Using insulin to control diabetes can lead to dangerously low blood glucose levels (hypoglycemia). For many years, researchers have worked to engineer an insulin that avoids this risk by adjusting its activity in response to glucose, but so far without success. Writing in Nature, Hoeg-Jensen et al. describe an insulin with a glucose-sensitive switch that reversibly responds to ambient glucose levels, potentially reducing the risk of hypoglycemia in diabetes treatment.

The authors built the switch by introducing a glucose-binding macrocycle and a glucoside with short linkers to different sites on an insulin molecule. When glucose levels are low, the glucoside binds to the macrocycle, causing steric hindrance that blocks the α-CT domain of insulin and prevents binding to its receptor. By contrast, at high concentrations, glucose replaces glucoside bound to the macrocycle, resulting in an open state that allows receptor binding of a fully active insulin. The engineered insulin, called NNC2215, showed a 3.2-fold increase in insulin receptor binding affinity when glucose was raised from 3 to 20 mM in vitro. Moreover, NNC2215 effectively reduced blood glucose when injected into rats and pigs, while causing a lower drop in glucose levels compared with insulin degludec, a long-acting form of insulin, once glucose infusions were stopped. These findings illustrate that engineering insulin with controlled bioactivity is a promising avenue in diabetic research, with the potential for translation to human use.

使用胰岛素控制糖尿病会导致危险的低血糖水平（低血糖症）。多年来，研究人员一直致力于设计一种胰岛素，通过调整其对葡萄糖的反应来避免这种风险，但到目前为止还没有成功。Hoeg-Jensen 等人在《自然》杂志上撰文描述了一种具有葡萄糖敏感开关的胰岛素，该开关可逆地对环境葡萄糖水平做出反应，从而可能降低糖尿病治疗中低血糖的风险。

作者通过将葡萄糖结合大环和带有短接头的葡萄糖苷引入胰岛素分子上的不同位点来构建开关。当葡萄糖水平低时，葡萄糖苷与大环结合，引起空间位阻，阻断胰岛素的 α-CT 结构域并阻止与其受体结合。相比之下，在高浓度下，葡萄糖取代了与大环结合的葡萄糖苷，导致开放状态，允许受体结合完全活性胰岛素。当体外葡萄糖从 3 mM 升高到 20 mM 时，称为 NNC2215 的工程胰岛素显示胰岛素受体结合亲和力增加了 3.2 倍。此外，当注射到大鼠和猪体内时，NNC2215 可有效降低血糖，同时在停止葡萄糖输注后，与德谷胰岛素（一种长效胰岛素）相比，葡萄糖水平下降的幅度较低。这些发现表明，具有受控生物活性的工程胰岛素是糖尿病研究中一条很有前途的途径，有可能转化为人类使用。