The Diabetes Unit and the Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Diabetes Obes Metab. 2018 Sep;20 Suppl 2:95-103. doi: 10.1111/dom.13379.
ER stress due to proinsulin misfolding has an important role in the pathophysiology of rare forms of permanent neonatal diabetes (PNDM) and probably also of common type 1 (T1D) and type 2 diabetes (T2D). Accumulation of misfolded proinsulin in the ER stimulates the unfolded protein response (UPR) that may eventually lead to apoptosis through a process called the terminal UPR. However, the β-cell ER has an incredible ability to cope with accumulation of misfolded proteins; therefore, it is not clear whether in common forms of diabetes the accumulation of misfolded proinsulin exceeds the point of no return in which terminal UPR is activated. Many studies showed that the UPR is altered in both T1D and T2D; however, the observed changes in the expression of different UPR markers are inconsistent and it is not clear whether they reflect an adaptive response to stress or indeed mediate the β-cell dysfunction of diabetes. Herein, we critically review the literature on the effects of proinsulin misfolding and ER stress on β-cell dysfunction and loss in diabetes with emphasis on β-cell dynamics, and discuss the gaps in understanding the role of proinsulin misfolding in the pathophysiology of diabetes.
胰岛素原错误折叠导致内质网应激在罕见的永久性新生儿糖尿病（PNDM）和可能的常见 1 型（T1D）和 2 型糖尿病（T2D）的病理生理学中起重要作用。内质网中错误折叠的胰岛素原的积累刺激未折叠蛋白反应（UPR），这可能最终通过称为终末 UPR 的过程导致细胞凋亡。然而，β 细胞内质网具有令人难以置信的能力来应对错误折叠蛋白的积累；因此，目前尚不清楚在常见形式的糖尿病中，错误折叠的胰岛素原的积累是否超过了终末 UPR 被激活的不可逆转点。许多研究表明，在 T1D 和 T2D 中 UPR 都发生了改变；然而，观察到的不同 UPR 标志物表达的变化不一致，尚不清楚它们是否反映了对压力的适应性反应，或者实际上介导了糖尿病的β 细胞功能障碍。在此，我们批判性地回顾了关于胰岛素原错误折叠和内质网应激对糖尿病中β 细胞功能障碍和丧失的影响的文献，重点关注β 细胞动力学，并讨论了对胰岛素原错误折叠在糖尿病病理生理学中作用的理解差距。
