PDF(Pubmed)
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.
摘要：
胰岛素icodec是一种每周一次的胰岛素类似物，具有约7天的长半衰期，使其适合每周一次给药。胰岛素icodec分子是基于降低胰岛素受体亲和力并引入强白蛋白结合部分将导致长胰岛素半衰期的假设而开发的。前提是非受体介导的清除减少。这里,我们报告了胰岛素清除机制，导致胰岛素分子通过硫醇-二硫化物交换反应分裂为其A链和B链。即使胰岛素icodec中的取代显着稳定胰岛素抵抗这种降解，在小型猪和2型糖尿病患者的血浆样本中观察到一些游离的B链。总之,我们确定硫醇-二硫化物交换反应是一种重要的胰岛素清除机制，并发现稳定icodec胰岛素对该反应显着有助于其长期药代动力学/药效学特征。
