莱顿大学Bart O. Roep研究组揭示了胰岛素mRNA加速衰减导致的1型糖尿病的遗传保护。相关论文于2025年3月19日发表于国际顶尖学术期刊《细胞》杂志上。

该研究团队发现IRE1α消化基序存在于携带SNP rs3842752的胰岛素mRNA中（G>A）。该SNP位于INS的3 '非翻译区，与保护T1D （INS^P）有关。与易感INS变体（INS^S）相比，伴有INS^P的β细胞内质网应激导致胰岛素mRNA衰变加速。与仅携带INS^P的胰岛相比，携带INS^P的人胰岛在移植到糖尿病小鼠体内时表现出更强的活力和功能，并能更快地逆转糖尿病。含有INS^P的替代β细胞表达较少的内质网应激和INS-DRiP新抗原。这种对T1D遗传保护的解释可能替代或与先前提出的归因于INS启动子多态性的机制一致。

研究人员表示，胰岛素基因（INS）变异和β细胞应激与1型糖尿病（T1D）发展风险和胰岛素自身免疫相关。未折叠蛋白反应缓解内质网（ER）应激涉及激活肌醇需要酶1α (IRE1α)，该酶通过mRNA衰变阻碍翻译。

附：英文原文

Title: Genetic protection from type 1 diabetes resulting from accelerated insulin mRNA decay

Author: René van Tienhoven, Denis O’Meally, Tristan A. Scott, Kevin V. Morris, John C. Williams, John S. Kaddis, Arnaud Zaldumbide, Bart O. Roep

Issue&Volume: 2025-03-19

Abstract: Insulin gene (INS) variation and beta-cell stress are associated with the risk of development of type 1 diabetes (T1D) and autoimmunity against insulin. The unfolded protein response alleviating endoplasmic reticulum (ER) stress involves activation of inositol-requiring enzyme 1α (IRE1α) that impedes translation by mRNA decay. We discover that the IRE1α digestion motif is present in insulin mRNA carrying SNP rs3842752 (G>A). This SNP in the 3′ untranslated region of INS associates with protection from T1D (INSP). ER stress in beta cells with INSP led to accelerated insulin mRNA decay compared with the susceptible INS variant (INSS). Human islets with INSP showed improved vitality and function and reversed diabetes more rapidly when transplanted into diabetic mice than islets carrying INSS only. Surrogate beta cells with INSP expressed less ER stress and INS-DRiP neoantigen. This explanation for genetic protection from T1D may act instead of or in concert with the previously proposed mechanism attributed to INS promoter polymorphism.

DOI: 10.1016/j.cell.2025.02.018

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00206-5