Authors: František Hubálek, Christian N. Cramer, Hans Helleberg, Eva Johansson, Erica Nishimura, Gerd Schluckebier, Dorte Bjerre Steensgaard, Jeppe Sturis, Thomas B. Kjeldsen
Published: 2024-07-20
DOI: 10.1038/s41467-024-50477-9
Source: Full article
AbstractInsulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol–disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol–disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.