Small Molecule Insulin Sensitisers: New Leads and Targets for Next-Generation Insulin Sensitising Strategies

Type 2 diabetes (T2D) is a major global health problem driven largely by insulin resistance, the impaired cellular response to insulin. Few current therapies directly address this underlying cause. Thiazolidinediones, potent peroxisome proliferator-activated receptor gamma (PPARγ) agonists, remain the only true small-molecule insulin sensitisers, but their clinical use is limited by adverse effects associated with non-selective activation of this target. Consequently, research has shifted toward alternative pathways that enhance insulin signalling without relying on PPARγ agonism. This review summarises advances from 2013 to 2025 in the development of novel small-molecule insulin sensitisers across diverse scaffolds and mechanisms. Structure-activity relationships, established and emerging molecular targets, and structural insights that inform rational drug design are highlighted. Selected leads were also evaluated using the BOILED-Egg model to assess oral drug-likeness and early "technology readiness." Overall, this review aims to inspire medicinal chemists by presenting promising leads and strategies for the development of next-generation insulin-sensitising therapeutics.