Objective

Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown.

Methods

We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals.

Results

Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets.

Conclusions

These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.

中文翻译：

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人类胰岛个体发育的单细胞转录组学定义了 T2D 中 β 细胞去分化的分子基础。

客观的

胰腺 β 细胞的去分化可能会降低 2 型糖尿病 (T2D) 的胰岛功能。然而，这种细胞状态的普遍性、可塑性和功能后果仍然未知。

方法

我们采用单细胞 RNAseq 来详细描述人类个体发育过程中 α 和 β 细胞的成熟程序。我们还比较了非糖尿病和 T2D 个体的胰岛。

结果

α 细胞和 β 细胞的成熟部分是通过抑制非内分泌基因实现的。然而，α 细胞保留了未成熟状态的特征，而 β 细胞则获得了完整的 β 细胞特异性基因表达程序。在来自 T2D 供体的胰岛中，α 细胞和 β 细胞的表达谱均不太成熟，从而解除了幼年遗传程序和外分泌基因的抑制，并增加了胞吐作用、炎症和应激反应信号通路的表达。这些变化与 T2D 胰岛中观察到的功能欠佳的 β 细胞比例增加一致。

结论

这些发现为人类个体发育过程中胰岛细胞成熟的分子程序以及 2 型糖尿病患者胰岛中发生的转录组成熟度丧失提供了新的见解。