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

A new oral agent, 5-[4-(2-(5-ethyl 12-pyridyl)ethoxy]- benzoyl]-2,4-thiazolidinedione (pioglitazone), has been developed for treatment of non-insulin-dependent diabetes mellitus (NIDDM). This agent increases insulin sensitivity in vivo in genetically obese Wistar fatty rats. Administration of the agent (3 mg/kg/day) for 10 days to the rats ameliorated hyperglycemia and hyperinsulinemia, indicating that it decreased insulin resistance. To clarify the mechanism of the drug to increase insulin sensitivity, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated rats. Pioglitazone treatment did not change insulin binding in Wistar fatty rats but increased insulin-stimulated autophosphorylation of insulin receptors to 78% over the level in the control but not the basal state. Kinase activity toward exogenous substrate, poly Glu4Tyr1, was also increased to 87% over the level of untreated control obese rats. In contrast, in lean rats, pioglitazone treatment did not increase autophosphorylation and kinase activity toward exogenous substrates. To further elucidate the mechanism, we incubated insulin receptors with the agent and measured kinase activity. Incubation of solubilized receptors with the agent did not increase kinase activity. However, the receptors from IM-9 cells, which were incubated with 10(-8) M pioglitazone for 7 days, showed a 46% increase over the control in insulin-stimulated autophosphorylation and kinase activity. These results suggested that pioglitazone increased insulin sensitivity in part by activating kinase of the receptors through indirect effect on insulin receptors and that the drug may have useful benefits in insulin resistance of NIDDM.
Diabetes 1992 Apr
PMID:Pioglitazone increases insulin sensitivity by activating insulin receptor kinase. 131 56

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.
Diabetes 1995 Aug
PMID:Insulin secretory defect in Zucker fa/fa rats is improved by ameliorating insulin resistance. 762 5

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

Tumor necrosis factor-alpha (TNF alpha) is a cytokine implicated in the development of septic shock, cachexia, and other pathological states. Recent studies indicated a direct role for adipose expression of TNF alpha in obesity-linked insulin resistance and diabetes. Pioglitazone, CP-86,325 (CP), AD-5075, CS-045, ciglitazone, and englitazone are members of a new class of insulin-sensitizing thiazolidinedione derivatives with in vivo antidiabetic activities. To test whether these agents antagonize the effect of TNF alpha, 3T3-L1 cells were induced to differentiate in the presence of TNF alpha with or without thiazolidinedione derivatives. Incubation of 3T3-L1 cells with TNF alpha alone completely inhibited adipocyte conversion and expression of fatty acid-binding protein messenger RNA (mRNA). However, coincubation of TNF alpha-treated cells with CP (1 microM), AD-5075 (1 microM), pioglitazone (10 microM), or CS-045 (10 microM) blocked these effects. Long term incubation of 3T3-L1 adipocytes with a low dose of TNF alpha (50 pM) significantly decreased the levels of the adipocyte/muscle-specific glucose transporter (GLUT4) and the CCAAT enhancer-binding protein mRNAs, but did not affect expression of the ubiquitously expressed glucose transporter (GLUT1) or lipoprotein lipase mRNAs. Incubation of 3T3-L1 adipocytes with TNF alpha also inhibited insulin-stimulated 2-deoxyglucose uptake as well as expression of GLUT4 protein. Furthermore, in 3T3-L1 adipocytes, incubation with TNF alpha attenuated the expression of fatty acid-binding protein mRNA in a time- and dose-dependent manner. These inhibitory effects were partially or completely blocked by coincubation of the cells with CP. These results implicate that the insulin-sensitizing agents may exert their antidiabetic activities by antagonizing the inhibitory effects of TNF alpha.
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PMID:Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. 789 57

The antidiabetic effects of pioglitazone hydrochloride were evaluated in 6 spontaneously obese, insulin-resistant rhesus monkeys. The animals were studied during six successive 2-wk treatment phases separated by 2-wk rest periods: two placebo phases; 0.3, 1.0, and 3.0 mg.kg-1 x day-1 pioglitazone hydrochloride phases; and a final placebo phase. During the second week of each treatment phase, serum insulin (immunoreactive insulin [IRI]), plasma glucose, and serum triglyceride (TG) levels were measured after an overnight fast and after a standardized meal. Blood pressure was measured and glucose tolerance tests (modified minimal model protocol) were performed a few days after the meal tests. Pioglitazone hydrochloride significantly improved fasting and postprandial levels of IRI, plasma glucose, and TG in a dose-related manner (P < 0.05). Fasting values during treatment with 3.0 mg.kg-1 x day-1 were reduced by 64% for IRI, 19% for plasma glucose, and 44% for TG compared with the placebo phase before treatment. Efficacy of pioglitazone hydrochloride was more marked for those animals with fasting hyperglycemia. Insulin sensitivity was increased by pioglitazone hydrochloride (P = 0.05), whereas glucose effectiveness and glucose disappearance rate were not detectably affected. Systolic and mean arterial blood pressures were significantly decreased by pioglitazone hydrochloride (P < 0.05). No toxic side effects of pioglitazone hydrochloride treatment were noted.
Diabetes 1994 Feb
PMID:Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys. 828 44

A new oral agent, 5-[4-[2-(5-ethyl-12-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione, or pioglitazone, has been developed for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). We examined its effectiveness in high-fat-fed rats resistant to insulin. Administration of the agent (10 mg.kg-1 x d-1) for 2 weeks resulted in decreases in hyperlipidemia and hyperinsulinemia, indicating that insulin sensitivity had increased in vivo in high-fat-fed rats. To clarify the mechanism of the drug, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated high-fat-fed rats. Pioglitazone treatment did not change insulin binding in high-fat-fed rats, but increased insulin-stimulated autophosphorylation of insulin receptors to the level of control animals. Kinase activity toward an exogenous substrate, poly Glu4-Tyr1, in pioglitazone-treated high-fat-fed rats was also increased to the level of control animals. These results suggest that pioglitazone increases insulin sensitivity by activating tyrosine kinase activity of receptors in high-fat-fed rats, and this drug appears to be a useful one with a new mode of action for the treatment of NIDDM with insulin resistance.
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PMID:Effect of pioglitazone on insulin receptors of skeletal muscles from high-fat-fed rats. 834 5


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