Neutrophils display functional heterogeneity upon responding diversely to physiological and pathological stimulations. During type 2 diabetes (T2D), hyperglycemia constitutively activates neutrophils, leading to reduced response to infections and on the other hand, elevated metabolic intermediates such as homocysteine induce bidirectional activation of platelets and neutrophils leading to thrombosis. Hence, in the context of T2D-associated complications, we examined the influence of high glucose, homocysteine, and LPS representing effector molecules of hyperglycemia, thrombosis, and infection, respectively, on human neutrophil activation to identify distinct signaling pathways by quantitative phosphoproteomics approach. High glucose activated C-Jun-N-Terminal Kinase, NTRK1, SYK, and PRKACA kinases associated with Rho GTPase signaling and phagocytosis, whereas LPS induced AKT1, SRPK2, CSNK2A1, and TTN kinases involved in cytokine signaling and inflammatory response. Homocysteine treatment led to activatation of  LRRK2, FGR, MAPK3, and PRKCD kinases which are associated with neutrophil degranulation and cytoskeletal remodeling. Diverse inducers differentially modulated phosphorylation of proteins associated with neutrophil functions such as oxidative burst, degranulation, extracellular traps, and phagocytosis. Further validation of phosphoproteomics data on selected kinases revealed neutrophils pre-cultured under high glucose showed impeded response to LPS to phosphorylate p-ERK1/2Thr202/Tyr204, p-AKTSer473, and C-Jun-N-Terminal KinaseSer63 kinases. Our study provides novel phosphoproteome signatures that may be explored to understand neutrophil biology in T2D-associated complications.

Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory ‘feed forward loop’. Nutrient ‘excess’ conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.