Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections.

复发性感染是2型糖尿病（T2D）受试者中的常见疾病之一。先天性免疫细胞（例如嗜中性粒细胞）的双向激活和T2D病情中的葡萄糖代谢会导致促炎性环境和嗜中性粒细胞功能降低，这可能是反复感染的潜在原因。在与无菌炎症相关的T2D的病理条件下，中性粒细胞由于高血糖而形成组成性细胞外陷阱（NETs），并且对感染的反应较差。本研究旨在了解细胞和代谢的后果以及T2D中的NETs形成。我们显示葡萄糖诱导NADPH氧化酶衍生的活性氧种类，并进一步瓜氨酸化组蛋白形成较弱的NETs，导致对脂多糖（LPS）的反应减少。在高葡萄糖条件下和来自T2D受试者的嗜中性粒细胞的非靶向代谢组学分析表明，多元醇途径中间体（1-脱水山梨糖醇）富集，谷胱甘肽代谢产物（半胱氨酰甘氨酸）减少。NADPH是1-脱水山梨糖醇形成的三个独立途径的绝对要求通过在过量葡萄糖下的醛糖还原酶，诱导谷胱甘肽合成和葡萄糖诱导的NETs形成。在T2D期间和存在高葡萄糖的情况下，这些过程性反应之间存在NADPH竞争，这导致其不足以产生对LPS的反应。有趣的是，补充NADPH和醛糖还原酶的药理抑制剂雷奈司他，可在LPS存在下恢复NETs的形成。我们的研究为嗜中性粒细胞的代谢重编程提供了新颖的见解，这可能导致T2D受试者易受感染。