**3. Hypoinsulinemia and apoptosis of pancreatic B-cell**

Crosstalk between pathogenic CD4+ and CD8+ T cells and CD11c**+** M1 macrophages in obese adipose tissue further intensifies the inflammatory immune response brought on by adipocyte apoptosis and macrophage infiltration, which worsens adipose tissue

inflammation and peripheral insulin resistance [12]. As a result, pancreas cells produce more insulin to offset peripheral insulin resistance, which leads to hyperinsulinemia. The causes of T2DM are multifaceted and include insulin resistance brought on by obesity, poor insulin production, and loss of cell mass due to cell death. Absolute cell insufficiency in T1DM and relative cell deficiency in T2DM are both caused by apoptosis. The TNF receptor superfamily includes Fas (CD 95), which is distinguished by having a death domain motif in the cytoplasmic terminus [13]. A membrane-bound protein called Fas L (CD 178) is increased on activated T cells. Apoptosis is considerably inhibited by the expression of dominant-negative Fas or neutralising antibodies to Fas, which also results in adequate cell function, prevents the adoptive transmission of diabetes by primed T-cells, and slows the progression of T1DM development [14].

Insulin resistance, impaired insulin production, loss of cell mass with increased cell death, and islet amyloid deposits are the hallmarks of T2DM. In T2DM, obesityrelated insulin resistance is followed by a failure of beta-cell insulin production to counteract the deteriorating insulin sensitivity. A balance between beta-cell replication and apoptosis, as well as islet hyperplasia and the creation of additional islets from exocrine pancreatic ducts, regulates beta-cell mass [15]. In cells from T2DM patients, elevated caspase-3 and -8 activate, which can be reduced by the anti-diabetic drugs. The delicate balancing act between cell replication and apoptosis, which is regulated by a balance between matrix metalloproteinase (MMP)-1 and -2 and tissue inhibitor of MMP (TIMP)-1 and -2, is essential for islet development and function in vivo. The -cells undergo continual remodelling [16]. However, chronic growing insulin resistance over time finally results in exhausted beta cells and an insulin shortfall. Additionally, the build-up of free fatty acids, amyloids, and inflammatory cytokines triggers the death of beta cells, resulting in long-term hyperglycemia and T2D.

### **4. Propensity of infection in hyperglycemia**

The immune system employs incredible defences to keep out the invading viruses, bacteria, fungi, poisons, and parasites. In healthy condition make it tough for viruses to get past this protection, but a number of illnesses and flaws make the immune system malfunction. Pus, for instance, indicates that there is an infection since bacteria can readily enter an open wound and convert it into a non-healing wound [17]. Natural barriers, such as healthy surfaces of the skin and mucosa, as well as the production of cytokines, chemokines, and ROS, aid our defence mechanisms in stopping pathogenic infiltration.

Unfortunately, diabetes disrupts the immunological response of the host. Neuropathy increases the probability of natural barrier deterioration, and T2D can also have an impact on cellular immunity. Insufficient insulin and high blood sugar are the causes of this [18]. As a result of the immune system's inability to defend against invasive microorganisms, infections are a significant problem for people with diabetes, according to the American Diabetes Association [19]. Numerous investigations have been made to identify the pathways connected to diabetes that weaken the host's defence against infections. These processes include inhibition of cytokine production, flaws in phagocytosis, immunodeficiency, and failure to eradicate microorganisms. There is a widespread perception that people with diabetes are more susceptible to infectious diseases, still very few studies have thoroughly examined the population's overall risk for infections. The first such study, conducted in Canada, looked back on the incidence of infection and/or

#### *Perspective Chapter: Immunosuppression in Patients with Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.107362*

death among diabetic patients and age-matched controls, accumulating more than 500,000 cases per group over two separate time periods. According to this data, diabetic patients have a noticeably increased prevalence of infections; the most common illnesses were bacterial infections including osteomyelitis, pyelonephritis, cystitis, pneumonia, cellulitis, sepsis, or peritonitis [20]. Another study, from Netherland, prospectively compared patients with type I or type II diabetes to patients with hypertension in terms of the frequency of certain infections. Diabetes increases the risk of bacterial skin and mucous membrane infections, urinary tract infections, and lower respiratory tract infections [21]. This is consistent with the widespread observation that diabetes individuals have an elevated risk for wound infections, most likely due to the higher prevalence of leg ulcers in these patients.

There are several other factors that connect diabetes to infections, in addition to the fact that it appears to be a separate risk factor for bacterial infections: (1) Diabetic individuals are more likely to contract specific (rare) illnesses, and (2) diabetic people are more likely to have particular consequences when exposed to pathogens. As a result, some uncommon illnesses, such as emphysematous pyelonephritis, invasive otitis externa, emphysematous cholecystitis, or rhinocerebralmucormycosis, are more common in patients with diabetes [22]. Diabetes also appears to raise the risk of infections brought on by specific bacteria, including *Staphylococcus aureus* and *Mycobacterium tuberculosis*. It was postulated to explain that increased fatality rates from pneumococcal pneumonia in these individuals are linked to infections by particular species, such as Streptococcus pneumonia thereby increasing the chances of bacteremia [18]. Additionally, a report from the Community-Acquired Pneumonia Organisation international cohort study revealed that diabetes was not a risk factor for death when suffering from bacteremic pneumococcal infection and that pneumococcal bacteremia did not affect the outcome in terms of clinical stability in patients with diabetes mellitus.

These findings fuel the debate over whether cardiovascular and renal comorbidities, which are frequently associated with diabetes, may actually increase susceptibilities to infections and affect the outcome from infections rather than the metabolic changes seen in diabetic subjects. This poses an uncertainty whether diabetes mellitus is actually a significant risk factor for important infections such as pneumonia (**Figure 2**).

#### **4.1 Impaired cytokines in diabetes**

Under hyperglycemic condition, peripheral blood mononuclear cells (PBMCs) and isolated monocytes from persons with T1D and T2D releases less interleukin 1 beta (IL-1) after being activated with lipopolysaccharides (LPS). T1D participants' monocytes derived from PBMCs produced fewer IL-1 and IL-6 as compared to healthy donors [23]. The PBMCs of non-diabetic subjects were activated by anti-CD3 antibodies, and when they were exposed to high glucose levels, they were found to reduce the production of the cytokines IL-2, IL-6, and IL-10.Because IL-6 is essential for pathogen defence as well as for adaptive immune response by inducing antibody production and effector T-cell development, studies have shown that inhibiting those cytokines in hyperglycemia may suppress the immune response against pathogens that are invading the body. Dextrose octreotide-induced PBMCs from healthy patients were shown to produce less IL-6 and IL-17A, particularly in CD14+ and CD16+ intermediate monocytes, suggesting that high blood glucose levels had an adverse effect on the functioning of the immune system [24].

**Figure 2.**

*Impact of T2DM on immune system leading to several associated complications.*

Loss of IL-10 release by Myeloid cells' and production of interferon gamma (IFN-) and TNF by T cells' is caused by increased glycation while is decreased during diabetes. When compared to normal mice, IL-22 cytokine levels were found to be lower in obese leptin-receptor-deficient (db/db) mice and high-fat dietinduced hyperglycemic animals. In PBMC cultivated in a high glucose medium and stimulated by poly I:C, type 1 IFN production reduces [22]. Following infection with *Burkholderia pseudomallei*, an IA investigation found that in diabetes patients PBMC cultures produce less IL-12 and IFN than PBMCs from healthy donors. Additionally, PBMCs from diabetics had a greater intracellular bacterial load than those from healthy controls, indicating that hyperglycemia weakens the host's defence against bacterial invasion. Recombinant IL-12 and IFN dramatically decreases bacterial load in PBMCs from diabetic people, demonstrating that low IL-12 and IFN production in diabetes reduces the ability of immune cells to control bacterial development during infection [25]. Therefore, it is believed that diabetic hyperglycemia reduces the ability of macrophages and other leukocytes to destroy infections. The impact of insulin shortage on macrophage activity against pathogens in T2D has not been as extensively studied as the influence of hyperglycemia on immune cell activity in T2D. The infusion of insulin into bone marrow-derived macrophages isolated from diabetic mice dramatically boosts the production of TNF and IL-6 after LPS stimulation, according to research on the effects of insulin deficit on immune response [7]. Another rat investigation found that insulin deficiency disrupts the alveolar macrophage phagocytosis and cytokine production, both of which gets recovered after insulin administration. This data suggest that the injection of exogenous insulin in diabetics may boost the immune function.

#### **4.2 Impediment of leukocyte recruitment**

A robust T-cell-mediated response is essential for host defence against intracellular bacterial infections. A variety of 120 T cell subtypes (Th1, Th2, Th17, and Treg) develop into diverse immune responses that are primarily based on released cytokine patterns. A key factor in the ability to resist intracellular bacterial infections is the early influx of IFN-producing Th1 cells [26]. There is compelling evidence to suggest that diabetic hosts experience an initial delay in the activation of Th1 cell-mediated immunity. Although it could be too late to prevent diabetic hosts from bacterial spread, there is also clinical and experimental evidence suggesting the late inflammatory response during chronic TB is strengthened. It's likely that the enhanced antigenic stimulus that caused this late hyper-inflammatory response, as a result of defective innate immune regulation, or as a result of cumulative build up contributing to the chronic inflammation underlying the immunopathology of diabetes itself [27]. Patients with co-morbid diabetes and tuberculosis have been reported to have elevated levels of circulating Th1- and Th17-associated cytokines.

Leukocyte recruitment, which typically occurs in three stages, is a well-organised cascade-like process that involves (a) selectin-dependent leukocyte rolling on the endothelium layer, (b) chemokine-dependent integrin activation with subsequent leukocyte adherence, and (c) diapedesis. Much has been learnt about the transmigration process which involves the final stage of leukocyte recruitment into inflamed tissues. Leukocyte transmigration is influenced by a number of adhesion molecules, including platelet cells adhesion molecule, junctional adhesion molecule-1, and CD99, while leukocyte motility in tissues is influenced by 1-integrins [28]. The infiltration of CD8 + T cells and CD45+ leukocytes was drastically decreased in the brains of db/db mice that had West Nile virus-associated encephalitis. This study demonstrated that reduced recruitment of CD45+ leukocytes and CD8+ T lymphocytes was related to lower expression of cell adhesion molecules (CAMs), such as E-selectin and intracellular adhesion molecule (ICAM)-1 [29]. *In vivo* investigation employing streptozotocin-induced diabetic mice infected with *Klebsiella pneumoniae* likewise proved this impairment in leukocyte recruitment. Granulocyte counts in the alveolar airspace of the diabetic mice were lower. They also discovered that after inhaling *Klebsiella pneumoniae* LPS, lung tissue produced less of several cytokines, including CXCL1, CXCL2, IL-1, and TNF [30].

#### **4.3 Erratum in pathogen recognition**

Pathogen recognition receptors that play a crucial role in the innate immune system include Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Different adaptor proteins, which are frequently identified to activate the NF-kB and hence stimulate the release of proinflammatory cytokines, mediate both the TLRs and NLRs pathways. The pathophysiology of inflammation-mediated insulin resistance, which further develops metabolic problems, has been hypothesised to include TLRs and NLRs significantly. Innate immunity is activated by TLR2 homodimers and TLR2 heterodimers with TLR1 or TLR6 upon detection of damage-associated molecular patterns (DAMPs) that are endogenous chemicals created and released during T2DM, an infection or inflammatory response [31]. Inflammation has been shown to play a significant role in type 2 diabetes-related pancreatic beta cell dysfunction [32]. Therefore, the inflammatory effects of the TLR2-ligand interaction may play

a significant role in the development of type 2 diabetes. According to a study the interaction between TLR2/6 and its associated ligands causes macrophage activation and the generation of pro-inflammatory cytokines IL-1 and IL-6, which contribute to islet inflammation.

The expression of TLR-2 and TIRAP, which are involved in the identification of pathogens, was found to be downregulated in diabetic mice [31]. However, numerous investigations have demonstrated enhanced TLR expression in neutrophils and monocytes isolated from diabetic individuals. TLR was found to be under expressed in diabetics with poor glycemic control, but higher in patients with controlled hyperglycemia without complications [33]. Therefore, it is yet unknown how hyperglycemia affects TLR expression and associated immunity in diabetic people.
