Chen Yadan, Ma Haiming, Zhu Dasheng, Zhao Guowei, Wang Lili, Fu Xiujuan, Chen Wei
Department of Pharmacy, The Second Hospital of Jilin University, Changchun 130041, China.
Department of Pharmacy, China-Japan Union Hospital of Jilin University, Changchun 130041, China.
PPAR Res. 2017;2017:8360919. doi: 10.1155/2017/8360919. Epub 2017 Jun 4.
Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor - (PPAR-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPAR agonists, selective PPAR modulators (sPPARMs), PPAR-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPAR, along with agents, such as heat shock protein (HSP) inducers, 5'-adenosine monophosphate-activated protein kinase (AMPK) activators, 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers.
胰岛素抵抗是2型糖尿病（T2DM）无可争议的根本原因。由于某些已获批的胰岛素增敏剂（如噻唑烷二酮类药物（TZDs））因安全性问题被限制处方或退市，目前对安全有效的胰岛素增敏剂存在未满足的需求。因此，没有类似TZDs副作用的有效胰岛素增敏剂对糖尿病患者将非常宝贵。在过去几十年中，对基于过氧化物酶体增殖物激活受体-（PPAR-）的药物的特别关注可能阻碍了新型和更安全的胰岛素增敏剂的研发。本综述讨论了新型胰岛素增敏剂未来研发的可能方向和有前景的策略，并描述了这些药物的潜在靶点。文中描述了直接PPAR激动剂、选择性PPAR调节剂（sPPARMs）、PPAR保留化合物（包括TZDs线粒体靶点的配体）、靶向PPAR下游效应器的药物，以及可能比传统TZDs更安全的药物，如热休克蛋白（HSP）诱导剂、5'-腺苷单磷酸激活蛋白激酶（AMPK）激活剂、11-β-羟基类固醇脱氢酶1型（11-HSD1）选择性抑制剂、双胍类药物和氯喹。因此，本小型综述旨在为新一代安全胰岛素增敏剂的研发提供新的视角。
