Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia.
Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia.
Eur J Pharmacol. 2015 May 15;755:50-7. doi: 10.1016/j.ejphar.2015.02.043. Epub 2015 Mar 5.
Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists.
长期以来，过氧化物酶体增殖物激活受体 (PPARs) 被描述为核受体超家族的成员，它调节参与葡萄糖和脂质代谢的蛋白质的基因表达。PPARs 确实调节了多种生理过程，包括脂质稳态、脂肪生成、炎症和伤口愈合。PPARs 结合天然或合成的 PPAR 配体可以作为细胞传感器发挥作用，调节基因转录。血脂异常和 2 型糖尿病 (T2DM) 伴胰岛素抵抗分别采用 PPARα 和 PPARγ 的激动剂进行治疗。PPARγ 是胰岛素敏感性和葡萄糖代谢的关键调节剂，因此被认为是对抗糖尿病代谢疾病和胰岛素抵抗的重要药理学靶点。值得注意的是，目前可用的 PPARγ 全激动剂，如罗格列酮，会显示出严重的不良反应，如液体潴留/水肿、体重增加和心血管事件发生率增加。另一方面，正在研究 PPARγ 部分激动剂，以避免或减少这些不良事件的发生，并且处于开发阶段。目前的研究正在开发新型 PPARγ 部分激动剂，以增强治疗效果并减少不良反应。这篇综述阐明了 PPARγ 部分激动剂在 T2DM 管理中的开发现状，与 PPARγ 全激动剂相比，这些激动剂的不良反应相对较少或没有。
