The therapeutic potential of inhibiting PPAR gamma phosphorylation to treat type 2 diabetes

A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor. (PPAR.) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPAR. signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPAR gamma ligands can abolish the phosphorylation of PPAR. at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPAR gamma in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.

Automated summary

This review discusses the role of PPAR gamma in type 2 diabetes mellitus and the effects of synthetic ligands on the modulation of these roles. It emphasizes the critical importance of understanding the mechanism by which ligands prevent phosphorylation for future research in T2DM treatment.