Morishita Ken-Ichi, Kakuta Hiroki
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700- 8530, Japan.
Curr Top Med Chem. 2017;17(6):696-707. doi: 10.2174/1568026616666160617085545.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that plays an important role in regulating glucose metabolism. Agonists of PPARγ, such as thiazolidinediones, have anti-hyperglycemic activity, and are therefore used to treat type 2 diabetes. However, the functional activity of PPARγ is manifested by heterodimers of PPARγ with retinoid X receptors (RXRs). Since RXR/PPARγ heterodimers can be activated not only by PPARγ agonists, but also by RXR agonists, RXR agonists are also attractive candidates for treatment of type 2 diabetes. However, RXR full agonists have side effects, such as triglyceride elevation and hypothyroidism. Therefore, RXR partial agonists have been developed as new anti-type 2 diabetes agent candidates with reduced side effects. In addition, RXR antagonists also show therapeutic potency in type 2 diabetes patients. Here, we review RXR full agonists, RXR antagonists, and RXR modulators (partial agonists) with reported anti-diabetic effects, and we discuss their potential suitability as anti-diabetic agents.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种依赖配体的转录因子，在调节葡萄糖代谢中起重要作用。PPARγ激动剂，如噻唑烷二酮类，具有抗高血糖活性，因此被用于治疗2型糖尿病。然而，PPARγ的功能活性由PPARγ与视黄酸X受体（RXR）的异二聚体表现出来。由于RXR/PPARγ异二聚体不仅可以被PPARγ激动剂激活，还可以被RXR激动剂激活，RXR激动剂也是治疗2型糖尿病的有吸引力的候选药物。然而，RXR完全激动剂有副作用，如甘油三酯升高和甲状腺功能减退。因此，RXR部分激动剂已被开发为副作用减少的新型抗2型糖尿病药物候选物。此外，RXR拮抗剂在2型糖尿病患者中也显示出治疗效力。在此，我们综述了具有报道的抗糖尿病作用的RXR完全激动剂、RXR拮抗剂和RXR调节剂（部分激动剂），并讨论了它们作为抗糖尿病药物的潜在适用性。
