Glucose-sensitive insulin with attenuation of hypoglycaemia

Affiliations

• Global Research Technologies, Novo Nordisk, Bagsværd, Denmark
• Global Drug Discovery, Novo Nordisk, Bagsværd, Denmark
• APIGENEX, Prague, Czech Republic
• University of Bristol, Bristol, UK
• Carbometrics, Bristol, UK
• Digital Science and Innovation, Novo Nordisk, Bagsværd, Denmark

PMID:  #  DOI: 10.1038/s41586-024-08042-3

Abstract

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fuctuating glucose levels is difcult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor afnity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions.

胰岛素治疗糖尿病的主要难题是可能引发低血糖（即血糖过低）的风险。为了保证血糖保持在正常范围内，胰岛素剂量需要进行精确调整。然而，由于血糖水平会波动，调整胰岛素剂量非常困难，稍微多一点的胰岛素就可能导致低血糖，严重时甚至会危及生命。因此，长期以来的目标是开发一种对葡萄糖敏感的胰岛素，能够根据血糖水平的变化自动调节其活性，从而实现更好的血糖控制，同时降低低血糖的风险。本文介绍了一种名为NNC2215的胰岛素结合物及其特性。这种胰岛素结合物在体外和体内试验中展示了可逆的葡萄糖响应性，适用于糖尿病患者的葡萄糖水平。NNC2215是通过将一个葡萄糖结合的大环化合物和一个糖苷与胰岛素结合，从而引入了一个可以响应葡萄糖的开关结构，使胰岛素在活性和低活性状态之间进行平衡。当葡萄糖浓度从3 mM上升到20 mM时，NNC2215对胰岛素受体的亲和力提高了3.2倍。动物实验表明，NNC2215的葡萄糖敏感性活性既能有效防止低血糖发生，同时还能部分覆盖血糖波动。

关键词：NNC2215，NNC2215抗体，NNC2215试剂盒，司美格鲁肽，semaglutide，司美格鲁肽抗体，司美格鲁肽试剂盒，替尔泊肽，Tirzepatide ，替尔泊肽抗体，替尔泊肽试剂盒