PPAR dual agonists: Are they opening Pandora's Box?
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- 作者：Pitchai Balakumar ; Madhankumar Rose ; Subrahmanya S. Ganti ; Pawan Krishan ; Manjeet Singh
- 关键词：PPAR dual agonists ; Diabetic cardiovascular complications ; PPAR pan agonists
- 刊名：Pharmacological Research
- 出版年：2007
- 出版时间：August 2007
- 年：2007
- 卷：56
- 期：2
- 页码：91-98
- 全文大小：391 K
文摘
Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARα, PPARγ and PPARδ/β. Activation of PPARα reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARγ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARδ enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARα and PPARγ ligands in preventing the cardiovascular risks. The PPARα/γ dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARα/γ dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARδ. Therefore, further studies are on the track to develop PPARα/δ and PPAR γ/δ dual agonists and PPARα/γ/δ pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPARα/δ and PPAR γ/δ dual agonists and PPARα/γ/δ pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.