Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC–urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism.

慢性炎症与多种疾病过程有关，但尚未完全了解决定细胞对炎症敏感性的内在机制。在这里，我们展示了葡萄糖代谢对炎症诱导的胰岛 β 细胞存活变化的贡献。我们使用代谢组学、生化和功能分析，研究了在存在促炎细胞因子的情况下葡萄糖的保护作用与非保护作用。当具有保护作用时，葡萄糖代谢通过丙酮酸羧化酶 (PC) 活性增强对 TCA 循环的回补输入，导致天冬氨酸水平升高。这种代谢机制支持精氨琥珀酸分流，它促进精氨酸的尿素生成，相反减少精氨酸用于生产一氧化氮 (NO) 的利用，炎性细胞毒性的主要介质。PC-尿素循环轴的激活足以抑制 NO 合成并保护细胞在炎症和其他应激范例的情况下免于死亡。总的来说，这些研究揭示了葡萄糖代谢和精氨酸利用途径之间以前未被重视的联系，通过 PC 指导的尿素生成作为一种保护机制。