PDF(Pubmed)
Abstract：
Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes, its therapeutic potential is compromised by its short half-life and narrow therapeutic index. Current long-acting insulin analogs, such as insulin-polymer conjugates, are mainly used to improve pharmacokinetics by reducing renal clearance. However, these conjugates are synthesized without sacrificing the bioactivity of insulin, thus retaining the narrow therapeutic index of native insulin, and exceeding the efficacious dose still leads to hypoglycemia. Here, we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance. By impairing the binding affinity to the receptor and the activation of the receptor, di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly, increases its maximum tolerated dose 10-fold. The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose. This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.
摘要：
尽管100年前胰岛素的发现彻底改变了糖尿病的治疗方法，其治疗潜力因其半衰期短和治疗指数窄而受损。目前的长效胰岛素类似物，如胰岛素-聚合物缀合物，主要用于通过减少肾脏清除率来改善药代动力学。然而,这些结合物是在不牺牲胰岛素生物活性的情况下合成的，因此保留了天然胰岛素的狭窄治疗指数，超过有效剂量仍然会导致低血糖。这里,我们报道了一种可以同时降低肾脏清除率和受体介导的清除率的双聚乙二醇化胰岛素。通过削弱与受体的结合亲和力和受体的激活，与经典的单聚乙二醇化胰岛素相比，双聚乙二醇化胰岛素不仅进一步延长了胰岛素的半衰期，而且最重要的是，增加其最大耐受剂量10倍。通过改善的药代动力学和高剂量已经实现了体内长期血糖管理的目标。这项工作代表了朝着长效胰岛素药物迈出的重要一步，在减少低血糖事件方面具有出色的安全性。
