An ultra-long acting insulin enables glucose-synchronised release

作者：Yang Zhang, Juan Zhang, Kangfan Ji, Shaoqian Mei, Su Chen, Yanfang Wang, Guangzheng Xu, Hui Zhang, Junhuan Lin, Xuehui Huang, Xiuwen Zhang, Kexin Xu, Jianchang Xu, Leihao Lu, Mowei Zhou, Wei Huang, Jian Yao, Chuhuan Jiang, Junjie Yan, Xiangsheng Liu, Peifeng Liu, John B. Buse, Shiming Zhang, Jinqiang Wang, Zhen Gu · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.10.12.681846 · 被引用次数：2 · 研究领域：Adipose Tissue and Metabolism、Diabetes Management and Research、Metabolism, Diabetes, and Cancer

Abstract Delayed and weak glucose-responsive kinetics, coupled with short plasma exposure and complicated formulation, remain major obstacles to the clinical translation of glucose-responsive insulin formulations. Here we report a rapidly absorbable, ultra-long acting, and glucose-responsive insulin analogue via engineering recombinant human insulin with two phenylboronic acids. The insulin analogue has a long circulating half-life (t 1/2 β ∼150 h) due to its unique, unprecedented, glucose-responsive binding to blood circulation-associated proteins. This interaction drives the formation of a unique systemic reservoir that allows synchronised dynamic response in insulin levels to glucose fluctuations. In type 1 diabetic mice and minipigs, a single subcutaneous dose can maintain normoglycaemia for over one week (47.5-fold compared to insulin glargine). After the last injection of four consecutive weekly administrations in mice, the glucose-lowering effect can last 800 hours. Administering this glucose-responsive insulin analogue with a fully automated insulin delivery system can leverage dual closed loops and achieve a glucose time in range of over 85% and a coefficient of variation of approximately 30%, better than the recommended targets for human therapy. Importantly, no toxicity was identified in the study.