Abstract
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 γ- (PPARγ-) 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 PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-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.
Highlights
According to the World Health Organization, the morbidity of diabetes mellitus (DM), which is a global noninfectious epidemic disease, is expected to continue to rise in the coming decades [1]
The surge in type 2 DM (T2DM) that affects more than 90% of diabetic patients can be attributed to the increasing prevalence of insulin resistance (IR) in the general population, which is partially triggered by the widespread occurrence of obesity and metabolic syndrome [2]
Selective peroxisome proliferator-activated receptor γ (PPARγ) modulators are mainly compounds that bind with PPARγ but exhibit little or no agonism and instead inhibit PPARγ phosphorylation at serine 273 in a tissue-selective manner [6]; peroxisome proliferator-activated receptor γ- (PPARγ-)sparing compounds include those that do not bind with PPARγ but bind with the newly identified mitochondrial targets of TZDs, that is, the mitochondrial outer or inner membrane proteins [7, 8], compounds that target the downstream effectors of PPARγ, such as the adiponectin and fibroblast growth factor 21 (FGF21) signaling pathways, heat shock protein (HSP) inducers, 5 adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, and molecules such as biguanides and chloroquines (CQs), whose molecular targets or mechanisms are still not completely understood
Summary
According to the World Health Organization, the morbidity of diabetes mellitus (DM), which is a global noninfectious epidemic disease, is expected to continue to rise in the coming decades [1]. IR, which has been considered a root cause of T2DM, is a pathological state in which the target cells in liver, skeletal muscle, and adipose tissue fail to respond properly to insulin, resulting in their inability to efficiently uptake and metabolize glucose [3,4,5]. Agents target to the downstream effectors of PPAR (i) Adiponectin activator/agonist (ii) FGF receptor targeted ligand (iii) Derivatives of FGF21 and FGF1. Market during the past decade for the treatment of T2DM and/or DM-related diseases, none of them target IR except for insulin sensitizers such as thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor γ (PPARγ) agonists. Insulin sensitizers, which exert positive effects on both insulin target tissues and the pancreas, can potentially reverse the course of the disease and prevent the progression to diabetic complications. This review focuses on recent advances in understanding the pathophysiological mechanisms of IR and describes the PPARγ targets of the classical insulin sensitizers and beyond PPARγ, some newly discovered targets
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