TITLE

Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons

AUTHOR(S)
Tenenbaum, Alexander; Motro, Michael; Fisman, Enrique Z.
PUB. DATE
January 2005
SOURCE
Cardiovascular Diabetology;2005, Vol. 4, p14
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs - the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in latestage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan - (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
ACCESSION #
28682781

 

Related Articles

  • Arterial Compliance, Renal, Cardiac, Endocrine and Metabolic Disorders as a Predictors of Hypertension Syndrome. Desouky, Abdallah Morsy; Raafat, Manar; Metwaly, Amna Ahmed; El Shamaa, Azza; Abdallah, Emad // Journal of Medical Sciences;2007, Vol. 7 Issue 4, p503 

    Hypertension is a late manifestation of a syndrome consisting of dyslipidemia, insulin resistance, endocrine and renal dysfunction, obesity, left ventricular hypertrophy and diastolic dysfunction. The aim of this research is to study the arterial compliance, renal, cardiac, endocrine and...

  • Behavior of Insulin Resistance and Its Metabolic Correlates in Prepubertal Children. Jeffery, Alison N.; Alba, Sandra; Murphy, Michael J.; Voss, Linda D.; Metcalf, Brad S.; Hosking, Joanne; Gardner, Daphne S.-L.; Sattar, Naveed; Wilkin, Terence J. // Diabetes Care;Nov2007, Vol. 30 Issue 11, p2962 

    The article focuses on a study on the relationship between adiposity and insulin resistance in a cohort of prepubertal British students. It reveals that insulin resistance was not significantly associated with high density lipoproteins (HDL) cholesterol and it correlated weakly with adiponectin...

  • Effect of Melia composita willd. on Lipid profile in alloxan induced diabetic rats. Jothi, G.; Brindha, P. // Journal of Pharmacy Research;Apr2011, Vol. 4 Issue 4, p1033 

    Diabetes is a complex and multifarious group of disorder characterized by conditions such as hyperglycaemia, lipoprotein abnormalities and foot infection. In the present paper an attempt was made to study the beneficial efficiency of Melia composita. Willd. an ayurvedic drug in treating...

  • Potentiation of Insulin Signaling in Tissues of Zucker Obese Rats After Acute and Long-Term Treatment With PPARγ Agonists. Jiang, Guoqiang; Guoqiang Jiang; Qing Dallas-Yang; Dallas-Yang, Qing; Zhihua Li; Li, Zhihua; Szalkowski, Deborah; Liu, Franklin; Xiaolan Shen; Shen, Xiaolan; Wu, Margaret; Gaochao Zhou; Zhou, Gaochao; Doebber, Thomas; Berger, Joel; Moller, David E.; Zhang, Bei B. // Diabetes;Aug2002, Vol. 51 Issue 8, p2412 

    Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor-γ (PPARγ), improve insulin sensitivity in vivo, and the mechanism remains largely unknown. In this study, we showed that, in Zucker obese (fa/fa) rats, acute (1-day) treatment with both rosiglitazone (a TZD)...

  • Increased Visceral Fat and Serum Levels of Triglyceride Are Associated With Insulin Resistance in Japanese Metabolically Obese, Normal Weight Subjects With Normal Glucose Tolerance. Katsuki, Akira; Sumida, Yasuhiro; Urakawa, Hideki; Gabazza, Esteban C.; Murashima, Shuichi; Maruyama, Noriko; Morioka, Kohei; Nakatani, Kaname; Yano, Yutaka; Adachi, Yukihiko // Diabetes Care;Aug2003, Vol. 26 Issue 8, p2341 

    OBJECTIVE — The purpose of this study was to investigate the association between visceral adiposity or triglyceride (TG) metabolism and insulin resistance in metabolically obese, normal weight (MONW) Japanese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS —...

  • Low Self-Efficacy Lead to Failure in Adopting CHO-Counting Approach to Control Diabetes: Pilot Study. Tayyem, Reema Fayez; Abu-Mweis, S. Suhad; Bawadi, A. Hiba // Pakistan Journal of Nutrition;2013, Vol. 12 Issue 7, p651 

    This study aimed to evaluate the impact of self-efficacy in adopting carbohydrate counting behavior on their glycemic control, lipid profile and body weight among patients with type 2 diabetes. Self-efficacy was measured using chwarzer and Renner self-efficacy scale. All patients, regardless of...

  • Association of Retinol-Binding Protein-4 (RBP4) with Lipid Parameters in Obese Women. Broch, Montserrat; Gómez, José Manuel; Auguet, Ma Teresa; Vilarrasa, Nuria; Pastor, Rosa; Elio, Iñaki; Olona, Montserrat; García-España, Antonio; Richart, Cristóbal // Obesity Surgery;Sep2010, Vol. 20 Issue 9, p1258 

    Background: Although the adipokine retinol-binding protein-4 (RBP4) has been implicated in the development of obesity-related insulin resistance, its role in human obesity is still unclear. Our objectives were to find out the effect on RBP4 systemic levels of a weight loss induced by gastric...

  • The G0/G1 Switch Gene 2 Is an Important Regulator of Hepatic Triglyceride Metabolism. Wang, Yinfang; Zhang, Yahui; Qian, Hang; Lu, Juan; Zhang, Zhifeng; Min, Xinwen; Lang, Mingjian; Yang, Handong; Wang, Nanping; Zhang, Peng // PLoS ONE;Aug2013, Vol. 8 Issue 8, p1 

    Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an...

  • Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance. Amati, Francesca; Dubé, John J.; Alvarez-Carnero, Elvis; Edreira, Martin M.; Chomentowski, Peter; Coen, Paul M.; Switzer, Galen E.; Bickel, Perry E.; Stefanovic-Racic, Maja; Toledo, Frederico G. S.; Goodpaster, Bret H. // Diabetes;Oct2011, Vol. 60 Issue 10, p2588 

    OBJECTIVE-Chronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercisetrained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics