There is a close interaction between metabolic and inflammatory pathways, both of
which are disrupted in the subject at hand, Type 2 diabetes (T2D). This condition is
characterized by the activation of inflammatory signaling networks, overproduction of
cytokines, and higher acute-phase reactants, establishing a pro-inflammatory cycle. In
T2D, consequences of an abundance of nutrients such as high glucose, elevated lipids
and branched-chain amino acids affect the functions of certain immune cells, notably
neutrophils. Metabolically active neutrophils utilize glycolysis for energy and rely on
stored glycogen. Furthermore, β-oxidation provides another important metabolic
pathway. Additionally, the pentose phosphate pathway produces NADPH required for
their chemotaxis and phagocytosis along with formation of extracellular traps but may
also provide energy sources (see above). T2D-induced metabolic shifts mean that
neutrophils are in a state of constant activation, unable to fulfill their regulatory
functions effectively. As a result, individuals with T2D are more prone to intermittent
infections. Increased polyol and hexosamine pathway fluxes, marked increases in
advanced glycation end-products (AGEs) levels as well as activation of certain protein
kinase C isoforms means that: (a) superoxide production can go up yet again; (b) it will
bring about the activation of inflammatory pathways; and (c) host responses can
become abnormal. When neutrophils become dysfunctional, wound healing processes
are less efficient and immune responses against pathogens compromised.
Consequently, the way neutrophils are metabolically reprogrammed has a significant
impact on how often, how severe and for how long infections occur in those with T2D