Balakumar Pitchai, Rose Madhankumar, Ganti Subrahmanya S, Krishan Pawan, Singh Manjeet
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Pharmacol Res. 2007 Aug;56(2):91-8. doi: 10.1016/j.phrs.2007.03.002. Epub 2007 Mar 14.
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 PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta 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 PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma 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, PPARalpha/gamma 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 PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta 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 PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.
心血管疾病是糖尿病患者死亡的主要原因。过氧化物酶体增殖物激活受体（PPARs）是核激素受体超家族的配体激活转录因子，包括PPARα、PPARγ和PPARδ/β三种亚型。PPARα的激活可降低甘油三酯，并参与能量稳态的调节。PPARγ的激活可导致胰岛素增敏并增强葡萄糖代谢，而PPARδ的激活可增强脂肪酸代谢。目前可用于治疗糖尿病的治疗策略并不能抑制相关的继发性心血管并发症。因此，开发能够降低高血糖并同时抑制继发性心血管并发症进展的多模式药物可能会提供有价值的治疗选择。多项基础和临床研究已例证了PPARα和PPARγ配体在预防心血管风险方面的有益作用。PPARα/γ双重激动剂已被开发出来，以提高胰岛素敏感性并同时预防糖尿病心血管并发症。此类化合物正在进行临床试验，并被提议用于治疗伴有继发性心血管并发症的II型糖尿病。然而，已注意到muraglitazar、tesaglitazar和ragaglitazar等PPARα/γ双重激动剂会产生多种心血管风险和致癌性，这引发了关于双重激动剂在糖尿病及其相关并发症临床应用的诸多问题。正在进行的基础研究已阐明了PPARδ的心脏保护作用。因此，进一步的研究正在进行中，以开发用于治疗糖尿病心血管并发症的PPARα/δ和PPARγ/δ双重激动剂以及PPARα/γ/δ泛激动剂。本综述批判性地分析了PPAR激动剂在糖尿病心血管并发症中的保护和有害作用。此外，还讨论了新开发的PPARα/δ和PPARγ/δ双重激动剂以及PPARα/γ/δ泛激动剂，它们可能在不久的将来为糖尿病心血管并发症的管理开辟新的前景。
