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

We determined the in vivo effects of thiazolidinediones on insulin resistance induced by dexamethasone (Dx), as well as that observed in Wistar fatty (WF) rats, using glucose clamp technique to measure glucose uptake (Gu) and percent suppression of hepatic glucose output (HGOsup) to evaluate insulin resistance. Male Wistar rats were treated with Dx (0.5 mg/kg/day) for 7 days. Pioglitazone (P) or troglitazone (T) was coadministered orally for the same period at 10 and 200 mg/kg/day, respectively. Two, 5 and 20 mU/kg/min. of insulin infusion rates (IIR) were used. The Gu levels at clamp steady-state at IIR20 in rats treated with Dx (16.4 +/- 4.7 mg/kg/min.) were significantly lower than those in control rats (36.3 +/- 2.4). The Gu levels at the same IIR in rats coadminstered with P (19.6 +/- 3.2) and T (21.3 +/- 6.3) were slightly but significantly higher than that in rat treated with Dx. HGOsup at IIR5 in control rats (97.5 +/- 6.2%) was decreased by Dx treatment (52.1+/- 31.3). This decrease was slightly but significantly ameliorated by addition of T (78.3 +/- 12.2). The Gu levels at IIR20 in WF rats (6.6 +/- 0.9) were decreased significantly from that in lean littermates of WF (WL) rats (25.8 +/- 2.1). This attenuation of Gu increase was completely ameliorated with administration of P (20.9+/-2.8) or T (22.2+/-3.9). The HGOsup at IIR20 in WF rats (17.4 +/- 11.2) was significantly decreased from that in WL rats. Administration of P or T ameliorated this decrease completely. These results indicate that Dx induces insulin resistance by mechanisms different from those in WF rat, hence thiazolidinedione administration can be only partially useful to treat insulin resistance induced by Dx.
 ...
PMID:Thiazolidinediones exert different effects on insulin resistance between dexamethasone-treated rats and wistar fatty rats. 1081 Dec 89

Subjects with hypertension are hyperinsulinemic and resistant to insulin-stimulated glucose uptake. A similar paradigm is found in the spontaneously hypertensive rat (SHR). These findings suggest the possibility that insulin resistance and hyperinsulinemia may play an important role in blood pressure regulation. Pioglitazone, a thiazolidinedione derivative, sensitizes target tissues to insulin and decreases hyperglycemia and hyperinsulinemia in various insulin-resistant animals. The purpose of this study was to assess the influence of pioglitazone administration on pre- and postprandial glucose and insulin concentrations and determine whether changes in beta-cell secretion resulted in any change in blood pressure measurements. Twelve SHR were fed custom diets ad libitum, six with and six without pioglitazone (20 mg/kg chow). Fasting and postprandial glucose levels were unaltered by pioglitazone treatment. Fasting insulin concentrations were similar at week 1, but were significantly lower (P < .01) in the pioglitazone group at weeks 3 (1.89 +/- 0.3 v7.94 +/- 1.5 ng/mL) and 4 (4.5 +/- 1.4 v9.1 +/- 0.7 ng/mL), compared with the control group. Pioglitazone also significantly (P < .01) lowered postprandial insulin concentrations after an oral glucose challenge. Systolic, mean, and diastolic blood pressures were significantly lower (P < .01), 177 +/- 3 v190 +/- 4.7 mm Hg, 162 +/- 2.1 v175 +/- 5.9 mm Hg, and 156 +/-2.1 v168 +/- 6.2 mm Hg, respectively, in the animals receiving pioglitazone versus the control group. Heart rate, body weight, serum cholesterol, and triglyceride levels were comparable between the two groups. In conclusion, pioglitazone significantly decreased fasting and postprandial insulin concentrations and effectively lowered blood pressure in the SHR.
 ...
PMID:Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat. 1082 38

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.
 ...
PMID:Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus. 1092 9

Pioglitazone is an orally administered insulin sensitising thiazolidinedione agent that has been developed for the treatment of type 2 diabetes mellitus. Pioglitazone activates the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), which leads to the increased transcription of various proteins regulating glucose and lipid metabolism. These proteins amplify the post-receptor actions of insulin in the liver and peripheral tissues, which leads to improved glycaemic control with no increase in the endogenous secretion of insulin. In placebo-controlled clinical trials, monotherapy with pioglitazone 15 to 45 mg/day has been shown to decrease blood glycosylated haemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus. The addition of pioglitazone 30 mg/day to preexisting therapy with metformin, or of pioglitazone 15 or 30 mg/day to sulphonylurea, insulin or voglibose therapy, has been shown to decrease HbA1c and fasting blood glucose levels significantly in patients with poorly controlled type 2 diabetes mellitus. Pioglitazone has also been associated with improvements in serum lipid profiles in randomised placebo-controlled clinical studies. The drug has been well tolerated by adult patients of all ages in clinical studies. Oedema has been reported with monotherapy, and pooled data have shown hypoglycaemia in 2 to 15% of patients after the addition of pioglitazone to sulphonylurea or insulin treatment. There have been no reports of hepatotoxicity.
 ...
PMID:Pioglitazone. 1098 37

Takeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocin-induced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucose-lowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator-activated receptor, (PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.
 ...
PMID:[Insulin resistance-reducing effect of a new thiazolidinedione derivative, pioglitazone]. 1141 43

To clarify the target phase of thiazolidinediones, which are ligands for peroxisome proliferator-activated receptor (PPAR)gamma, during adipocyte differentiation, the effects of a thiazolidinedione, pioglitazone, on every stage during the course of adipocyte differentiation were investigated. Pioglitazone did not affect the cellular protein content and [3H]thymidine incorporation into preconfluent 3T3-L1 preadipocytes. Induction of differentiation of confluent 3T3-L1 preadipocytes with insulin, dexamethasone and isomethylbutylxanthine for 48 h resulted in 30% inhibition of [3H]thymidine incorporation into the cells and 354% increase in cellular protein content. Pioglitazone at 1 microM accelerated the increase in cellular protein content by 33% and the inhibition in the [3H]thymidine incorporation by 12%. Pioglitazone, when added from the start of the induction stage, dose-dependently enhanced cellular triglyceride accumulation, and both basal and insulin-stimulated glucose transporting activity producing only a slight increase in the ratio of insulin stimulation to basal glucose transporting activity. In mature adipocytes, however, pioglitazone did not enhance either of the transporting activities. PPARgamma messenger RNA (mRNA) levels estimated by a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) increased during the course of adipocyte differentiation. Although pioglitazone dose-dependently up-regulated PPARgamma mRNA levels in postconfluent preadipocytes without induction, it down-regulated them in mature adipocytes. Thus, a PPARgamma agonist, pioglitazone, arrested the growth, and increased protein content and PPARgamma mRNA levels in postconfluent preadipocytes, followed by commitment and hypertrophy of 3T3-L1 cells without changing insulin sensitivity, whereas it failed to stimulate glucose transporting activities and down-regulated PPARgamma mRNA expression in mature adipocytes.
 ...
PMID:Stage-specific effects of a thiazolidinedione on proliferation, differentiation and PPARgamma mRNA expression in 3T3-L1 adipocytes. 1143 Sep 9

Thiazolidinediones are a powerful and clinically important new class of oral antidiabetic agents that act by improving insulin sensitivity. Troglitazone is the prototype drug in this class but was withdrawn from the market in March 2000 due to its association with idiosyncratic hepatotoxicity. Currently two thiazolidinediones, rosiglitazone and pioglitazone, are U.S. Food and Drug Administration (FDA) approved for treatment of type 2 diabetes. These agents bind to and activate peroxisome proliferator-activator receptor gamma (PPAR-gamma) and work by altering the expression of genes involved in glucose uptake, glucose disposal, and lipid metabolism. The drugs differ in receptor binding and potency due to differences in their side chain moieties. These agents are rapidly absorbed from the gastrointestinal tract and are metabolized mainly in the liver. Rosiglitazone is FDA approved for monotherapy and for use in combination therapy with metformin or sulfonylureas. Pioglitazone is FDA approved for monotherapy as well as for use in combination therapy with metformin, insulin, or sulfonylureas. These drugs may also cause significant changes in plasma lipid concentrations, and improved insulin sensitivity may improve ovulatory function and fertility in women with polycystic ovary syndrome. The most serious side effect of the thiazolidinediones is hepatotoxicity. Although rosiglitazone and pioglitazone were not associated with hepatotoxicity in premarketing clinical trials, there were two recent case reports of idiosyncratic hepatotoxicity in patients treated with rosiglitazone. In addition, these agents may be associated with edema and some hematological changes. The purpose of this review is to provide an overview of the two currently approved thiazolidinediones and to suggest an approach for their safe and rational use.
 ...
PMID:Thiazolidinediones: a comparative review of approved uses. 1146 45

The discovery of a new class of oral antidiabetic drugs was stimulated by difficulties with the treatment currently available for patients with type 2 diabetes mellitus. Thiazolidinediones can lower blood glucose values due to their special insulin-sensitiser effect. In this way, these drugs seem to be very effective in the treatment of type 2 diabetic patients with characteristics of metabolic syndrome. The intracellular action caused by thiazolidinediones differs markedly from that of other oral antidiabetic drugs available. Apart from antihyperglycaemic effect, thiazolidinediones have further beneficial effects in experimental diabetes which require corroboration by clinical studies. Troglitazone was the first drug which reached the market. Unfortunately, this drug was withdrawn soon due to its hepatotoxicity. Rosiglitazone proved to be much safer in clinical studies. Pioglitazone is being tested nowadays in clinical studies. Thiazolidinediones have been already listed among oral antidiabetic drugs in international therapeutical guidelines. Nevertheless, further clinical studies and experiences are needed to determine the final exact indication of thiazolidinediones for the treatment of type 2 diabetic patients.
 ...
PMID:[Thiazolidinediones--a new class of oral antidiabetic drugs]. 1149 46

Uncoupling protein 3 (UCP3), which uncouples electron transport from ATP synthesis, is expressed at high levels in the skeletal muscle, an important organ in glucose and lipid metabolism. Because several reports proposed that fatty acids induced UCP3 gene expression in skeletal muscle in vivo, in the present study we examined the regulation of UCP3 gene expression by various fatty acids using L6 myotubes. UCP3 gene expression was increased in L6 myotubes by various fatty acids or by alpha-bromopalmitate, a nonmetabolized derivative of palmitic acid. Because fatty acids are also known as agonists for PPARs, we examined the involvement of PPARs in the regulation of the UCP3 gene expression. L-165041, a PPAR delta agonist, increased UCP3 gene expression in L6 myotubes, whereas neither Wy 14,643, a PPAR alpha agonist, nor Pioglitazone, a PPAR gamma agonist, increased it. Therefore, we conclude that UCP3 gene expression is increased by the activation of PPAR delta in L6 myotubes and postulate that PPAR delta mediates at least some part of the increased UCP3 gene expression by fatty acids in skeletal muscle in vivo.
 ...
PMID:Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes. 1156 73

Pioglitazone is a thiazolidinedione that increases insulin sensitivity in target tissues. It is well-absorbed, with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5 hours. It is metabolised by the hepatic cytochrome P450 enzyme system. However, unlike troglitazone, studies have provided no evidence to suggest that pioglitazone administration leads to inhibition or induction of any of the P450 isoenzymes involved in drug metabolism. Therefore pioglitazone may have lower potential for drug interaction. The half-life is about 9 hours but two active metabolites mainly contribute to the extended glucose-lowering effects. It is administered once daily without regard to meals. The pharmacokinetics are not significantly altered in Type 2 diabetes, renal or hepatic insufficiency or in the elderly. In placebo-controlled clinical studies, pioglitazone effectively improved glycaemic control in people with Type 2 diabetes as evidenced by significant reductions in HbA1c and fasting plasma glucose, whether used as monotherapy or in combination with sulphonylurea, metformin or insulin. Pioglitazone also had a beneficial effect on the abnormal lipid profile seen in Type 2 diabetes. Compared with placebo, pioglitazone significantly reduced serum triglycerides and increased high density lipoprotein cholesterol with no change in low density lipoprotein or total cholesterol.
 ...
PMID:Pharmacokinetics and clinical efficacy of pioglitazone. 1159 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>