Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
Institute of Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
Nat Metab. 2020 Feb;2(2):192-209. doi: 10.1038/s42255-020-0171-3. Epub 2020 Feb 20.
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.
胰岛中胰岛素分泌β细胞的去分化被认为是β细胞功能障碍的主要机制。然而，去分化的β细胞是否可以通过药物干预来靶向治疗糖尿病缓解，以及如何实现这一目标，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β细胞去分化。胰岛的单细胞 RNA 测序（scRNA-seq）鉴定了与β细胞去分化和功能障碍相关的标志物和途径。单一和组合药理学进一步表明，胰岛素治疗会触发β细胞中胰岛素受体途径的激活，并恢复成熟和功能，从而实现糖尿病缓解。通过胰高血糖素样肽-1（GLP-1-雌激素缀合物）对β细胞进行额外的β细胞选择性雌激素传递，可使每日胰岛素需求降低 60%，触发雌激素特异性激活内质网相关蛋白降解系统，进一步增加β细胞的存活和再生。GLP-1-雌激素还可以保护人β细胞免受细胞因子诱导的功能障碍。这项研究不仅描述了β细胞去分化和再生的机制，还揭示了针对去分化β细胞治疗糖尿病缓解的药理学切入点。
