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Query: CAS:111025-46-8 (Pioglitazone)
 802 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pioglitazone, a thiazolidinedione, is a novel antidiabetic compound that can lower blood glucose in diabetic rodents by increasing insulin sensitivity in target tissues. We have previously demonstrated that pioglitazone can enhance the insulin- or insulin-like growth factor-1-regulated differentiation of 3T3-L1 cells, a cell line that undergoes morphological and biochemical differentiation to mature adipocytes [Mol. Pharmacol. 41:393-398 (1992)]. In this study, we have examined the effect of pioglitazone on the expression of the adipocyte fatty acid-binding protein (aFABP) in ob/ob mice and 3T3-L1 cells. Administration of the drug to mice was observed to cause a dose-dependent increase in aFABP mRNA expression in epididymal fat, which was correlated with a decrease in blood glucose and insulin levels. Treatment of 3T3-L1 cells with pioglitazone enhanced aFABP expression in a time-dependent fashion. To explore a possible direct effect of pioglitazone on aFABP expression, a chimeric gene was constructed containing the aFABP promoter fused upstream of the bacterial reporter gene for chloramphenicol acetyltransferase. After transfection into 3T3-L1 cells and selection of stable transformants, regulation of the chimeric gene was studied. Pioglitazone, in combination with insulin or insulin-like growth factor-1, was observed to elicit a dose-dependent increase in expression, indicating a role for pioglitazone in regulating transcription of the aFABP gene. Several thiazolidinedione analogs were tested for their ability to induce the expression of the chimeric gene, and it was found that activity in this assay paralleled the structure-activity relationships observed for enhancement of 3T3-L1 cell differentiation. These observations on control of aFABP gene expression by pioglitazone suggest possible mechanisms by which cellular sensitivity to insulin may be regulated.
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PMID:Adipocyte fatty acid-binding protein: regulation of gene expression in vivo and in vitro by an insulin-sensitizing agent. 143 36

The thiazolidinediones are a class of novel antidiabetic compounds that enhance the response of target tissues to insulin. Pioglitazone, a thiazolidinedione analog, lowers blood glucose and insulin levels in rodent models of non-insulin-dependent diabetes mellitus. We have studied the effect of pioglitazone on 3T3-L1 cells, a cell line that undergoes differentiation from a preadipocyte fibroblastic morphology to that of an adipocyte. Pioglitazone treatment of preadipocytes enhanced the insulin- or insulin-like growth factor-1 (IGF-I)-regulated differentiation (monitored by the rate of lipogenesis or triglyceride accumulation), whereas treatment of the cells in the absence of insulin or IGF-I resulted in no apparent change in the cellular phenotype. Pioglitazone caused both a leftward shift and enhanced maximum response for the IGF-I-regulated differentiation of the cells, consistent with the idea that the drug enhances the sensitivity of cells to polypeptide hormones. A series of pioglitazone analogs were tested in this system, and variations in activity relative to that of the parent compound were observed. A study of the time required for the drug to exert an effect on differentiation revealed that an increased rate of lipogenesis occurred 16-24 hr after drug treatment in appropriately staged cells. An increased rate of glucose transport and increased activity of lipogenic enzymes were noted in a time frame that correlated with the change in lipogenesis. Analysis of mRNA abundance for Glut-4, lipoprotein lipase, and glucose-6-phosphate dehydrogenase showed that pioglitazone enhanced the insulin induction of these mRNA species. Thus, pioglitazone, in combination with insulin or IGF-I, appears to be exerting effects on the cellular phenotype by eliciting changes in the expression of genes that regulate metabolic pathways leading to the acquisition of the differentiated phenotype.
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PMID:Enhancement of adipocyte differentiation by an insulin-sensitizing agent. 153 16

Insulin resistance is one of pathogenic factors for non-insulin-dependent diabetes mellitus (NIDDM). Pioglitazone (5-[4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzyl]-2,4-thiazolidinedione, AD-4833, also known as U-72, 107E) is a promising candidate to lower hyperglycemia by reducing insulin resistance. The genetically obese-hyperglycemic rats. Wistar fatty, were used to test the action of pioglitazone, because they develop severe insulin resistance in the peripheral tissues (muscle and adipose tissue) and liver. Pioglitazone administered orally (0.3-3 mg/kg/d for 7 days) dose dependently reduced hyperglycemia, hyperlipidemia, and hyperinsulinemia in male fatty rats. Pioglitazone improved glucose tolerance and augmented the glycemic response to exogenous insulin and clearance of plasma triglyceride. These effects on glucose and lipid metabolism seem to be due to increased insulin sensitivity and responsiveness in the peripheral tissues, because pioglitazone increased insulin-stimulated glycogen synthesis and glycolysis in the isolated soleus muscles, and insulin-stimulated glucose oxidation and lipogenesis in adipocytes. The latter effects were not accompanied by any changes in insulin binding. The actions of insulin mimickers (vanadate and vitamin K5), which act on the post-insulin binding sites, on these metabolic events were also potentiated by pioglitazone. These findings suggest that pioglitazone can improve glucose and lipid metabolism by reducing insulin resistance on the post-binding system. Therefore, pioglitazone may be efficacious for treating human NIDDM.
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PMID:Effects of pioglitazone on glucose and lipid metabolism in Wistar fatty rats. 218 19

Effects of pioglitazone (5-[4-[2-(5-etyl-2-pyridyl)ethoxy] benzyl]-2,4-thiazolidinedione, AD-4833, also known as U-72, 107E) on peripheral and hepatic insulin resistance were examined using genetically obese-hyperglycemic rats, Wistar fatty. Pioglitazone was administered to fatty rats (3 mg/kg/d) and lean rats (10 mg/kg/d) for 6 days. Pioglitazone decreased hyperglycemia and hypertriglyceridemia without affecting hyperinsulinemia in the fatty rats, and significantly reduced plasma levels of triglyceride and insulin without altering normoglycemia in the lean rats. The same rats were subjected to an isotopic method combined with a euglycemic clamp technique for assessing insulin sensitivity in hepatic glucose production (HGP) and peripheral glucose utilization (PGU). HGP decreased and PGU increased in response to infused insulin in the lean rats but did not in the fatty rats, indicating that insulin resistance was present in the liver and peripheral tissues of the fatty rats. Treatment with pioglitazone restored the responses of HGP and PGU to infused insulin in the fatty rats, but did not produce any changes in the lean rats. When the same levels of glycemia and insulinemia were established by 480 mU/h of insulin in both treated and control fatty groups, PGU was 1.5-fold higher and HGP was 3-fold lower in the pioglitazone treated group. Pioglitazone also corrected the abnormality in hepatic enzyme regulation by insulin of the fatty rats: glucose-6-phosphatase decreased and glucokinase increased, suggesting the increased response of the liver to insulin and the resultant suppression of HGP. Therefore, pioglitazone is expected to be useful for treating abnormal glucose and lipid metabolism in non-insulin-dependent diabetes mellitus through reducing insulin resistance of the peripheral tissues and liver.
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PMID:Effects of pioglitazone on hepatic and peripheral insulin resistance in Wistar fatty rats. 219 15

The antidiabetic effects of pioglitazone (5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, AD-4833, also known as U-72, 107E) were examined in normal, obese, and/or diabetic animals. When orally administered to genetically obese and diabetic yellow KK mice (2.4-24.5 mg/kg/d), and Zucker fatty rats (0.1-10 mg/kg/d) for 4 days, pioglitazone markedly decreased hyperglycemia, hyperlipidemia, hyperinsulinemia, and glucose intolerance characterized as insulin resistant states in these animals. Pioglitazone potentiated insulin-mediated glucose metabolism in the diaphragm and adipose tissues of yellow KK mice and enhanced the glycemic response to exogenous insulin in Zucker fatty rats. Four-day administration of pioglitazone (1 mg/kg/d) to aged and obese beagle dogs with moderate insulin resistance decreased plasma glucose and lipids in the fasting state, and postprandial rises in plasma triglyceride. Pioglitazone decreased plasma lipids but did not alter the plasma glucose level in young normal rats. Pioglitazone did not alter plasma glucose and lipid levels in streptozocin-diabetic rats. These results indicate that pioglitazone is effective on abnormal glucose and lipid metabolism associated with insulin resistance by enhancing insulin action on peripheral tissues. Therefore, pioglitazone is expected to be useful in treating obese non-insulin-dependent diabetes.
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PMID:Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals. 233 55

The role of insulin resistance in the impaired glucose-stimulated insulin release of Zucker fatty rats was investigated using the insulin-sensitizing thiazolidinedione drug pioglitazone. Fatty rats had fasting hyperinsulinemia yet a blunted secretory response to intravenous glucose compared with lean age-matched controls. Islets from fatty rats secreted less insulin (based on islet DNA) in response to high glucose than islets from lean rats but secreted normal amounts of insulin when tolbutamide or alpha-ketoisocaproic acid (alpha-KIC) was the stimulus. Administering pioglitazone for 9 days diminished basal hyperinsulinemia and increased the insulin response to high glucose by fatty rats but not by lean controls. Pioglitazone pretreatment augmented the secretory response by isolated islets to high glucose, alpha-KIC, and tolbutamide. Augmentation of islet insulin release was not associated with reduced plasma glucose concentration, suggesting that altered glycemia was not involved. Pancreas and islet insulin content was greater in fatty rats than in lean controls and was decreased by pioglitazone; hence, insulin stores and glucose-stimulated insulin release did not correlate. Pioglitazone treatment did not affect the rate of islet glucose usage or ATP/ADP in the presence of 2.75 or 16 mmol/l glucose. These data indicate that ameliorating insulin resistance reverses defective glucose-stimulated insulin release by Zucker fa/fa rats. After pioglitazone administration, insulin secretion may be augmented by increased generation of a metabolic coupling factor from glucose or at a later step in the secretory process that is common to both glucose and nonglucose secretagogues.
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PMID:Insulin secretory defect in Zucker fa/fa rats is improved by ameliorating insulin resistance. 762 5

Consumption of diets rich in fats or sugars is correlated with the onset of insulin resistance and hypertension in rats. In the present study, rats were fed diets that induce hypertension; 50% of the rats were also treated with pioglitazone, a thiazolidinedione derivative that sensitizes target tissues to insulin and decreases plasma insulin concentration in insulin-resistant animals. Pioglitazone treatment prevented the development of hypertension and reduced plasma insulin concentration by 70% and 37% in rats fed a high-fat or glucose diet, respectively (P < .05 compared with rats fed the same diet without pioglitazone). In rats fed a control diet, neither insulin nor blood pressure (BP) was affected by pioglitazone treatment. The effect of pioglitazone on insulin and BP could not be attributed to a reduction in body weight, since pioglitazone increased the weight gain of rats fed the high-fat or glucose diet. These findings suggest that in rats fed a diet high in fat or glucose, treatment with pioglitazone maintains plasma insulin concentration and BP at control levels, regardless of body weight.
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PMID:Pioglitazone attenuates diet-induced hypertension in rats. 766 81

Insulin resistance in the obese (fa/fa) Zucker rat is associated with decreased insulin stimulated glucose transport in skeletal muscle, due primarily to a failure of insulin to stimulate GLUT4 translocation to the plasma membrane from an intracellular pool (1). The thiazolidinedione analog Pioglitazone (PIO) has been shown to improve glucose tolerance in this and other animal models of insulin resistance. The current study was designed to determine whether 7 days of Pioglitazone treatment (20 mg/kg/day by gavage) would improve glucose transport and/or glucose transporter translocation and intrinsic activity in plasma membranes prepared from hindlimb skeletal muscle of obese Zucker (fa/fa) rats. Basal plasma glucose and insulin concentrations in these animals were unchanged by Pioglitazone, while basal plasma triglyceride and nonesterified fatty acid concentrations (NEFA) were reduced by Pioglitazone treatment (501 +/- 88 vs 161 +/- 13 mg/dl, P < 0.0001) and (678 +/- 95 vs 467 +/- 75 microM, P < 0.05) respectively. Pioglitazone had no effect on basal or insulin stimulated glucose influx (Vmax or Km) into plasma membrane vesicles determined under equilibrium exchange conditions compared to controls. Plasma membrane glucose transporter number (R0) (measured by cytochalasin B binding) under basal or insulin stimulated conditions was unchange by Pioglitazone and R0 failed to increase following insulin stimulation in either group. Glucose transporter turnover number (Vmax/R0) increased 2-fold with insulin stimulation compared to basal in both control and Pioglitazone groups, similar to turnover numbers observed in normal rats. These data confirm that impaired glucose transporter translocation in muscle of the Zucker rat is a major factor contributing to its insulin resistance. We conclude that the improved glucose tolerance observed in fa/fa rats following Pioglitazone treatment is not due to an improvement in basal or insulin stimulated skeletal muscle plasma membrane glucose transport or glucose transporter translocation and that Pioglitazone treatment does not affect transporter intrinsic activity.
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PMID:Pioglitazone treatment for 7 days failed to correct the defect in glucose transport and glucose transporter translocation in obese Zucker rat (fa/fa) skeletal muscle plasma membranes. 769 42

This study aimed to demonstrate directly that the thiazolidinedione pioglitazone acts as an insulin sensitizer. We tested the hypothesis that pioglitazone treatment of diabetic rats alters liver function such that responsiveness of selected genes to subsequent insulin regulation is enhanced. Although flux through gluconeogenic/glycolytic pathways involves regulation of many enzymes, we presently report the effects of insulin on expression of two key enzymes in these metabolic pathways, ie, phosphoenolpyruvate carboxykinase (PEPCK) and glucokinase (GK). Rats were either studied as nondiabetic controls or injected with streptozotocin as a model for insulin-deficient diabetes. Diabetic animals were treated without or with pioglitazone and subsequently examined for acute responses to insulin. Pioglitazone treatment of diabetic animals significantly enhanced the effects of insulin to reverse elevated blood glucose. Although the mean level of liver mRNA transcripts encoding PEPCK was increased to nearly 300% in diabetic animals as compared with nondiabetic controls (100%), it was significantly lower in pioglitazone-treated diabetic rats (119% of control) than in diabetic rats without pioglitazone (223% of control) after insulin treatment. By contrast, mRNA transcripts encoding GK were not detectable in diabetic animals, but were increased markedly by insulin treatment in all animal groups. Insulin-enhanced expression of GK was significantly greater in liver from animals that were treated earlier with pioglitazone (291% of control) than in liver from those that were untreated (214% of control). An amplified acute response of liver to insulin thus established pioglitazone as an insulin sensitizer. Our findings further showed that such sensitization can be developed even in the insulin-deficient state.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin sensitization in diabetic rat liver by an antihyperglycemic agent. 788 86

Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic insulin clamp studies in conscious animals, the glucose clearance rate was increased (P < .05) in pioglitazone-treated DS rats (36 +/- 3 mg/kg per minute) compared with control DS rats (27 +/- 1 mg/kg per minute). However, pioglitazone did not affect the glucose clearance rate in one-kidney, one clip hypertensive rats. Metformin, an unrelated agent that also improves glucose tolerance, had no significant effect on blood pressure or glucose clearance rate in either DS or one-kidney, one clip rats. Thus, the hypotensive effect of pioglitazone is not invariably associated with its capacity to improve insulin-induced glucose utilization.
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PMID:Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity. 802 Sep 98


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