Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.

Summary

By functionally profiling ~14,000 extracellular INSR missense variants for expression, ligand binding, and signalling, the study generates a sequence–function atlas that correlates with clinical phenotypes and reveals variants responsive to monoclonal antibody agonism. These data enable rapid classification of variants of uncertain significance and inform precision treatment strategies in severe insulin resistance.

Key Findings

• Generated function scores for ~14,000 INSR extracellular missense variants across expression, insulin binding, and signalling readouts.
• Function scores strongly correlated with clinical insulin resistance syndromes, enabling variant stratification.
• Identified variants amenable to activation by monoclonal antibody agonists, revealing translational therapeutic opportunities.

Clinical Implications

Facilitates clinical interpretation of INSR variants, supports patient stratification for anti-receptor antibody therapies, and may accelerate precision care for genetic insulin resistance syndromes.

Limitations

• Focus on the ectodomain may not capture defects from intracellular domains or trafficking in native tissues
• Cell-based overexpression systems may not fully recapitulate in vivo glycosylation and receptor context

Future Directions

Extend mapping to full-length receptor and in vivo models; prospectively integrate function scores into clinical variant interpretation pipelines and trial patient selection for anti-INSR therapies.