Wilcox Nicholas S, Rui Jinxiu, Hebrok Matthias, Herold Kevan C
Department of Immunobiology, Yale University, New Haven, CT, USA; Department of Internal Medicine, Yale University, New Haven, CT, USA.
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
J Autoimmun. 2016 Jul;71:51-8. doi: 10.1016/j.jaut.2016.02.001. Epub 2016 Mar 24.
Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.
1型糖尿病（T1D）是一种自身免疫性疾病，其特征是产生胰岛素的胰腺β细胞被破坏。免疫调节剂在改变T1D疾病进展过程方面已取得了一些成功。然而，在初始反应后，治疗组和对照组的C肽水平均出现了平行下降。在本综述中，我们讨论了T1D中β细胞死亡的机制，包括坏死和凋亡。正在开发新技术，以实现对胰岛炎和β细胞量的可视化，其中涉及正电子发射断层扫描（可识别β细胞配体）和磁共振成像（可识别血管渗漏）。已经描述了识别从死亡细胞释放的β细胞衍生胰岛素DNA的分子特征，并将其应用于临床环境。我们还考虑了疾病进展过程中β细胞发生的变化，包括可能影响β细胞功能和分化的DNA甲基转移酶的诱导。我们从最新数据中得出的发现表明，应重新考虑慢性长期β细胞杀伤模型。这些研究表明，病理生理学在诊断前期加速，并表现为β细胞杀伤率增加和胰岛素分泌受损，且持续时间比以前认为的更短。最后，我们考虑了细胞层面的解释，以说明尽管持续进行免疫治疗，但胰岛素分泌仍持续丧失的原因，这可能有助于确定潜在的治疗靶点。β细胞功能的逐渐下降引发了一个问题，即是否可能涉及与免疫攻击无关的β细胞衰竭。
