JCI Insight. 2018 Jan 11;3(1). doi: 10.1172/jci.insight.97476.
Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose. Yet, these analogs retain capacity for binding to the insulin receptor (IR). When the blood glucose level is elevated, as in individuals with diabetes mellitus, MR binding diminishes due to glucose competition, leading to reduced MR-mediated clearance and increased partitioning for IR binding and consequent glucose lowering. These studies demonstrate that a glucose-dependent locus of insulin clearance and, hence, insulin action can be achieved by targeting MR and IR concurrently.
低血糖症通常与胰岛素治疗有关，限制了其安全性和疗效。大约 40 年前就提出了将胰岛素修饰为从注射库（外源性与重组凝集素复合的胰岛素复合物）中释放葡萄糖反应性的概念，但实现起来具有挑战性。这里提供的数据表明，甘露糖化胰岛素类似物可以通过与内源性甘露糖受体（MR）相互作用而经历另一种清除途径，并且这种清除途径可以是葡萄糖依赖性的，即在低血糖时与 MR 的结合增加。然而，这些类似物仍然能够与胰岛素受体（IR）结合。当血糖水平升高时，例如在糖尿病患者中，由于葡萄糖竞争，MR 结合减少，导致 MR 介导的清除减少，而与 IR 结合增加，从而导致血糖降低。这些研究表明，通过同时靶向 MR 和 IR 可以实现葡萄糖依赖性胰岛素清除和胰岛素作用的位置。
