An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling

Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (1_Ins), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. 1_Ins binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo-electron microscopy structures reveal how minimal substitutions in 1_Ins enable effective binding to both IR-A and IGF-1R. In neuronal cells, 1_Ins robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, 1_Ins regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to 1_Ins. These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.