Discipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University of South Australia, Bedford Park, SA, Australia.
School of Chemistry, Monash University, Clayton, VIC, Australia.
Front Endocrinol (Lausanne). 2022 Jun 27;13:907864. doi: 10.3389/fendo.2022.907864. eCollection 2022.
The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6-A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
胰岛素激活胰岛素受体以促进代谢过程和细胞生长的机制仍不清楚。最近在理解胰岛素如何与其受体结合的结构研究方面取得了重大进展。然而，特定相互作用导致代谢或有丝分裂信号的方式仍然未知。目前只有少数胰岛素受体激动剂具有偏向信号的特性。在这里，我们使用仅在 A6-A11 键的化学成分上有所不同的新型胰岛素类似物，因为它已被改变为刚性、不可还原的 C=C 键（二碳键），以揭示信号偏向的机制。我们表明，在天然胰岛素或基础/长效胰岛素 glargine 中引入 A6-A11 二碳键会导致具有低有丝分裂效力的偏向信号类似物。这可以归因于胰岛素受体激活减少，从而阻止有效的受体内化和有丝分裂信号。对插入 A6-A11 二碳键影响受体相互作用的深入了解将最终有助于开发用于治疗糖尿病的新型胰岛素类似物，这些类似物具有低有丝分裂活性，因此长期使用不会增加促进癌症的风险。
