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 gamma- (PPAR gamma-) 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 gamma agonists, selective PPAR gamma modulators (sPPAR gamma Ms), PPAR gamma- sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstreameffectors of PPAR gamma, along with agents, such as heat shock protein (HSP) inducers, 5'-adenosine monophosphate-activated protein kinase (AMPK) activators, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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.
[1]Jilin Univ, Hosp 2, Dept Pharm, Changchun 130041, Peoples R China.
[2]Jilin Univ, China Japan Union Hosp, Dept Pharm, Changchun 130041, Peoples R China.
[3]Beijing Boai Hosp, Dept Pharm, China Rehabil Res Ctr, Beijing 100068, Peoples R China.
[4]Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China.
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