Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study β-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with β-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in β cells and restores maturation and function for diabetes remission. Additional β-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1–oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases β-cell survival and regeneration. GLP-1–oestrogen also protects human β cells against cytokine-induced dysfunction. This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals pharmacological entry points to target dedifferentiated β cells for diabetes remission.

已提出朗格汉斯胰岛中分泌胰岛素的 β 细胞去分化是 β 细胞功能障碍的主要机制。去分化的β细胞是否可以通过药物干预来缓解糖尿病，以及实现这一目标的方式，目前尚不清楚。在这里，我们报告了使用链脲佐菌素诱导的糖尿病来研究小鼠的 β 细胞去分化。胰岛的单细胞 RNA 测序 (scRNA-seq) 确定了与 β 细胞去分化和功能障碍相关的标志物和通路。单一和组合药理学进一步表明，胰岛素治疗触发 β 细胞中的胰岛素受体通路激活，并恢复糖尿病缓解的成熟和功能。胰高血糖素样肽 1（GLP-1-雌激素偶联物）额外的 β 细胞选择性递送雌激素可将每日胰岛素需求量降低 60%，触发内质网相关蛋白降解系统的雌激素特异性激活，并进一步增加β细胞的存活和再生。GLP-1-雌激素还保护人类 β 细胞免受细胞因子诱导的功能障碍。该研究不仅描述了 β 细胞去分化和再生的机制，还揭示了靶向去分化 β 细胞以缓解糖尿病的药理学切入点。GLP-1-雌激素还保护人类 β 细胞免受细胞因子诱导的功能障碍。该研究不仅描述了 β 细胞去分化和再生的机制，还揭示了靶向去分化 β 细胞以缓解糖尿病的药理学切入点。GLP-1-雌激素还保护人类 β 细胞免受细胞因子诱导的功能障碍。该研究不仅描述了 β 细胞去分化和再生的机制，还揭示了靶向去分化 β 细胞以缓解糖尿病的药理学切入点。