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Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec.


ABSTRACT: Insulin 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.

SUBMITTER: Hubalek F 

PROVIDER: S-EPMC11271312 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec.

Hubálek František F   Cramer Christian N CN   Helleberg Hans H   Johansson Eva E   Nishimura Erica E   Schluckebier Gerd G   Steensgaard Dorte Bjerre DB   Sturis Jeppe J   Kjeldsen Thomas B TB  

Nature communications 20240720 1


Insulin 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  ...[more]

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