In immune-suppressed diabetic conditions, increased glucose may raise ROS (Reactive Oxygen Species) and proinflammatory cytokines, limiting macrophage activity in systemic circulation ^[1][2][3][16,17,18]. TheOur recent observation documented GSH (glutathione) production and activated AGE (advanced glycation end products) and RAGE (receptor for advanced glycation end products) for the elevation of TGF-β (transforming growth factor- β) due to excess hyperglycaemia ^[4][5][19,20]. If NADPH (nicotinamide adenine dinucleotide phosphate) is available, the enzyme GR (glutathione reductase) may recycle GSSH (oxidized glutathione). However, in diabetic individuals, NADPH is intensively used on the polyol pathway, resulting in a drop in GSH and an increase in ROS, which may change cytokine levels ^[2][17]. Diabetes mellites may also impair cellular immunity and weaken natural barriers. Studies have established that insulin insufficiency and hyperglycaemia are highly responsible for this phenomenon. Peripheral neuropathy, a consequence of diabetes mellitus (DM), is related to the polyol pathway and sorbitol accumulation in the nerve tissue due to SDH (sorbitol dehydrogenase) deficiency ^[6][7][21,22]. Additionally, immune system abnormalities are also caused by excessive use of NADPH. The loss of NADPH results in reduced GSH, increased ROS, varying cytokine profiles, and, eventually, advances immunological impairment ^[8][23].

In response to a pathogen, several immune cells, including macrophages and neutrophils, produce cytokines. The pattern recognition receptors of these cells identify bacterial cell wall components and release chemicals and nucleic acids to produce cytokines. These cells release cytokines that regulate and generate granulomas to confine and kill germs ^[1][16]. Granulomas include macrophages, multinucleated giant cells, CD4+ and CD8+ (clusters of differentiation) T-cells, B-cells, and neutrophils ^[9][24]. In immunocompetent people, bacterium and granulomatous immune system cells interact and release cytokines such as TNF-α (tumour necrosis factor-alpha), IL-10 (interleukin), IL-6, IL-2, IL-12, and IFN-γ (interferon-gamma) ^[10][25]. These cytokines play a crucial role in innate immunity. They are involved in diabetes pathogenesis and its affected, immune-mediated infection. In a study, the peripheral blood mononuclear cells (PBMCs) and isolated monocytes of patients with Type 1 diabetes (T1D) and Type 2 diabetes (T2D) released less IL-1β than controls following lipopolysaccharides (LPS) stimulation ^[11][12][26,27]. Tessaro et al. found that the insulin treatment of bone-marrow-derived macrophages from diabetic mice boosted the production of TNF-α and IL-6 after LPS stimulation ^[13][28]. In another study, T1D monocytes from PBMCs produced less IL-1 and IL-6 than healthy donors. Interestingly, another study proved that PBMCs from non-diabetics are activated by anti-CD3 antibodies and subjected to high glucose levels, suppressing cytokines IL-2, IL-6, and IL-10 ^[14][29]. Furthermore, in another study, the authors observed that PBMCs taken from healthy people and stimulated with dextrose octreotide exhibited less IL-6 and IL-17A production, particularly in the CD14+ and CD16+ intermediate monocytes, suggesting multiple faulty immune responses in acute hyperglycaemia ^[15][30]. Compared to normal mice, obese leptin-receptor-deficient (DB/DB) mice and high-fat-diet-induced hyperglycaemic mice demonstrated decreased IL-22 levels ^[16][31]. Tan et al. found reduced IL-12 and IFN-γ levels in diabetic PBMC cultures after infection with Burkholderia pseudomallei when compared with healthy donors. The PBMCs of diabetics had a more significant intracellular bacterial burden than healthy controls, indicating that hyperglycaemia affects the host’s defense against infectious microorganisms. Recombinant IL-12 and IFN-γ treatment decreased the bacterial load in diabetic PBMCs, demonstrating that the low production of IL-12 and IFN-γ n diabetes inhibits the immune cells’ ability to regulate bacterial development during an infection ^[17][32]. Therefore, hyperglycaemia in diabetes may reduce pathogen-fighting macrophage and leukocyte function.

As previously mentioned, hyperglycaemia also changes macrophage function. A study found that chronic hyperglycaemia impaired phagocytosis by affecting the activity of complement receptors on isolated monocytes. Long-term glucose sensitivity may impair the glycolic ability and reserves of macrophages. In contrast to hyperglycaemia, insulin deficiency in T2D has not been thoroughly studied regarding the function of macrophages against infections, necessitating research in this direction. ^[18][33]. In an in vitro study, elevated glucose inhibited antibacterial activity and phagocytosis in mouse bone marrow macrophages ^[19][34]. Additionally, peritoneal macrophages from diabetic animals showed decreased phagocytosis in the same research. Many studies have documented that, in diabetic conditions, increased TNF-α expression induces a local inflammatory response through a cascade of cytokines. This increases vascular permeability, recruiting macrophages and neutrophils to the site of infection ^[20][21][35,36]. In another in vitro study, insulin intervention restored alveolar macrophage phagocytosis and cytokine release. This study suggests that exogenous insulin in diabetes may boost immune cell activity to fight pathogens by activating TNF-α and IL-6 ^[22][37]. In contrast, it is also possible that TNF- and IL-6 may cause insulin resistance. Therefore, exogenous insulin should be administered under strict control ^[23][24][38,39]. Furthermore, elevated plasma levels of TNF-α and IL-6 were shown to be associated with DM-induced LV dysfunction ^[25][40]. Liu et al. found that resident peritoneal macrophages (RPMs) from DB/DB mice had substantially lower phagocytosis and adherence ^[26][41].

In addition to the generation of ROS, immunoglobulin-mediated opsonization, and phagocytosis, hyperglycaemia also impairs neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). In one study, researchers found that individuals with induced hyperglycaemia who were exposed to bacterial wall components displayed lower neutrophil degranulation. ^[27][42]. Following previous results, Joshi et al. found that hyperglycaemia reduced neutrophil activity to create NETs, making infections more likely ^[28][43]. Natural killer (NK) cells regulate conditions in the innate cellular immune system, similar to other resistant components. The diabetes-related metabolic disorder affects NK cell activity, particularly the (natural killer group 2D) NKG2D/ligand axis. On the other hand, hyperglycaemia-mediated ER (endoplasmic reticulum) stress may contribute to diabetes-related NK cell dysfunction. Further research is needed to identify the dynamics of this interaction and how anti-diabetic medications affect ER stress protein expression in diabetes ^[29][44].

T1D is a congenital autoimmune disorder produced by autoreactive CD4+ and CD8+ T-cells, which identify pancreatic antigens such as insulin or glutamic acid cecarboxylase (GAD) and kill insulin-producing β-cells ^[30][45]. How endogenous β-cell antigens become immunogenic is still open to exhaustive study. There is growing evidence that viral infection is a major environmental factor in the development and progression of T1D. Nevertheless, patients with T1D are also more susceptible to infections of the lower respiratory tract, urinary tract, and skin and mucosal membranes, as well as bacterial skin and mucous membrane infections and mycotic skin and mucous membrane infections ^[31][46]. Genome-wide association studies have helped achieve an understanding of genetic vulnerability. By contrast, immunological research has shown new immune-dysregulation mechanisms in the central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells in T1D ^[32][33][34][47,48,49].

Thus far, several lines of evidence imply that diabetes-related comorbidities significantly contribute to immune disorders. Many studies explored diabetic immune responsive function to explain that the putative vulnerability to infections and hyperglycaemia was shown to decrease the immune response system against antimicrobial activity in various trials. However, most immune response studies on diabetes-related infections show persistent immunological impairment. The above discussion makes understanding the issue challenging and explains the significant findings of different epidemiological studies. Therefore, diabetes is a complicated disease with several metabolic problems, making it challenging to trace the increased infection susceptibility through a single pathway or cell type. Additionally, multiple dysregulated physiological reactions affect organ failure and the 10% mortality rate. Furthermore, many diabetic survivors eventually die from recurring, nosocomial, and secondary infections, despite having a history of recovery. Recent studies demonstrate that even after clinical “recovery” from a deadly invasive infection, innate and adaptive immune responses remain altered, causing chronic inflammation, immunological suppression, and bacterial persistence. Moreover, diabetes lowers immune cell function directly; thus, diabetic patients demonstrated a decreased bactericidal clearance, increased infectious comorbidities, and an increased mortality. Since diabetes-associated immune abnormalities increase mortality, immunological modulatory medication may enhance patient outcomes. Over the next two decades, diabetic infectious mortality is expected to climb significantly higher due to the increasing older and obese populations, worldwide adoption of a Western diet and lifestyle, and multidrug-resistant bacterial development and persistence. Understanding the underlying mechanism of diabetes-induced immune cell abnormalities that remain after an infection attack helps to identify possible targeted treatment strategies to boost innate and adaptive immune function, minimize infectious complications, and improve diabetic survival from fatal invasive infectious diseases.