**Background:** Type 2 diabetes (T2D) is characterized by a chronic low-grade inflammatory state and metabolic dysregulation, including hyperglycemia, elevated lipids, and branched-chain amino acids. Neutrophils, the most abundant white blood cells and first line of defense against infections, rely on glycolysis, the pentose phosphate pathway (PPP), glutaminolysis, and fatty acid oxidation for energy to perform effector functions such as chemotaxis, phagocytosis, degranulation, and neutrophil extracellular trap (NET) formation. In T2D, the altered immuno-metabolic axis leads to constitutive activation and impaired acquisition of effector or regulatory activities in neutrophils, predisposing individuals to recurrent infections. This review catalogs how the altered immuno-metabolic axis in T2D influences neutrophil functioning during various infections and discusses challenges and therapeutic opportunities.
**Methods:** This is a narrative review that synthesizes findings from preclinical and clinical studies, including metabolomics, transcriptomics, and functional assays, to describe the impact of T2D on neutrophil metabolism and function. The authors discuss data from their own lab and others, covering studies on hyperglycemia, advanced glycation end products (AGEs), polyol pathway flux, and the effects of metabolic inhibitors on neutrophil activities such as NETosis, phagocytosis, and reactive oxygen species (ROS) production.
**Key Results:** The review reports that in T2D, hyperglycemia drives glucose through the polyol pathway via aldose reductase, consuming NADPH and leading to sorbitol accumulation. This depletes NADPH pools needed for glutathione regeneration and NADPH oxidase-dependent ROS production, impairing NET formation and phagocytosis. For example, the authors' metabolomics analysis in neutrophils from T2D individuals showed increased sorbitol levels. Hyperglycemia also increases flux through the hexosamine pathway, elevates AGEs, and activates protein kinase C isoforms, resulting in enhanced superoxide generation, stimulation of inflammatory pathways, and abnormal host responses. Neutrophils from T2D subjects exhibit constitutive NETosis but fail to form NETs in response to LPS. Phagocytosis of pathogens such as *Klebsiella pneumoniae* capsular serotypes K1/K2 and *Mycobacterium tuberculosis* is reduced in T2D. The review notes that T2D confers a threefold increased risk for tuberculosis. Additionally, hyperglycemia impairs neutrophil degranulation and increases procoagulant responses. The paper also discusses that elevated homocysteine in T2D induces NETosis via calcium flux and mitochondrial superoxide. The review summarizes that T2D neutrophils show reduced glycolytic rate, decreased glycogen synthase activity, and impaired glutaminase and glucose-6-phosphate dehydrogenase (G6PDH) activity, leading to reduced energy production and effector functions.
**Clinical Implications:** The review emphasizes that recurrent infections in T2D are a major cause of mortality and morbidity, driven by neutrophil dysfunction. Therapeutic strategies to restore neutrophil function include targeting the polyol pathway with aldose reductase inhibitors (e.g., ranirestat, epalrestat) to preserve NADPH pools, which may enhance NET formation and phagocytosis. For instance, ranirestat reduced cytosolic ROS and neutrophil elastase induced by high glucose, and NADPH supplementation in high-glucose conditions markedly enhanced NET formation in response to LPS. Other potential interventions include metformin, which activates AMPK and improves neutrophil-mediated bacterial killing; 2-deoxyglucose (2-DG), a hexokinase inhibitor that restores NET formation in diabetes; and glutathione supplementation, which reduces glucose-induced neutrophil elastase and ROS. The review also highlights the potential of nicotinamide mononucleotide (NMN) therapy to restore NAD+ levels and improve insulin sensitivity, though its effects on neutrophil function require further study. The authors conclude that therapeutic lowering of blood glucose alone may not suffice due to metabolic memory, and that shunting metabolic pathways with enzyme inhibitors may help resensitize neutrophil function. Future studies are warranted to test these hypotheses in clinical models.