Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:111025-46-8 (Pioglitazone)
 802 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiazolidinediones (TZDs), agonists for PPARs, have been shown to block the inhibitory effects of TNF-alpha on insulin action using cultured cells. In order to clarify the in vivo effects of TZDs on the inhibition of insulin sensitivity by TNF-alpha, insulin action in muscles and adipose tissues was assessed in the TNF-alpha-overexpression mice model using transplantation of cells secreting the TNF-alpha protein. After the pioglitazone treatment for 4 weeks, glucose uptake, insulin-induced IRS-1 phosphorylation, and lipoprotein lipase mRNA levels were analyzed. Pioglitazone did not ameliorate TNF-alpha-induced hyperinsulinemia in this model, as assessed by the OGTT. Glucose uptake and lipoprotein lipase mRNA levels were decreased by TNF-alpha in adipose tissues from the TNF-alpha-overexpressing mice, and pioglitazone blocked these inhibitions by TNF-alpha. On the other hand, in muscles, pioglitazone did not reverse the effects of TNF-alpha on insulin-induced phosphorylation of IRS-1, glucose uptake, and lipoprotein lipase mRNA levels. Present study revealed the different sensitivities of pioglitazone for the recovery of decreased insulin action in a TNF-alpha-overexpressing model using cell transplantation. These results suggest that the effect of TZDs is dependent on the fat distribution and accumulation in humans.
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PMID:A PPAR agonist improves TNF-alpha-induced insulin resistance of adipose tissue in mice. 1295 Oct 66

Women with polycystic ovary syndrome (PCOS) are known to exhibit insulin resistance with compensatory hyperinsulinemia. To determine the role of hyperinsulinemia on follicle function in PCOS, we examined 24-h estradiol (E(2)) responses to recombinant human FSH (r-hFSH), 75 IU, before and during insulin infusion both before and after administration of pioglitazone (30 mg/d) in seven PCOS women. Each subject underwent two 10-h hyperinsulinemic-euglycemic clamps at rates of 30 (low dose) and 200 (high dose) mU/m(2).min, respectively. During both low- and high-dose insulin infusions, E(2) responses to r-hFSH were unaltered compared with that observed in the absence of insulin. Pioglitazone administration for 5 months improved insulin sensitivity as indicated by significantly (P < 0.05) increased glucose infusion rates during the clamp studies. At 3 months of treatment, r-hFSH-stimulated E(2) responses were not different from those observed before treatment. With pioglitazone treatment, E(2) responses to r-hFSH remained unchanged during low-dose insulin infusion, whereas a highly significant (P < 0.02) increased response was noted with the high-dose hyperinsulinemic-euglycemic clamp. In addition to a greater magnitude of response, peak levels of E(2) were sustained longer compared with that seen before treatment. The data indicate that granulosa cell responsiveness to FSH was enhanced by insulin after improved insulin sensitivity induced by pioglitazone. These findings are consistent with the possibility that PCOS granulosa cells are insulin resistant.
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PMID:Enhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone. 1467 Nov 44

The present study was performed to investigate whether nitric oxide synthase (NOS) inhibition influences the increased whole-body insulin action by pioglitazone in high-fructose-fed rats. Male Wistar rats aged 6 weeks were randomly divided into 3 groups and each group was fed one of the following diets for 3 weeks: standard chow diet (control group), high-fructose diet (fructose-fed group), and high-fructose diet plus pioglitazone (pioglitazone-treated group). The control and pioglitazone-treated groups were further divided into 2 subgroups respectively, and some rats of each subgroup were infused the NOS inhibitor, N(G)-monomethyl-l-arginine (L-NMMA), during the euglycemic clamp studies. In vivo insulin action was determined by the 2-step (3 and 30 mU/kg body weight [BW]/min low- and high-dose, respectively) hyperinsulinemic euglycemic clamp procedure in the awake condition. Glucose infusion rate (GIR) was considered as the index of insulin action. Endothelium-type NOS (eNOS) and inducible NOS (iNOS) in skeletal muscle were also measured. At the low-dose clamp, high-fructose feeding produced a marked decrease in GIR compared with the control group. Pioglitazone-treated animals showed a significant increase in GIR, reaching a similar level as the control group. However, the improved GIR was decreased to the level of the fructose-fed group by L-NMMA infusion. The GIR of the control group was not affected by L-NMMA infusion. The same tendency as the low-dose clamp was found at the high-dose clamp. In skeletal muscle, eNOS and iNOS protein content were not affected by high-fructose feeding and/or pioglitazone treatment. These results suggest that NOS inhibition can decrease the improved insulin resistance by pioglitazone in high-fructose-fed rats. Therefore, although NOS protein content is not changed by high-fructose feeding and/or pioglitazone treatment, it could be concluded that nitric oxide (NO) plays an important role in the improvement of insulin action by pioglitazone.
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PMID:The effect of nitric oxide synthase inhibitor on improved insulin action by pioglitazone in high-fructose-fed rats. 1468 37

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.
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PMID:Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. 1473 53

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study.
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PMID:A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. 1475 37

Patients with type 2 diabetes have dual defects: insulin resistance and beta-cell dysfunction. Thiazolidinediones (TZDs), a new class of oral drugs used for the treatment of type 2 diabetes, reduce insulin resistance via an action on peroxisome proliferator-activated receptors. There is also growing evidence that TZDs may preserve beta-cell function. Pioglitazone is a TZD that provides appropriate monotherapy or combination treatment for patients with type 2 diabetes. Studies of up to 32-week duration have shown that pioglitazone significantly reduces HbA1c and fasting plasma glucose when used alone or in combination with another glucose-lowering agent. Four recently published 52-week clinical trials, involving over 3700 patients with type 2 diabetes, show that pioglitazone is an effective long-term treatment, both as monotherapy and in combination with metformin or sulphonylurea. As well as maintaining glycaemic control over the long term, pioglitazone also confers benefits in terms of improvements in fasting insulin, lipid parameters, C-peptide and 32,33-split proinsulin (independent predictors of cardiovascular risk) and hypoglycaemia compared with other monotherapies or combination therapies. It is well tolerated, with a low incidence of adverse events. These long-term data support the concept that pioglitazone should be used earlier in the treatment of type 2 diabetes, either as monotherapy or as add-on therapy.
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PMID:Long-term glycaemic control with pioglitazone in patients with type 2 diabetes. 1505 68

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.
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PMID:Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. 1516 71

The present study was undertaken to determine the effect of pioglitazone (3, 10 and 30 mg/kg p.o.), an insulin sensitizer, on glucose intolerance in high fat diet- (HFD) fed rats (a nongenetic model of insulin resistance). In addition, the effect of pioglitazone (3, 10 and 30 mg/kg p.o.) on diet-induced changes in body weight, plasma glucose, insulin, triglyceride and total cholesterol levels were also determined. The feeding of HFD for 4 weeks produced a significant increase in body weight, total fat pad weight, basal/fasting plasma glucose, insulin, basal triglyceride (TG) and total cholesterol (TC) levels in male rats. Furthermore, the rats fed HFD exhibited fasting hyperglycemia and hyperinsulinemia as well as enhanced glycemic response to exogenously administered glucose (2 g/kg p.o.) during an oral glucose tolerance test (OGTT) at the end of 4 weeks of dietary manipulation, indicating that the rats had developed insulin resistance and glucose intolerance. Treatment with pioglitazone (10 and 30 mg/kg p.o.) once daily for 2 weeks significantly diminished the elevated basal plasma insulin and TG levels in HFD-fed rats. In addition, a statistically significant reduction in TC level was observed only with the high dose of pioglitazone (30 mg/kg p.o.). However, pioglitazone had no significant effect on body weight, total fat pad weight and basal plasma glucose level. Pioglitazone (10 and 30 mg/kg p.o.) significantly reduced fasting hyperglycemia and reversed oral glucose intolerance to normal in HFD-fed rats compared with control normal rats. The above findings suggest that pioglitazone has potent insulin-sensitizing and lipid-lowering properties in a HFD-fed rat model. In conclusion, the present study demonstrates that the adult male rats on a HFD for 4 weeks exhibited the characteristic features of obesity, insulin resistance and glucose intolerance, namely increased body weight, increased total fat pad weight, mild basal/fasting hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and impaired oral glucose tolerance, that closely resemble the human prediabetic obese insulin-resistant and glucose-intolerant state. Further treatment with pioglitazone once daily for 2 weeks significantly ameliorated changes in basal plasma insulin, TG and TC, and reversed oral glucose intolerance to normal in HFD-fed rats, suggesting its potential in the treatment of insulin resistance and glucose intolerance associated with abnormal lipid metabolism.
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PMID:Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats. 1531 10

Decreased functional beta-cell mass in type 1 and type 2 diabetes is due to beta-cell apoptosis and impaired secretory function suggested to be mediated, in part, by immune- and/or high-glucose-induced production of IL-1beta acting through the nuclear factor kappaB (NFkappaB)/Fas pathway. The aim of this study was to determine whether two drugs believed to block NFkappaB activation, the thiazolidinedione (glitazone) pioglitazone and the nonsteroidal antiinflammatory drug sodium salicylate, can protect human beta-cells against the toxic effects of IL-1beta and high glucose in vitro. Human islets were maintained in culture 2-4 d at 100 mg/dl (5.5 mm) glucose with or without (control) IL-1beta or at 600 mg/dl (33.3 mm) glucose. IL-1beta and 600 mg/dl glucose increased beta-cell apoptosis and abolished short-term glucose-stimulated insulin secretion. Both drugs protected partially against loss of glucose-stimulated insulin secretion and prevented completely increased apoptosis caused by IL-1beta or 600 mg/dl glucose. IL-1beta secretion from islets was increased by 4-d culture at 600 mg/dl, and this was blocked by pioglitazone. Both drugs prevented activation of beta-cell NFkappaB by high glucose. Pioglitazone and sodium salicylate thus protect human islets against the detrimental effects of IL-1beta and high glucose by blocking NFkappaB activation and may therefore be useful in retarding the manifestation and progression of diabetes.
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PMID:Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. 1547 6

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression is very low in skeletal muscle cells, which is one of the most important target tissues for insulin and plays a predominant role in glucose homeostasis. It has recently been shown that muscle-specific PPAR-gamma deletion in mouse causes insulin resistance. However, it is likely that the observed effects might be due to secondary interaction in whole animal. The aim of the study was to explore the role of muscle PPAR-gamma in insulin sensitivity. We stably transfected C2C12 skeletal muscle cells with plasmids containing sense or antisense constructs of PPAR-gamma and examined the effect of modulation of PPAR-gamma expression in terms of glucose uptake. Effect was also examined in insulin-resistant C2C12 skeletal muscle cells. In transfected C2C12 cell line, the inhibition of PPAR-gamma expression (23.0 +/-0.005%) was observed to induce insulin resistance as determined by functional assessment of 2-deoxyglucose incorporation. Overexpression of PPAR-gamma (28.5 +/- 0.008%) produced an additional effect on insulin (100 nM) and Pioglitazone (50 microM), resulting in 42.7 +/- 3.5% increase in glucose uptake as against 29.2+/-2.8% in wild-type C2C12 skeletal muscle cells differentiated under normal (2% horse serum) condition. Under similar treatment, PPAR-gamma overexpressing cells resistant to insulin exhibited enhanced glucose uptake upto 60.7 +/- 4.08%, as compared to 23.8 +/- 5.1% observed in wild-type C2C12 skeletal muscle cells. These data demonstrate a direct involvement of PPAR-gamma in insulin sensitization of TZD action on skeletal muscle cells, and suggest that pharmacological overexpression of muscle PPAR-gamma gene in skeletal muscle might be a useful strategy for the treatment of insulin resistance.
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PMID:PPAR-gamma expression modulates insulin sensitivity in C2C12 skeletal muscle cells. 1550 54


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