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)

The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
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PMID:Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats. 1734 27

Visfatin is a newly identified adipocytokine that mimics insulin action. However, the pathophysiological role of visfatin in diabetic patients is not fully understood. The main purpose of this study was to investigate the association of plasma visfatin with endothelial function in patients with type 2 diabetes mellitus. In addition, the relationships of visfatin with oxidative stress, low-grade inflammation, atherosclerosis, adiponectin, plasma renin activity, and aldosterone were also explored, and the effect of pioglitazone on visfatin was examined. Visfatin levels were measured in 80 patients with type 2 diabetes mellitus and in 28 age-matched healthy subjects. Endothelial function was evaluated by using flow-mediated vasodilatation (FMD), oxidative stress was assessed by the level of urinary 8-iso-prostaglandin F2alpha, and atherosclerosis and inflammation were measured by using the intimal-medial complex thickness and the levels of high-sensitivity C-reactive protein and fibrinogen. Pioglitazone was administered for 12 weeks at a dose of 30 mg/d in a further 20 patients with type 2 diabetes mellitus. There was a significant negative correlation between the log10-transformed (log) plasma visfatin concentration and FMD or creatinine clearance (R=-0.2672, P=.0167; R=-0.2750, P=.0136). Log visfatin was also positively correlated with log urinary albumin excretion (R=0.2305, P=.0397). In addition, it was also found that visfatin had a significant negative correlation with plasma aldosterone (R=-0.2432, P=.0297). In stepwise regression analysis, creatinine clearance, log aldosterone, FMD, and sex showed a significant association with log visfatin (P=.0040, P=.0069, P=.0444, and P=.0487, respectively), and log 8-iso-prostaglandin F2alpha showed a tendency for an association (P=.0515). Pioglitazone therapy did not affect the visfatin concentration in the 20 pioglitazone-treated patients with diabetes, although a significant elevation of visfatin was obtained in a subgroup of 11 female patients (P=.0381). In conclusion, the current study showed that visfatin is negatively associated with vascular endothelial function evaluated by FMD and creatinine clearance, and positively associated with log urinary albumin excretion. Visfatin was also negatively correlated with circulating aldosterone. Pioglitazone therapy for 12 weeks did not affect the plasma visfatin concentration significantly in all diabetic patients, but a significant elevation in visfatin was obtained in women only.
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PMID:Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus. 1737

Inhibition of the renin-angiotensin system reportedly exerts potent antiatherogenic effects by reducing vascular inflammation. We tested the hypothesis that pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, further reduces vascular inflammation in patients receiving angiotensin II receptor blockers. Patients with hypertension who had developed type 2 diabetes mellitus were randomly assigned to receive either pioglitazone (15 mg/d, n = 20) or voglibose, an alpha-glucosidase inhibitor (0.6 mg/d, n=19) for 6 months, and changes in their serum concentrations of C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were monitored. Pioglitazone, but not voglibose, reduced CRP levels within 1 month (-51%+/-7%, mean+/-SEM; P<.001). C-reactive protein levels were decreased after 6 months of treatment with either pioglitazone or voglibose, with the former being more effective (-57%+/-8% vs -9%+/-18%; P<.05). The levels of ICAM-1 and VCAM-1 were significantly reduced after 1 month of pioglitazone therapy (-9%+/-3% and -8%+/-3%, respectively; both P<.05), with the beneficial effects persisting throughout the study period. In contrast, the levels of ICAM-1 and VCAM-1 were not altered during the study period in patients on voglibose. There was no correlation between the reduction of hemoglobin A1c and that of CRP, ICAM-1, or VCAM-1. These results suggest that augmentation with pioglitazone further reduces vascular inflammation in patients with hypertension and diabetes who are receiving angiotensin II receptor blockers. This may contribute to the reduction of cardiovascular events in this at-risk population.
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PMID:Pioglitazone produces rapid and persistent reduction of vascular inflammation in patients with hypertension and type 2 diabetes mellitus who are receiving angiotensin II receptor blockers. 1737 17

The recent analysis of the French MONICA registries report a reduction in the incidence of fatal MI related to improvement of care whereas the overall incidence of coronary events remain stable, suggesting the need for a better primary prevention. The extensive review of the death certificates and the analysis of the death classification from the same registries indicate an under estimation of MI-related death in the national death registry. It is also confirmed that instead of 50%, approximately 80% of coronary death are explained by the four major risk factors including smoking, hypercholesterolemia, hypertension and diabetes. The international REACH registry has enrolled more than 67 000 individuals including patients with symptomatic atherothrombotic disease and patients with multiple risk factors. The analysis of baseline characteristics and of the one year FU shows a high residual risk and a lack of efficacy of secondary prevention. The existence of a symptomatic disease and the number of symptomatic localization of atherothrombosis are critical factors to predict recurrence of major vascular events Secondary analysis of the INTERHEART study provide the essence of what should any physician know about the relationship between coronary heart disease and smoking, either active or passive. Prevention with respect to this risk factor remains very insufficient. Varenicline, a new nicotinic receptor partial agonist, should help patients involved in smoking cessation program. The established detrimental effects of perioperative smoking represent a unique opportunity to promote smoking cessation in individuals scheduled for surgery. The major cardiovascular impact of second hand smoking has been recently demonstrated by the short-term effects of banning smoking in public places on the incidence of acute coronary events. The SPARCL study has demonstrated the benefit of high dose of atorvastatine to prevent recurrent acute ischemic cerebrovascular event in patients with a prior history of stroke or TIA. In the open ASTEROID study, high doses of rosuvastatine confirm the possibility of reducing the volume of coronary atheroma analyzed by IVUS. The expected benefit of glitazones to reduce the incidence of death, MI and stroke in diabetes patients with a prior history of vascular event has been confirmed in the PROactive study. Pioglitazone provided a clear reduction of recurrent vascular events in diabetes patient with a prior MI at a cost of a significant increase of the risk of heart failure. In the DREAM study, neither ramipril nor rosiglitazone have reduced the incidence of cardiovascular events significantly. The moderate benefit of the fenofibrate to prevent cardiovascular events in the FIELD study, which was carried out in diabetics mostly in primary prevention, needs to be considered after adjustment on statin use in a higher proportion of patients of the placebo group. Postprandial hyperglycaemia, analyzed by the peak of glycaemia after a load in glucose, has been confirmed as a more powerful independent predictive factor of the risk of cardiovascular event than fasting glycaemia. The systematic screening postprandial hyperglycaemia represents an interesting strategy for primary prevention which warrants further investigation. If obesity is a risk factor whose impact on morbi-mortality is well established, a French study shows that body mass index has an unfavourable influence on the cognitive functions in middle-aged men and women.
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PMID:[The best of epidemiology and cardiovascular prevention in 2006]. 1740 66

Traumatic spinal cord injury (SCI) is accompanied by a dramatic inflammatory response, which escalates over the first week post-injury and is thought to contribute to secondary pathology after SCI. Peroxisome proliferator-activated receptors (PPAR) are widely expressed nuclear receptors whose activation has led to diminished pro-inflammatory cascades in several CNS disorders. Therefore, we examined the efficacy of the PPARgamma agonist Pioglitazone in a rodent SCI model. Rats received a moderate mid-thoracic contusion and were randomly placed into groups receiving vehicle, low dose or high dose Pioglitazone. Drug or vehicle was injected i.p. at 15 min post-injury and then every 12 h for the first 7 days post-injury. Locomotor function was followed for 5 weeks using the BBB scale. BBB scores were greater in treated animals at 7 days post-injury and significant improvements in BBB subscores were noted, including better toe clearance, earlier stepping and more parallel paw position. Stereological measurements throughout the lesion revealed a significant increase in rostral spared white matter in both Pioglitazone treatment groups. Spinal cords from the high dose group also had significantly more gray matter sparing and motor neurons rostral and caudal to epicenter. Thus, our results reveal that clinical treatment with Pioglitazone, an FDA-approved drug used currently for diabetes, may be a feasible and promising strategy for promoting anatomical and functional repair after SCI.
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PMID:The PPAR gamma agonist Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury. 1743 95

Impaired glucose tolerance (IGT) is associated with cardiovascular risk factors, but the effects of pioglitazone and metformin on IGT are not well described. We tested the hypothesis that each drug would exhibit antiatherogenic and anti-inflammatory effects in subjects with IGT and early diabetes. The study design was a prospective, randomized, open label, cross-over study. Blood tests, including a 75-g oral glucose tolerance test (OGTT), were performed at baseline and after each treatment. Pioglitazone 15 mg/day or metformin 500-750 mg/day was given for 3 months. Biochemical markers to assess insulin resistance as well as lipid, inflammatory, neurohumoral, and hemostatic factors were included. Twenty-five subjects (17 male, 8 female; age [mean+/-SD]: 61+/-9 years; 84% hypertensive) completed the protocol. Of 25 subjects, 14 were diagnosed as IGT and 11 as diabetes with 75-g OGTT. Pioglitazone significantly reduced fasting glucose (p<0.05), and homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.05) and metformin (p<0.01) reduced cholesterol. Both drugs significantly reduced aldosterone (both p<0.05) and von Willebrand factor (vWF) (both p<0.05). Plasma adiponectin was increased only by pioglitazone (p<0.001). Neither drug affected BP levels. In conclusion, pioglitazone was superior to metformin for the improvement of insulin resistance and adiponectin, and both drugs were equally effective in reducing vWF and aldosterone in subjects with IGT and early diabetes. Early intervention with pioglitazone or metformin therapy may reduce the incidence of future cardiovascular disease in subjects with impaired glucose tolerance or early diabetes.
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PMID:Comparison of the effects of pioglitazone and metformin on insulin resistance and hormonal markers in patients with impaired glucose tolerance and early diabetes. 1746 Mar 68

In mice, eNOS (endothelial nitric oxide synthase) maintains in vivo pancreatic secretory responses to carbachol or cholecystokinin octapeptide (CCK-8), maintains insulin sensitivity, and modulates pancreatic microvascular blood flow (PMBF). eNOS(-/-) mice are insulin resistant, and their exocrine pancreatic secretion is impaired. We hypothesized that the reduced exocrine pancreatic secretion in eNOS(-/-) mice is due to insulin resistance or impaired PMBF. To test this hypothesis, we gave eNOS(-/-) and wild-type (WT) mice pioglitazone (20 or 50 mg.kg(-1).day(-1)), an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator, and measured pancreatic protein secretion evoked by CCK-8 (160 pmol.kg(-1).h(-1), a maximal stimulus). We also measured insulin resistance, serum glucose, C-peptide, insulin, pancreatic RNA digestive enzyme expression, and PMBF (microsphere technique). In WT mice, pioglitazone did not increase CCK-8-stimulated protein output over baseline. In eNOS(-/-) mice, however, pioglitazone substantially increased the low CCK-8-stimulated protein output that is characteristic of these mutant mice (P < 0.005). Pioglitazone abolished the CCK-8-evoked hyperinsulinemia (P < 0.005) and increased insulin sensitivity of eNOS(-/-) mice (P < 0.05), the latter based on hyperinsulinemic-euglycemic clamp studies. Pioglitazone had no effect on PMBF or pancreas mRNA expression of insulin or digestive enzymes. We conclude that in hyperinsulinemic eNOS(-/-) mice, a nonobese model of insulin resistance relevant to diabetes mellitus and possibly chronic pancreatitis, reduced pancreatic secretion is caused, at least in part, by insulin resistance. Insulin-sensitizing PPAR-gamma agonists such as pioglitazone may thus simultaneously correct endocrine and exocrine pancreatic disorders.
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PMID:Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(-/-) mice: therapy for exocrine pancreatic disorders? 1751 Jan 94

Angiogenesis, the formation of new blood vessels, is a physiological response to tissue ischemia. Clinical evidence suggests that diabetic patients have endothelial dysfunction and impaired angiogenesis in response to ischemia. Here, we investigated the impact of diabetes on ischemia-induced collateral growth, and tested the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist augments collateral flow to ischemic tissue. We conducted unilateral hindlimb ischemia surgery in KKAy mice. Blood flow recovery was markedly impaired in diabetic mice compared with that in wild-type mice as determined by laser Doppler imaging. Treatment of KKAy mice with pioglitazone partially restored the blood flow recovery. Anti-CD31 immunostaining revealed that pioglitazone also significantly improved the capillary density in ischemic limb muscle. Endothelial NO synthase (eNOS) activity was ameliorated in diabetic mice treated with pioglitazone as determined by vasorelaxation in response to acetylcholine. Pioglitazone normalized vascular endothelial growth factor (VEGF) protein levels, which was decreased in ischemic muscle of KKAy mice, and up-regulated eNOS phosphorylation at Ser-1177 and Akt phosphorylation at Ser-473 in ischemic muscle. Pioglitazone had no beneficial effects on blood flow recovery in diabetic mice treated with N(G)-nitro-l-arginine methyl ester (L-NAME). Our findings demonstrate that pioglitazone significantly ameliorates endothelial dysfunction and enhances blood flow recovery after tissue ischemia in diabetic mice. Activation of eNOS appears to be essential for pioglitazone to promote angiogenesis in ischemic tissue.
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PMID:Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. 1769 99

Pioglitazone, a member of the PPAR-gamma agonist drug family, has been demonstrated to improve both metabolic and vascular insulin resistance when applied to patients with Type 2 diabetes mellitus. The drug is well tolerated with fluid retention and weight gain being the most frequently described side effects. The observed effects (e.g., improvements in glucose and lipid metabolism, improvements of endothelial function and microcirculation, reduction of surrogate markers of atherosclerosis and inflammation and an improvement in hypertension) have made pioglitazone one of the frequently prescribed antidiabetic drugs in the US and Europe. Several trials have shown its potency to reduce carotid intima-media thickness, and outcome studies with pioglitazone have shown its potential to delay the progression of Type 2 diabetes and atherosclerosis and even reduce cardiovascular mortality. The purpose of this review is to provide an overview about recently published clinical results with pioglitazone. They underline the value of this drug when used alone or in combination with other antidiabetic drugs for a successful management of Type 2 diabetes mellitus.
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PMID:Pioglitazone: update on an oral antidiabetic drug with antiatherosclerotic effects. 1769 99

We assessed the effect of the addition of pioglitazone on metabolic control and heart function of patients with type 2 diabetes already receiving sulfonylurea plus metformin. Forty-four patients were given 30 mg of pioglitazone for 3 months. Physical examination, laboratory tests including N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography, were performed at baseline and at study completion. Target HbA(1c) levels were achieved by 44.2% of the patients. Pioglitazone ameliorated lipid profile and lowered liver enzymes and C-reactive protein. Significant increases in NT-proBNP by 39% (P < 0.005) were noticed, but echocardiographic parameters were not altered, even in high-risk subgroups (patients older than 60 years, with diabetes for more than 10 years, with hypertension, with elevated baseline NT-proBNP levels, with left ventricular hypertrophy). In patients with a greater than 60% increase in NT-proBNP levels, a significant increase in left ventricular ejection fraction (P < 0.05) and in fractional shortening (P < 0.05) was found. None of the patients developed edema or signs or symptoms of heart failure. Triple oral combination antidiabetic treatment is an effective therapeutic strategy and weight gain does not abrogate its beneficial actions. Pioglitazone does not affect heart function and even though it increases NT-proBNP, this appears to represent a reaction to volume overload.
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PMID:Effect of pioglitazone on heart function and N-terminal pro-brain natriuretic peptide levels of patients with type 2 diabetes. 1776 92


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