Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress–activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet–fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

中文翻译：

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他克莫司诱导的 BMP/SMAD 信号与代谢应激激活的 FOXO1 相关，以触发 β 细胞衰竭

通过微调关键转录因子来积极维护 β 细胞身份，确保 β 细胞功能。他克莫司是一种广泛使用的免疫抑制剂，可加速器官移植后糖尿病的发病，但潜在的分子机制尚不清楚。在这里，我们表明，在轻度代谢应激条件下给药时，他克莫司通过激活 BMP/SMAD 信号通路诱导人类 β 细胞成熟度的丧失和 β 细胞衰竭。他克莫司诱导的磷酸化 SMAD1/5 通过形成复合物与代谢应激激活的 FOXO1 协同作用。这种相互作用与关键 β 细胞转录因子 MAFA 的表达减少和胰岛素分泌减少有关，无论是在体外在原代人胰岛中还是在移植到高脂肪饮食喂养的小鼠体内的人胰岛中。BMP 信号的药理学抑制保护人 β 细胞免受他克莫司诱导的体外 β 细胞功能障碍。此外，我们确认 BMP/SMAD 信号在他克莫司接受者的方案胰腺同种异体移植活检中被激活。总之，我们提出了他克莫司在原代人 β 细胞中致糖尿病的新机制。这一见解可能会导致新发糖尿病的新治疗策略，并可能对其他形式的糖尿病产生影响。