An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42139356.
- Also identified by DOI 10.1126/sciadv.aeb7558 and PMC identifier 13178572.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 (<b>1</b><sub>Ins</sub>), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. <b>1</b><sub>Ins</sub> binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo-electron microscopy structures reveal how minimal substitutions in <b>1</b><sub>Ins</sub> enable effective binding to both IR-A and IGF-1R. In neuronal cells, <b>1</b><sub>Ins</sub> robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, <b>1</b><sub>Ins</sub> regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to <b>1</b><sub>Ins</sub>. These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.
Medical subject headings
- Insulin
- Signal Transduction
- Receptor, IGF Type 1
- Receptor, Insulin
- Protein Engineering