Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.

1 型糖尿病 (T1D) 是一种自身免疫性疾病，可选择性地破坏胰腺中产生胰岛素的 β 细胞。糖尿病管理中未满足的需求，目前的治疗主要集中在移植上。虽然还提出了将祖细胞重编程为功能性产生胰岛素的β细胞，但这仍然存在争议且知之甚少。挑战在于确定为什么默认的转录抑制对外分泌再激活是无效的。在一名 13 岁的女孩患有胰岛素依赖型 T1D 死亡后，为了恢复和了解外分泌能力，我们收集了胰腺细胞。胰腺表现出经典的 β 细胞祖基因沉默，几乎无法检测到胰岛素（Ins) 成绩单。GSK126 是一种 EZH2 甲基转移酶活性的高选择性抑制剂，影响 H3K27me3 染色质含量和转录控制，导致核心 β 细胞标志物和导管祖基因的表达。尽管绝对 β 细胞破坏，GSK126 也恢复了Ins基因表达。这些研究表明，染色质的难治性表征了影响 β 细胞可塑性的外分泌抑制。有必要进行额外的再生研究，以确定这项 n-of-1 研究的方法是否适用于更广泛的 T1D 人群。