AbstractDespite decades of intense research, the mechanisms underlying insulin resistance are still poorly understood. What if one of the major causes of insulin resistance is not related to defects in the target tissues and/or insulin receptor signaling, but rather to a reduced survival of endogenously secreted insulin on its way to activating the receptor on the cell surface of the target tissues? Here, we present data and lay out arguments in support of this novel hypothesis, which is fundamentally different from the common view that insulin resistance is caused by the body’s cells becoming less sensitive to insulin..

摘要尽管进行了数十年的深入研究，但对胰岛素抵抗的潜在机制仍知之甚少。如果胰岛素抵抗的主要原因之一与靶组织缺陷和/或胰岛素受体信号传导无关，而是与内源性分泌的胰岛素在激活靶组织细胞表面受体的过程中存活率降低有关呢？在这里，我们提供了数据并提出了支持这一新假设的论点，这与普遍认为胰岛素抵抗是由人体细胞对胰岛素的敏感性降低引起的观点根本不同。。

IntroductionIt was recently demonstrated that the major metabolic degradation pathway for the insulin analog insulin icodec in human plasma is due to the separation of the A- and B-chains of insulin by a thiol-disulphide exchange reaction (chain splitting)1. Furthermore, disulphide bonds in native human insulin (HI) were also shown to be subject to chain splitting when exposed to exogenous thiols in solution, and the rate of this degradation depends on redox potential, with lower redox potential leading to more chain splitting1.

引言最近证明，人血浆中胰岛素类似物胰岛素icodec的主要代谢降解途径是由于通过硫醇-二硫化物交换反应（链分裂）分离胰岛素的A链和B链1。此外，天然人胰岛素（HI）中的二硫键在暴露于溶液中的外源硫醇时也显示出链分裂，并且这种降解的速率取决于氧化还原电位，较低的氧化还原电位导致更多的链分裂1。

Moreover, chain splitting of HI in our redox assay occurs at redox potential values typical for human plasma2. In this paper, we present data demonstrating that chain splitting of HI in vivo has physiological relevance by showing that this phenomenon occurs (1) in human plasma and (2) in vivo to a substantial extent when HI is infused to rats.

此外，在我们的氧化还原测定中，HI的链分裂发生在人血浆2典型的氧化还原电位值。在本文中，我们提供的数据表明，HI在体内的链分裂具有生理相关性，表明这种现象发生在（1）人血浆中，（2）当HI输注到大鼠体内时，在很大程度上发生在体内。

We present evidence from the literature supporting the novel hypothesis that redox-mediated changes in chain splitting may be a direct mechanism of insulin resistance.ResultsFigure 1 shows disappearance of HI and a corresponding appearance of both insulin A- and B-chain upon incubation in human plasma.

我们从文献中提供的证据支持了新的假设，即氧化还原介导的链分裂变化可能是胰岛素抵抗的直接机制。结果图1显示HI的消失以及在人血浆中孵育后胰岛素a链和B链的相应外观。

These results demonstrate that chain splitting is relevant not only for the acylated insulin analogs as published recently1, but also for native HI. Furthermore, in the hyperinsulinaemic euglycaemic clamp study in rats using HI, in addition to HI, we also detected A- and B-chain, as well as an isomer of HI in plasma as shown in Fig.

这些结果表明，链分裂不仅与最近发表的酰化胰岛素类似物1有关，而且与天然HI有关。此外，在使用HI的大鼠高胰岛素血症-正常血糖钳夹研究中，除HI外，我们还检测到血浆中的A链和B链以及HI的异构体，如图所示。

2. Based on the plasma A-chain levels in the clamp study and on the A-chain clearance kinetics determined in the separate PK experiment (Fig. 3), we estimate that the A-chain appearance rate (i.e., the rate of HI chain splitting) in the clamp study corresponds to 0.40 nmol/kg/min.

2.根据钳夹研究中的血浆A链水平和单独PK实验中确定的A链清除动力学（图3），我们估计钳夹研究中的A链出现率（即HI链分裂率）对应于0.40 nmol/kg/min。

Data Availability

数据可用性

Data is supplied within the manuscript.

数据在手稿中提供。

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Download referencesAcknowledgementsThe authors would like to thank Kira Meyhoff-Madsen and Lene Ottesen for assistance with the LC-MS analysis, Bettina Lyngsø Bengtsen and Sara Louise Riisberg for conducting the in vivo studies, and Gitte Norup and Dorthe Egholm Jensen for preparing and purifying the insulin A-chain.Author informationAuthor notesThese authors contributed equally: Christian N.

下载参考文献致谢作者要感谢Kira Meyhoff-Madsen和Lene Ottesen对LC-MS分析的帮助，Bettina LyngsøBengtsen和Sara Louise Riisberg进行体内研究，以及Gitte Norup和Dorthe Egholm Jensen制备和纯化胰岛素A链。作者信息作者注意到这些作者做出了同样的贡献：Christian N。

Cramer, František Hubálek.Authors and AffiliationsNovo Nordisk A/S, Maaloev, DenmarkChristian N. Cramer, František Hubálek, Christian Lehn Brand, Hans Helleberg & Jeppe SturisNovo Nordisk A/S, Soeborg, DenmarkPeter KurtzhalsAuthorsChristian N. CramerView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsC.N.C., F.H., and J.S. wrote the main text. F.H. provided materials. C.N.C., F.H., C.L.B., H.H., and J.S. designed the experiments. C.N.C., C.L.B., and H.H. performed the experiments. C.N.C, C.L.B., H.H., and J.S. prepared the figures. J.S. formulated the initial hypothesis.

PubMed谷歌学术贡献中心。N、 C.，F.H。和J.S.写了正文。F、 。C、 N.C.，F.H.，C.L.B.，H.H。和J.S.设计了实验。C、 N.C.，C.L.B。和H.H.进行了实验。C、 N.C，C.L.B.，H.H。和J.S.准备了这些数字。J、 美国提出了最初的假设。

C.N.C., F.H., C.L.B., H.H., P.K., and J.S. all contributed to maturing the hypothesis and reviewed and approved the manuscript.Corresponding authorCorrespondence to.

C、 N.C.，F.H.，C.L.B.，H.H.，P.K。和J.S.都有助于使假设成熟，并审查和批准了手稿。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleCramer, C.N., Hubálek, F., Brand, C.L. et al. Chain splitting of insulin: an underlying mechanism of insulin resistance?.

转载和许可本文引用本文Cramer，C.N.，Hubálek，F.，Brand，C.L.等人的《胰岛素的链分裂：胰岛素抵抗的潜在机制？》？。

npj Metab Health Dis 2, 38 (2024). https://doi.org/10.1038/s44324-024-00042-1Download citationReceived: 02 September 2024Accepted: 26 November 2024Published: 18 December 2024DOI: https://doi.org/10.1038/s44324-024-00042-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

npj Metab Health Dis 2,38（2024）。https://doi.org/10.1038/s44324-024-00042-1Download引文接收日期：2024年9月2日接受日期：2024年11月26日发布日期：2024年12月18日OI：https://doi.org/10.1038/s44324-024-00042-1Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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