Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, we show that deleting RNLS, a genome-wide association study candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modelling identified the U.S. Food and Drug Administration–approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, thus leading to disease reversal. Furthermore, pargyline prevented or delayed diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.

1 型糖尿病 (T1D) 是由胰腺β细胞的自身免疫性破坏引起的。多能干细胞现在可以分化为 β 细胞，从而提高了 T1D 细胞替代疗法的前景。然而，自身免疫会迅速破坏新移植的β细胞。在 T1D 小鼠模型中使用基因组规模的 CRISPR 筛选，我们表明删除RNLS是 T1D 的全基因组关联研究候选基因，使 β 细胞对自身免疫性杀伤具有抗性。基于结构的建模将美国食品和药物管理局批准的药物 pargyline 确定为潜在的 RNLS 抑制剂。口服pargyline治疗保护糖尿病小鼠移植的β细胞，从而导致疾病逆转。此外，pargyline 在几种 T1D 小鼠模型中预防或延迟了糖尿病的发作。我们的结果将RNLS确定为 β 细胞脆弱性的调节剂，并且是避免 T1D 中 β 细胞丢失的潜在治疗靶点。