Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects

Chaiken, Rochelle L; Eckert-Norton, Margaret; Pasmantier, RoseMarie; Boden, Günther; Ryan, I.; Gelfand, R

doi:10.1007/s001250050428

Cited by 6 publications

(9 citation statements)

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“…The antihyperglycaemic properties of TZDs were brought to attention by descriptions of ciglitazone in the early 1980s[17] ( Table 2). Amongst the succession of TZDs that followed, troglitazone, pioglitazone, englitazone, darglitazone and rosiglitazone (BRL 49653) have been most extensively reported[18–21] ( Fig. 1).…”

Section: Historical Perspectivementioning

confidence: 99%

Thiazolidinediones: a new class of antidiabetic drugs

1999

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Thiazolidinediones (TZDs) are a new class of oral antidiabetic agents. They selectively enhance or partially mimic certain actions of insulin, causing a slowly generated antihyperglycaemic effect in Type 2 (noninsulin dependent) diabetic patients. This is often accompanied by a reduction in circulating concentrations of insulin, triglycerides and nonesterified fatty acids. TZDs act additively with other types of oral antidiabetic agents (suphonylureas, metformin and acarbose) and reduce the insulin dosage required in insulin-treated patients. The glucose-lowering effect of TZDs is attributed to increased peripheral glucose disposal and decreased hepatic glucose output. This is achieved substantively by the activation of a specific nuclear receptor - the peroxisome proliferator-activated receptor-gamma (PPARgamma), which increases transcription of certain insulin-sensitive genes. To date one TZD, troglitazone, has been introduced into clinical use (in Japan, USA and UK in 1997). This was suspended after 2 months in the UK pending further investigation of adverse effects on liver function. TZDs have been shown to improve insulin sensitivity in a range of insulin-resistant states including obesity, impaired glucose tolerance (IGT) and polycystic ovary syndrome (PCOS). In Type 2 diabetes, the TZDs offer a new type of oral therapy to reduce insulin resistance and assist glycaemic control.

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Section: Historical Perspectivementioning

confidence: 99%

Thiazolidinediones: a new class of antidiabetic drugs

1999

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“…R e c e n t l y, thiazolidinedione and its derivatives, which enhance insulin action without stimulating -cell insulin secretion (52)(53)(54), have become available for the treatment of NIDDM. These agents bind to peroxisome proliferatoractivated receptor-and restore the impaired early steps of insulin action preceding PI 3-kinase activation (55)(56)(57)(58) and thus have been shown to improve insulin resistance dramatically in several diabetic animal models in which PI 3-kinase activation is impaired-for example, Zucker fatty rats, Zucker diabetic rats, o b/o b mice, d b/d b mice, and KK-Ay mice (59)(60)(61).…”

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confidence: 99%

Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.

Anai

Funaki²,

Ogihara³

et al. 1999

Diabetes

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Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. In contrast with the liver, tyrosine phosphorylation levels and associated PI 3-kinase proteins and activities were decreased in the muscle and adipose tissue of high-fat-fed rats. Thus, high-fat feeding appears to cause insulin resistance in the liver by a mechanism different from the impaired PI 3-kinase activation observed in muscle and adipose tissue. Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. This is the first report to show increased PI 3-kinase activation by insulin in an insulin-resistant diabetic animal model. These findings may be important for understanding the mechanism of insulin resistance in human NIDDM, since a high-fat diet is considered to be one of the major factors exacerbating insulin insensitivity in humans.

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“…Thiazolidinediones (TZD) are a recently identified class of antidiabetic agents that act by improving insulin sensitivity in various animal models of obesity and diabetes (1)(2)(3) as well as in humans (4,5). In addition to improving glucose and insulin levels, the circulating free fatty acids (FFA) and triglycerides are also lowered.…”

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confidence: 99%

Thiazolidinediones (PPARγ agonists) but not PPAR α agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes¹

et al. 2001

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Thiazolidinediones (TZD) improve insulin sensitivity in human as well as in different animal models of insulin resistance and Type 2 diabetes. However, no clear link to the insulin signaling events has been identified. Using differentiated 3T3-L1 adipocytes, we found that TZD rapidly and markedly increased IRS-2 gene expression. This effect was specific for PPARgamma agonists and was not seen with PPARalpha agonists. It was rapidly induced (within 4 h) and maintained throughout the observation period of 48 h. It was also concentration dependent (EC50 approximately 50 nM) and not inhibited by cycloheximide, suggesting a direct effect on the IRS-2 promoter. There was no evidence that TZD altered IRS-2 mRNA stability, supporting that the increased mRNA levels were due to an increased gene transcription. IRS-2 protein expression was increased approximately 30% after 48 h and approximately 50% after 96 h. No effects of TZD were seen on IRS-1, PKB/Akt, or GLUT4 gene expression. TZD also increased IRS-2 mRNA levels in cultured human adipose tissue. These data show the first direct link between TZD and a critical molecule in insulin's signaling cascade in both 3T3-L1 and human adipocytes, and indicate a novel mode of action of these compounds.

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Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects

Cited by 6 publications

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Thiazolidinediones: a new class of antidiabetic drugs

Thiazolidinediones: a new class of antidiabetic drugs

Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.

Thiazolidinediones (PPARγ agonists) but not PPAR α agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes¹

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Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects

Cited by 6 publications

References 0 publications

Thiazolidinediones: a new class of antidiabetic drugs

Thiazolidinediones: a new class of antidiabetic drugs

Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.

Thiazolidinediones (PPARγ agonists) but not PPAR α agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes1

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Thiazolidinediones (PPARγ agonists) but not PPAR α agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes¹