Inflammation and oxidative stress in pancreatic islets amplify the appearance of various post-translational modifications (PTMs) to self-proteins. Herein, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in non-obese diabetic mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase beta subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found the carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin to insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.

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羰基翻译后修饰与早发型 1 型糖尿病自身免疫相关

胰岛的炎症和氧化应激会放大自身蛋白的各种翻译后修饰 (PTM) 的出现。在此，我们鉴定了非肥胖糖尿病小鼠在高血糖发作之前产生的一组选定的羰基化胰岛蛋白。有趣的是，我们发现脯氨酰 4 羟化酶 β 亚基 (P4Hb) 的羰基修饰负责胰岛素原折叠和运输，作为人类和小鼠 1 型糖尿病中的自身抗原。我们发现，在应激胰岛中，羰基化 P4Hb 扩增，与葡萄糖刺激的胰岛素分泌减少和胰岛素原与胰岛素比率改变同时发生。在糖尿病前期的 NOD 小鼠和抗胰岛素自身免疫发作之前的早期人类 1 型糖尿病中检测到了针对 P4Hb 的自身抗体。此外，我们还确定了 1 型糖尿病患者循环中针对羰基-P4Hb 表位的自身反应性 CD4+ T 细胞反应。我们的研究为 1 型糖尿病中胰岛素原代谢途径和胰岛素自身抗原形式的产生提供了机制上的见解。