sulfonylurea had failed to improve glycemia. It is frequently very effective for those who are very obese and show hyperinsulinemia. Recent reports demonstrate the good therapeutic power of troglitazone in combination with a sulfonylurea or metformin, or insulin. In future, a possibility that reduction of insulin resistance by troglitazone reduce cardiovascular risk will be discussed. Unfortunately, wider use has led to recognition of potential for serious liver damage. Until now, the mechanisms of the liver toxicity has not been known. We have to monitor GOT, GPT and LDH levels as recommended.

Chromans↗
PubMed1998

Pharmacological and pharmacokinetic studies of the newly synthesized thiazolidinedione derivative 5-(4-(1-phenyl-1-cyclopropanecarbonylamino)benzyl)-thiazolidine-2 ,4-dio ne.

DN-108 (5-(4-(1-phenyl-1-cyclopropanecarbonylamino)benzyl)thiazolidine-2, 4-dione, CAS 195604-21-8) is a newly synthesized thiazolidinedione derivative. Pharmacological and pharmacokinetic studies of DN-108 were done. In diabetic animal models KKAy and db/db mice, DN-108, orally given at doses of 3-30 mg/kg for 10 consecutive days, improved hyperglycemia, hypertriglyceridemia or hyperinsulinemia from day 1 or day 4 and the effects were almost maintained through the experiment. In KKAy mice, DN-108, orally given at doses of 3-30 mg/kg for 4 consecutive days, potently decreased serum glucose level as compared with troglitazone (CAS 97322-87-7) and the ED25 values of DN-108 and troglitazone were 7 and 283 mg/kg/day, respectively. DN-108 increased 2-deoxyglucose uptake in L6 muscle cell line to the same extent as troglitazone. Moreover, DN-108 inhibited aldose reductase activity in vitro as potently as troglitazone did. Pharmacokinetic parameters, Cmax and AUC of DN-108 after oral administration in rats were higher than those of troglitazone. These results suggest that DN-108 has antidiabetic effect with tissue sensitization for glucose uptake and high absorption after oral administration. It is expected that DN-108 will be a promising oral antidiabetic agent.

Aldehyde Reductase↗
PubMed2000

Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor-alpha exert synergistic antiproliferative effects on human coronary artery smooth muscle cells.

In human coronary artery vascular smooth muscle (hcaVSM) cells, the mechanisms that mediate the antiproliferative effects of ligands for the peroxisome proliferator-activated receptor-gamma (PPAR gamma) and the retinoid X receptor-alpha (RXR alpha) are unclear. Dimerization of PPAR gamma with RXR alpha and occupancy by both ligands is required for maximal activation. Accordingly, we determined whether the antiproliferative activity of the PPAR gamma ligands, troglitazone or 15-deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2), was enhanced with the RXR alpha ligand, 9-cis-retinoic acid (9-cis-RA). Incubation of actively proliferating hcaVSM cells with either troglitazone or 15d-PGJ2 resulted in a dose-dependent inhibition of proliferation with half-maximal inhibitory concentrations (IC(50)s) of 13 and 2 microM, respectively. Quiescent cells incubated with troglitazone or 15d-PGJ2 and subsequently stimulated with PDGF-BB showed a concentration-dependent decrease in the active form of MAP kinase, suggesting that inhibition of cell growth by troglitazone may involve the MAP kinase pathway, an important growth activation pathway in VSM cells. Incubation of cells with either 0.1 or 1.0 microM 9-cis-RA inhibited cell growth to a similar degree. Addition of troglitazone or 15d-PGJ2 to cells in combination with either concentration of 9-cis-RA resulted in a striking increase in growth inhibition, and was accompanied by an approximately 4-fold reduction in the IC(50)s for both PPAR gamma ligands. These findings imply that RXR alpha activation by 9-cis-RA synergistically enhanced inhibition of hcaVSM cell growth. The precise nature of this cooperative interaction between PPAR gamma and RXR alpha remains to be determined.

Cell Division↗
PubMed2001

Expression and characterization of recombinant rat Acyl-CoA synthetases 1, 4, and 5. Selective inhibition by triacsin C and thiazolidinediones.

Inhibition by triacsins and troglitazone of long chain fatty acid incorporation into cellular lipids suggests the existence of inhibitor-sensitive and -resistant acyl-CoA synthetases (ACS, EC ) that are linked to specific metabolic pathways. In order to test this hypothesis, we cloned and purified rat ACS1, ACS4, and ACS5, the isoforms present in liver and fat cells, expressed the isoforms as ACS-Flag fusion proteins in Escherichia coli, and purified them by Flag affinity chromatography. The Flag epitope at the C terminus did not alter the kinetic properties of the enzyme. Purified ACS1-, 4-, and 5-Flag isoforms differed in their apparent K(m) values for ATP, thermolability, pH optima, requirement for Triton X-100, and sensitivity to N-ethylmaleimide and phenylglyoxal. The ACS inhibitor triacsin C strongly inhibited ACS1 and ACS4, but not ACS5. The thiazolidinedione (TZD) insulin-sensitizing drugs and peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, troglitazone, rosiglitazone, and pioglitazone, strongly and specifically inhibited only ACS4, with an IC(50) of less than 1.5 microm. Troglitazone exhibited a mixed type inhibition of ACS4. alpha-Tocopherol, whose ring structure forms the non-TZD portion of troglitazone, did not inhibit ACS4, indicating that the thiazolidine-2,4-dione moiety is the critical component for inhibition. A non-TZD PPARgamma ligand, GW1929, which is 7-fold more potent than rosiglitazone, inhibited ACS1 and ACS4 poorly with an IC(50) of greater than 50 microm, more than 100-fold higher than was required for rosiglitazone, thereby demonstrating the specificity of TZD inhibition. Further, the PPARalpha ligands, clofibrate and GW4647, and various xenobiotic carboxylic acids known to be incorporated into complex lipids had no effect on ACS1, -4, or -5. These results, together with previous data showing that triacsin C and troglitazone strongly inhibit triacylglycerol synthesis compared with other metabolic pathways, suggest that ACS1 and ACS4 catalyze the synthesis of acyl-CoAs used for triacylglycerol synthesis and that lack of inhibition of a metabolic pathway by triacsin C does not prove lack of acyl-CoA involvement. The results further suggest the possibility that the insulin-sensitizing effects of the thiazolidinedione drugs might be achieved, in part, through direct interaction with ACS4 in a PPARgamma-independent manner.

3T3 Cells↗
PubMed2001

Thiazolidinediones and liver toxicity.

Thiazolidinediones or glitazones specifically target insulin resistance. They have proven efficacy for reducing plasma glucose levels of type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. In addition, they may be associated to some improvement of cardiovascular risk profile. However, troglitazone, the first compound approved by the FDA in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy on blood glucose control of type 2 diabetic patients as compared to troglitazone. In controlled clinical trials, the incidence of significant increases in liver enzyme levels (ALT) was similar with rosiglitazone or pioglitazone as compared to placebo, whereas troglitazone was associated with a threefold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only two cases of severe reversible liver failure have been reported in patients treated with rosiglitazone, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. While regular monitoring of liver enzymes is still recommended and more long-term data are desirable, current clinical evidence supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.

Blood Glucose↗
PubMed2004

[Ovarian insulin resistance and insulin sensitizer effect on polycystic ovary syndrome].

OBJECTIVE: To explore the molecular defects of insulin signalling in polycystic ovary and in vitro effects of troglitazone, one of the insulin sensitizers-thiazolidinediones on polycystic ovary syndrome (PCOS). METHOD: The metabolic and mitogenic effects of insulin and insulin-like growth factor 1 (IGF-1) were examined in cultured human ovarian luteinizing granulosa cells from PCOS (n = 11) and normally ovulatory (as control, n = 33) women with vehicle or troglitazone (1 microg/ml). RESULTS: Basal rates were similar, but there were significant decreases in insulin-stimulated glucose incorporation into glycogen in PCOS cells, a metabolic action of insulin. However, IGF-1 response was found to be about twice greater in PCOS cells at all experimental concentrations with respect to thymidine incorporation compared to control cells, a mitogenic action. Troglitazone increased 2-3 fold the insulin-induced glycogen synthesis, but reduced the IGF-1 augmented responses of DNA synthesis in PCOS cells to within the range of control granulosa cells. As compared with control, PCOS granulosa cells had higher insulin receptor substrate 1 (IRS -1) expression, but lower IRS-2 expression. IRS-2 protein levels were increased and IRS-1 levels were reduced by troglitazone treatment, with a greater extent in the former. CONCLUSIONS: There is a selective defect in insulin actions in PCOS granulosa cells, suggesting ovarian insulin resistance and this metabolic phenotype is associated with an enhanced IGF-1 mitogenic potential. Troglitazone could divergently alter signal protein expressions and thus insulin actions, as an ovarian insulin sensitizer and mitogen/steroidogenic inhibitor in PCOS.

Adult↗
PubMed1998

[The thiazolidinones--a new therapeutic agent for type 2 diabetes].

Both, impaired beta-cell function and insulin resistance, predominantly of the skeletal muscle, are considered to be the key factors in the pathogenesis of type-2 diabetes (non-insulin-dependent diabetes; NIDDM). In the early stage of the disease, impaired insulin-mediated glucose disposal is accompanied by increased insulin secretion and hyperinsulinaemia. The thiazolidinediones (e.g. troglitazone), by improving insulin sensitivity of target tissues, appear to be a novel pathophysiologically interesting approach for the treatment of patients with NIDDM or impaired glucose tolerance. Troglitazone mainly elicits the following actions: Enhancement of insulin-mediated glucose disposal in patients with insulin resistance, impaired glucose tolerance and NIDDM, reduction of hyperglycaemia (blood glucose; HbA1c) and concomitant hyperinsulinaemia, improvement of dyslipidaemia in NIDDM. These actions are attained with monotherapy (200-600 mg once daily; plasma concentrations 0.3-3.0 micrograms/ml) or, with increased effects, when troglitazone is added to previously insufficient treatment with sulfonylureas or insulin. Potentially therapeutic actions with clinical relevance include (a) improvement of insulin resistance-associated hyperglycaemia-independent states of dyslipidaemia, (b) inhibition of LDL-oxidation and (c) amelioration of function and/or protection of beta-cells, an effect indicating to a beneficial modulation of the second pathogenetic relevant factor of NIDDM. Troglitazone appears to be well tolerated by the majority of patients. Post-marketing reports of partly severe liver injury including deaths from liver failure among Japanese and U.S. patients taking troglitazone require a critical evaluation of the benefit to risk ratio of the drug and a careful monitoring of the patients.

Animals↗
PubMed2006

Effects of eicosapentaenoic acid (EPA) on adiponectin gene expression and secretion in primary cultured rat adipocytes.

Adiponectin, a hormone produced by adipocytes, is involved in glucose metabolism and insulin sensitivity. The production of this adipokine is impaired in obesity and insulin resistance. Eicosapentaenoic acid (EPA) is a dietary n-3 polyunsaturated fatty acid that improves insulin sensitivity in several models of obesity and diabetes, which has been suggested to be related to adiponectin induction. An increase in adiponectin production has been also associated with an up-regulation of the transcriptional factor PPARgamma. The aim of this trial was to evaluate the direct effects of EPA on adiponectin gene expression and protein secretion in isolated rat adipocytes as well as to explore the potential mechanisms involved. A comparative study with troglitazone, a PPARgamma agonist, was also performed. For these purposes, primary rat adipocytes were cultured with EPA (100 and 200 microM) and with troglitazone (10 microM) for 96 hours. Both EPA and troglitazone improved glucose utilization by adipocytes. As expected, troglitazone enhanced adiponectin secretion and increased PPARgamma gene expression. However, EPA significantly decreased adiponectin gene expression and protein secretion and reduced PPARy mRNA levels, suggesting that the inhibition of adiponectin by EPA is likely to be secondary to the down-regulation of this adipogenic transcription factor. Moreover, these results suggest that other mechanisms different from the direct stimulation of adiponectin by the fatty acid are underlying the insulin-sensitizing properties observed after EPA treatment in vivo.

Adipocytes↗
PubMed1995

Regulation of glucose transport in cultured muscle cells by novel hypoglycemic agents.

The antidiabetic agent troglitazone (CS-045) and a metabolite designated M3 have potent blood glucose-lowering actions. The mechanism of the hypoglycemic effects of troglitazone and M3 was investigated in cultured L6 muscle cells. Short-term (2-hour) exposure of fully differentiated myotubes to troglitazone had no effect on glucose transport activity; M3 exposure caused a modest (50% to 60%) increase in basal and insulin-stimulated transport. Long-term (72-hour) treatment of myotubes with troglitazone resulted in a doubling of glucose transport in the absence of insulin, whereas M3 treatment resulted in a fivefold increase in basal glucose transport. Transport activity in M3-treated myotubes was greater than that seen after short-term insulin treatment. Insulin did not stimulate transport further in long-term M3-treated cells. A similar effect of prolonged exposure to M3 was observed in nondifferentiated myocytes. The agent had no influence on cell growth or the extent of differentiation. Augmentation of basal glucose transport by M3 was slow in onset, requiring 18 to 24 hours before significant effects were observed and 72 hours for full stimulation. M3 action on glucose transport was also dose-dependent, with half-maximal stimulation at 5 micrograms/mL of the agent and full effects at 10 to 20 micrograms/mL. Total membranes were prepared from control and M3-treated L6 myocytes and myotubes, and glucose transporter (GLUT1 and GLUT4) protein levels were measured by Western blotting. GLUT1 content was increased 2.9- +/- 1.3- and 2.8- +/- .2-fold by M3 treatment in myocytes and myotubes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration.

Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Recent studies demonstrating that PPARgamma occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-delta12,14-prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARgamma. These ligands for PPARgamma also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-delta12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re-endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.

Alitretinoin↗
PubMed2005

Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase.

The drugs troglitazone and metformin are used to reduce the degree of insulin resistance in type 2 diabetes. Both compounds act through different mechanisms which might include opposing effects on the production of adiponectin, an insulin-sensitizer released by adipocytes. This study compared the effects of troglitazone and metformin on adiponectin production by 3T3-L1 adipocytes during 48 h culture. Troglitazone increased adiponectin mRNA and protein expression as well as release, whereas metformin did not affect transcription but reduced protein expression and release. The effect of metformin was also seen with phenformin, and with low-glucose culture, all conditions with a reduced mitochondrial activity and an activated AMP activated protein kinase (AMPK). Addition of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR) also caused a decrease in adiponectin protein expression. These data indicate that metformin and troglitazone exert opposing effects on adiponectin expression and release by differentiated 3T3-L1 adipocytes. The metformin-induced suppression involves an activation of AMP activated protein kinase.

3T3-L1 Cells↗
PubMed2005

Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones.

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.

Alanine Transaminase↗
PubMed2000

Role of glucose and insulin in thiazolidinedione-induced alterations in hepatic gluconeogenesis.

Previous studies from our laboratory as well as from others have suggested that the thiazolidinediones have the capacity to act as insulinomimetic agents, especially in the liver. In order to further characterize this insulinomimetic action, we evaluated the effect of troglitazone, a representative thiazolidinedione, on lactate- and glucagon-stimulated gluconeogenesis, in the presence or absence of insulin (10 nM) in isolated rat hepatocytes. The antigluconeogenic effect of troglitazone under basal (lactate-stimulated) conditions was found to be due to an elevation in the fructose 2,6-bisphosphate content, which was, however, not mediated by an activation of 6-phosphofructo 2-kinase. Troglitazone (125 and 250 microM) in the absence of insulin, produced a dose-dependent reduction in glucagon-stimulated gluconeogenesis, thereby suggesting an insulinomimetic effect. In addition, troglitazone (125 and 250 microM), in combination with insulin, produced an additive inhibition of gluconeogenesis during glucagon-stimulated conditions. However, unlike insulin, the metabolic mechanism responsible for these effects (in the presence or absence of insulin) does not involve fructose 2,6-bisphosphate.

Animals↗
PubMed2001

Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle.

Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Some thiazolidinediones modify ion channels in smooth muscles; however, the mechanism by which their actions occur has not been clarified. We, thus, examined the effects of three thiazolidinediones (troglitazone, pioglitazone, and rosiglitazone) and isoxazolidinedione (JTT-501), as well as an intrinsic ligand for PPAR gamma, 15-deoxy-Delta(12,14) prostaglandin J(2) (prostaglandin J(2)), on voltage-operated Ca(2+) currents (I(Ca)), voltage-dependent K(+) currents (I(Kv)), and Ca(2+)-activated K(+) currents (I(Kca)), to clarify whether a thiazolidinedione structure or PPAR gamma activation is related to their actions on ion channels. The whole-cell patch clamp method was used to record currents in smooth muscle cells from guinea-pig mesenteric arteries. Thiazolidinediones inhibited I(Ca) in a dose-dependent manner (troglitazone>pioglitazone=rosiglitazone). Troglitazone (> or =1 microM) and rosiglitazone (100 microM), but not pioglitazone, inhibited I(Kv). Rosiglitazone (> or =10 microM) enhanced, troglitazone (> or =1 microM) inhibited, and pioglitazone did not affect I(Kca). A high concentration of JTT-501 (100 microM) inhibited I(Ca), I(Kv), and I(Kca) to a similar extent. Prostaglandin J(2) enhanced I(Kca), but affected neither I(Ca) nor I(Kv). In summary, the three thiazolidinediones and isoxazolidinedione act differently on Ca(2+) and K(+) channels in vascular smooth muscle. The action of thiazolidinediones on I(Ca) could be attributed to specific regions of the molecules and not to activation of PPAR gamma. Involvement of PPAR gamma activation in the stimulation of I(Kca) is possible but should be tested further.

Analysis of Variance↗
PubMed2003

Neuroprotective effects of PPARgamma agonists against oxidative insults in HT-22 cells.

Peroxisome proliferator-activated receptors (PPARs) are involved in regulating many metabolic and inflammatory processes. The present study explores the role of PPAR ligands in protecting neuronal cultures from toxic insults. For that purpose, we used WY14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid] as a PPARalpha agonist, L-165041 and L-783483 as PPARbeta ligands, and 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2), troglitazone, and ciglitazone for PPARgamma. Experiments were performed using HT-22, an immortalized mouse hippocampal cell line, and SK-N-SH, a human neuroblastoma cell line. Cell viability against glutamate, hydrogen peroxide (H(2)O(2)), and serum deprivation insults was determined using a calcein acetoxymethyl (AM) assay. Of the compounds tested, only 15d-PGJ2 and troglitazone showed a dose-dependent neuroprotection from glutamate and H(2)O(2) insults in HT-22 cells. None of the PPAR agonists was protective in SK-N-SH cells. A minimum of 4-6 h preincubation with 15d-PGJ2 was required to achieve significant neuroprotection. On the other hand, troglitazone was protective even when administered simultaneously with glutamate, or for up to 8 h postglutamate insult. To investigate whether the neuroprotective effects are mediated through PPARgamma, we first determined through Western blotting that HT-22 and SK-N-SH cells express PPARgamma. However, the neuroprotective effects of those compounds are unlikely to be mediated through the PPARgamma for two reasons: (1) various concentrations of another PPARgamma agonist (ciglitazone) were not neuroprotective; (2) by itself, PPAR exhibits a low affinity for DNA, and high-affinity binding requires heterodimerization with RXR, the 9-cis-retinoic acid receptor; administering 9-cis-retinoic acid in conjunction with 15d-PGJ2 did not alter the neuroprotective effects of the latter. Our results demonstrate neuroprotective effects of 15d-PGJ2 and troglitazone that are likely independent of PPARgamma.

Alitretinoin↗
PubMed2003

Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome.

OBJECTIVE: Insulin resistance is a common feature of both polycystic ovary syndrome (PCOS) and non-insulin-dependent diabetes mellitus (NIDDM); however, the persistent reproductive disturbances appear to be limited to the former, suggesting that insulin resistance in the ovary itself may confer this susceptibility. DESIGN: Prospective study. SETTING: University-affiliated department. PATIENT(S): Forty-four women undergoing IVF treatment, of whom 11 had polycystic ovaries and 33 had normal ovulation (NO). INTERVENTION(S): The various effects and signaling of insulin and insulin-like growth factor-1 (IGF-1) were examined in cultured ovarian granulosa cells treated with troglitazone (1 microg/mL) or with vehicle by reverse transcription-polymerase chain reaction, western blot, and in vitro functional analyses. MAIN OUTCOME MEASURE(S): Glycogen and DNA syntheses, mRNA and protein expression, and cellular localization of insulin/IGF-1 receptors and insulin receptor substrates (IRSs). RESULT(S): There were significant decreases in insulin-stimulated glucose incorporation into glycogen in PCOS cells, which is a metabolic action of insulin. However, IGF-1 stimulation was found to be greater in PCOS cells at all experimental concentrations with respect to thymidine incorporation compared with NO cells, which is a mitogenic action. Troglitazone increased the insulin-induced glycogen synthesis but reduced the IGF-1-augmented responses of DNA synthesis in PCOS cells to the range within those of NO granulosa cells. We then found that troglitazone treatment reversed the expression imbalance between IRS-1 and IRS-2 in PCOS cells. CONCLUSION(S): There is a selective defect in insulin actions in PCOS granulosa cells, which suggests ovarian insulin resistance, and this metabolic phenotype is associated with an enhanced IGF-1 mitogenic potential. Troglitazone could divergently alter expression of various IRS molecules and insulin actions and could be used as an ovarian insulin sensitizer and mitogen/steroidogenic inhibitor in PCOS.

Adult↗