PPARy agonists

Thiazolidinediones Pioglitazone, rosiglitazone Improve insulin action (PPARy agonists) Oral... 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

Khanna S, Bahai R, Bharatam PV (2006) In silica Studies on PPARy Agonistic Heterocyclic Systems. 3 149-182... 

PPARy agonists Novel biomarine lipoproteins E-SAR-94010 Ebiotec... 

The authors postulated that there had been an increase in orbital fat in parallel to the increase in abdominal fat. Rosiglitazone can reactivate thyroid inflammatory orbito-pathy and treatment of orbital fibroblasts in culture with PPARy agonists can stimulate thyrotropin hormone receptor expression and subsequently promote adipogen-esis (69). 

E. Thiazolidinedione PPARy Agonists Improve Insulin Sensitivity. 197... 

I). Mechanisms of Insulin Sensitization by PPARy Agonists 1. Correlation Between PPARy Activation and in Vivo Efficacy by Compounds... 

When studied under more controlled conditions using the eug-lycemic hyperinsulinemic clamp method, it is apparent that chronic treatment of insulin-resistant rats with PPARy agonists can substantially improve peripheral insulin-stimulated glucose disposal and the ability of insulin to suppress hepatic glucose production (67, 71, 72). 

We have observed that suppression of elevated FFA levels is a very rapid (less than 12 hour) response to treatment of insulin-resistant rats with PPARy agonists (T. Doebber, unpublished data). Since PPARy agonists are known to promote adipose tissue uptake and storage of fatty acids, it is plausible that this effect constitutes a major mechanism of insulin sensitization, whereby elevated FFAs—a known cause of hepatic and muscle insulin resistance—can be alleviated. An additional effect of in vivo PPARy activation, shown to occur in rats, was an increase in the number of small white adipocytes, along with a relative shift in the size of visceral (decreased) versus subcutaneous (increased) adipose depots (73). This has important implications because visceral adiposity and larger fat cells are both associated with insulin resistance. 

Although chronic in vivo PPARy activation promotes insulin sensitization of both muscle and fat, we recently showed that, despite the presence of low levels of PPARy protein in this tissue, direct in vitro incubation of skeletal muscles with PPARy agonists does not enhance... 

Several studies have attempted to define specific effects of thiazo-lidinediones on aspects of insulin-mediated signal transduction in cultured cells. The most consistent results involve an increase in insulin-mediated PI-3-K activation (81, 82). A potential mechanism for enhanced insulin signaling at this level is an increase in insulin stimulation of IRS-1 phosphorylation, as demonstrated by Liu et al. (83). Since direct effects on insulin signaling have not been carefully correlated with in vivo effects or demonstrated with nonthiazolidinedione PPARy agonists, it is not clear if such effects are PPARy-mediated or if they really contribute to in vivo efficacy. 

Thiazolidinedione PPARy agonists have also been reported to induce terminal differentiation of malignant breast epithelial cells (105), which suggests that PPARy activation could be used in the treatment of breast cancer. Recently, it was also shown that ligands for PPARy are inhibitors of angiogenesis (106) however, the dose-response characteristics in this study do not agree with those for receptor binding and activation (9). 

Administration of high dose of thiazolidinedione PPARy agonists to animals has reportedly resulted in a number distinct toxic effects, such... 

Actos Pioglitazone Takeda/Eli Lilly diabetes PPARy agonist 1151 (79%)... 

Avandia Rosiglitazone GlaxoSmithKline diabetes PPARy agonist 1128 (65%)... 

Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer s disease inhibition of f -amyloid-stimulated proinflammatory responses and neurotoxicity by PPARy agonists. J Neurosci 20 558-567... 

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