Peroxisome proliferator-activated receptor insulin sensitization

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 . 

Thiazolidinediones (synonyms glitazones, insulin sensitizers rosiglitazone, pioglitazone) are a novel class of oral antidiabetic drugs that activate the transcription factor peroxisome proliferator-activated receptor (PPARy). Thiazolidinediones ameliorate insulin resistance in obese animal models and in individuals... 

Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-y). Stimulation of PPAR-y results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. 

HP-jS-CD were added. All compounds were resolved in 20 min (see Figure 5). The data indicated that the validated method offered equivalent and complementary information, in terms of selectivity, sensitivity, accuracy, linearity, and precision, to that of an established gradient LC method employed for similar purposes. Ragaglitazar is a dual peroxisome proliferator-activated receptor ot and y agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. A chiral CZE method combining two CDs, sulfobutylether-jS-CD and dimethyl-/i-CD, lent itself to the analysis of ragaglitazar, its distomer (the (+)... 

Thiazolidinediones are the newer agents that favourably influence insulin sensitivity and possibly also pancreatic fS-cell function. The biological response of thiazolidinediones is mediated by binding to the nuclear peroxisome proliferator-activated receptor-y (PPAR)... 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998). A novel insulin sensitizer acts as a coligand for peroxisome proliferator-Activated Receptor-Alpha (PPAR-alpha) and PPAR-Gamma Effect of PPAR-Alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats. Diabetes AT, 1841-1847. 

Mori, Y., Kim-Motoyama, H., Katakura, T., Yasuda, K., Kadowaki, H., Beamer, B. A., Shuldiner, A. R., Akanuma, Y., Yasaki, Y., and Kadowaki, T. (1998). Effect of the Prol2Ala Variant of the Human Peroxisome Proliferator-Activated Receptor y2 Gene on Adiposity, Fat Distribution, and Insulin Sensitivity in Japanese Men. Biochem. Biophys. Res. Commun. 251, 195-198. 

Thiazolidinediones (e.g., rosiglitazone 4) reduce insulin resistance (insuhn sensitizers). These compounds stimulate peroxisome-proliferator-activated receptors (PPARs) on the nuclear surface, leading to increased glucose uptake and reduced hepatic gluconeogenesis [50]. 

Troglitazone is an example of the thiozolidinedione class of antidiabetic agents. It enhances insulin sensitivity in liver, muscle, and adipose tissue. Troglitazone promotes the conversion of non-lipid-storing preadipocytes to mature adipocytes (discussed later) with increased insulin sensitivity. The cellular target for the action of troglitazone, which functions as a transcription factor, is the nuclear receptor known as peroxisome proliferation-activated receptor-/ (PPAR-/). PPAR-/ upon binding... 

Bind to nuclear peroxisome proliferator-activating receptors (PPARs) involved in transcription of insulin-responsive genes —> sensitization of tissues to insulin, plus 4- hepatic gluconeogenesis and triglycerides and t insulin receptor numbers (Figure VII-2-2). 

Drew, B.G. and Calkin, A.C. (2007) Drug evaluation K-lll, an insulin-sensitizing peroxisome proliferators activated receptor a agonist. Current Opinion in Investigational Drugs, 8, 324—330. 

SREBPs interact with several co-activators and act in conjunction with several other transcription factors (Bengoechea-Alonso and Ericsson, 2007 Weber et ah, 2004). This could lead to other signal-sensitive co-activation of SREBP activity. For instance, the peroxisome proliferator activated receptor general co-activator (3 (PGC-1 p) interacts with and stimulates SREBP-lc activity in the liver of mice fed a diet rich in saturated fatty acids (Lin et ah, 2005). Chromatin remodelling complexes have also recently been shown to interact with SREBP-lc and contribute to insulin sensitivity (Lee et ah, 2007). 

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