Type 1 diabetes (T1D) results from the progressive loss of β cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1β and interferon-γ, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1β+interferon-γ-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.

中文翻译：

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应激人类胰岛的综合蛋白质组学分析将 GDF15 确定为 1 型糖尿病干预的目标。

1 型糖尿病 (T1D) 是由 β 细胞的进行性丢失引起的，这是一个由促炎细胞因子信号传播的过程，它破坏了促凋亡蛋白和抗凋亡蛋白之间的平衡。为了鉴定参与这一过程的蛋白质，我们对用白细胞介素-1β 和干扰素-γ 处理的人胰岛进行了全面的蛋白质组学研究，鉴定出 11,324 种蛋白质，其中 387 种受到治疗的显着调节。然后我们测试了生长/分化因子 15 (GDF15) 的功能，它被治疗抑制了。我们发现 GDF15 翻译在炎症期间被阻断，并且它在患有 T1D 的个体的胰岛中被耗尽。添加外源性 GDF15 可抑制白细胞介素-1β+干扰素-γ 诱导的人胰岛细胞凋亡。施用 GDF15 使 NOD 小鼠的糖尿病发病率降低了 53%。我们的方法为鉴定受细胞因子调节的人类胰岛蛋白提供了独特的资源，并有效地发现了 T1D 治疗的潜在靶点。