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Diabetes is an age-dependent health issue prevalent worldwide and specially seen in those families with prevalent history of the disorder. Insufficient insulin production by the defective pancreas that leads to high blood glucose levels in the systemic circulation makes the patients more prone to an infection that exaggerates with time as compared to their counterparts. This increased prevalence of infections in diabetics may be due to defects in the immune functionality of the diabetes patients. High blood glucose level evokes inflammatory responses due to provoked inflammatory immune response against hyperglycemic condition in adipocytes and macrophages. The inflammatory mediators attack the pancreatic beta cells thus affecting the insulin production, which in-turn again results in hyperglycemia. Dysfunction of the immune response could not control the invasion of pathogens thereby, increasing the incidence of infectious diseases and related co- morbidities. This chapter discusses about immune dysfunction and suppression in T2DM and the underlying inflammation and infections in diabetics. An elaborate and in-depth understanding of the immune dysfunction in T2DM patients can help in the management and development of better targeted therapeutics to cure the disorder. It may also provide an insight in how to take care of one’s health as a precautionary measure to avoid the complications leading to diabetes and vice versa.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Lucknow, UP, India
*Address all correspondence to: pratimatripathi.lko@gmail.com
1. Introduction
Diabetes caused by chronic hyperglycemia due to failure of the pancreatic beta cells to produce adequate insulin or ineffective utilisation of the produced insulin by the body is a severe health issue worldwide [1]. Diabetes exists in two major forms: type 1 (T1D) and type 2 (T2D) diabetes. Type 1 diabetes is caused by the body’s immune system damaging the pancreas thereby making the body incapable to produce sufficient insulin. Impaired regulation and use of glucose due to insulin resistance or inefficiency in insulin production by the body leads to Type 2 diabetes. Family history is the well risk factors for Type 1 diabetes whileobesity, advancing age, family history, sedentary lifestyle, ethnicity and certain medications are the risk factors associated with Type 2 diabetes. Diabetes affects the brain, kidney, heart, and eyes as an acute condition that rises the risk of various diseases brought on by damage to the macro and microvasculature [2]. Patients with diabetes are also more prone to infections. Numerous studies have shown that individuals with diabetes are more likely to develop diseases of the lower respiratory tract, including pulmonary tuberculosis (TB) urinary tract infections, and pneumonia and infections of the skin and internal organ tissues [3]. Diabetes patients typically have poor outcomes from infection treatment. Diabetes patients are more financially burdened by infection because of the high cost of therapy, the time of treatment, and the associated consequences.
Around 425 million people worldwide have diabetes, according to the International Diabetes Federation [2]. Both developed and developing nations expect this number to rise. By 2045, there could be 629 million diabetes patients worldwide if adequate care and control are not implemented. Around 5 million persons perished from diabetes in 2017; 850 million USD were spent on diabetic care. In developing nations, especially those with tropical climates have high prevalence of communicable disease, along with whooping number of diabetics, which inevitably results in increased incidence of infectious diseases posing huge burden on the nation’s economy [4].
Due to decreased insulin synthesis by islet cells in the pancreas and insufficient insulin action (insulin resistance), T2D accounts for over 90% of all cases of diabetes. The condition causes the blood glucose levels to rise. Obesity, inactivity, and ageing are all linked to insulin resistance in T2D. In order to counteract insulin resistance, the pancreatic islets expand their cell mass and produce more insulin [5]. When this attempt falls short of making up for insulin resistance, T2D develops. Pancreatic cell damage due to years of insulin resistance leads above half of T2D patients to take insulin therapy. In T2D, long-term chronic insulin resistance has a number of negative effects, such as atherosclerosis and microvascular problems such nephropathy, neuropathy, and retinopathy [6].
Following a meal, blood islet cells produce and release insulin in response to elevated blood glucose levels. Lower blood glucose level results due to increased glucose uptake by cells as a result of the insulin binding to its receptors present on the cell membranes. This process causes the translocation of glucose transporters to the cell membrane. Hyperglycemia is a condition where the pancreas either fails to generate enough insulin, produces insufficient insulin, or both. It has been observed that TNF levels elevated in adipose tissue of obese mice have been linked to insulin resistance in these experimental models [7]. Additionally, increased levels of interleukin (IL)-6, plasminogen activator inhibitor, C-reactive protein and other inflammatory mediators in the plasma of obese mice exaggerates the damage associated with these factors. Suppression of insulin receptor substrate (IRS-1) is brought on by TNF, ceramide, diacylglyceride, free fatty acids, hypoxia, reactive oxygen species (ROS), and c-Jun N-terminal kinase I (JNK1) in liver and adipose tissue (Figure 1). Additionally, TNF- causes insulin resistance by impairing the activity of the gamma subunit of the peroxisome proliferator-activated receptor [8].
Figure 1.
Oxidative stress promotes a cascade of responses leading to adipogenesis.
Tyrosine phosphorylation at IRS-1 and -2 results from the binding of insulin with its receptor. IKK and JNK1, the mediators of inflammatory and stress responses, phosphorylate IRS substrates on serine, which inhibits insulin signalling. The transcriptional activation of several genes linked to the inflammatory response is also caused by JNK1 and IKK, which leads to insulin resistance. JNK1 and IKK signalling pathways are activated by the influx of more free fatty acids and glucose [9]. The transcription inflammation associated genes causes the phosphorylation and activation of IKK that further encourages the ubiquitination and destruction pathways in proteasome thereby translocating NF into the nucleus. IKK also blocks insulin signalling pathways in adipocytes by phosphorylating IRS-1 serine residues [10]. TNF-induced JNK activation phosphorylates IRS-1 to suppress insulin signalling. The transducers and activators of Janus kinase/signal transcription (JAK/STAT) pathway also results in the suppression of insulin signalling. STAT’s tyrosine is phosphorylated by JAK kinases, which causes STAT to dimerize and go to the nucleus and phosphorylate IRS-1 at Ser636 and Ser307.The Glut-4 translocation to cell membranes is eventually hampered by this suppression of insulin signalling, which results in hyperglycemia [11].
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, obesity-related 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.
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 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).
Figure 2.
Impact of T2DM on immune system leading to several associated complications.
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].
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 diet-induced 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.
The quick release of ROS and the presence of pre-formed proteolytic granules make neutrophils one of the first phagocytic cells to reach infection sites. Clinically, the majority of infected cells in patients with active tuberculosis’ sputum and bronchoalveolar lavage are neutrophils. The results of in vitro research on neutrophils’ capacity to kill M. tuberculosis and B. pseudomallei vary, which is likely due to a variety of host- and organism-specific variables as well as variations in experimental methodology [29]. Unstimulated neutrophils in diabetics have been shown to produce more inflammatory cytokines and ROS, which has been linked to AGE-direct activation. However, in diabetic hosts, neutrophil responses to infection seem to be primarily inhibited. Reduced glucose metabolism via the pentose-phosphate route, which generates NADPH, a need for adequate NADPH oxidase function, may be linked to decreased pathogen-stimulated ROS generation [28]. Furthermore, neutrophil dysfunction in diabetic hosts may be caused by diminished glutathione reductase activity, which also controls neutrophil-based ROS generation and phagocytosis. ROS induces the release of neutrophil extracellular traps (NET), another significant bactericidal mechanism in addition to directly killing germs. Such deficiencies in neutrophil function might make it easier for internal bacteria to use neutrophils as a haven and a vehicle for spreading in diabetic hosts [34].
Following stimulation with phorbol 12-myristate-13-acetate, isolated neutrophils from T2D TB patients produced less ROS. Increased resistin levels in the blood of T2D patients were linked to this ROS generation deficiency [35]. When exposed to a high glucose content media, isolated neutrophils from healthy patients suppressed superoxide (O2−). Through the suppression of glucose-6-phosphate dehydrogenase (G6PD), which interfered with nicotinamide adenine dinucleotide phosphate synthesis, this impairment was caused.
When healthy individuals’ blood was exposed to bacterial wall components after becoming hyperglycemic the blood’s neutrophil degranulation reduces. Another example of neutrophil dysfunction in S. aureus phages was provided by C3-mediated complement suppression brought on by hyperglycemia [36]. It is reported that NETs, which increase susceptibility to infections, are less likely to form when hyperglycemia is present. All of these studies showed that hyperglycemia causes neutrophil dysfunction, which includes irregularities in ROS production, impairments in neutrophil degranulation, inhibition of immunoglobulin-mediated opsonization decreased phagocytosis, and errors in NET formation.
Early host defence against intracellular bacterial infections is greatly aided by macrophages. In order to control infection, macrophages perform crucial effector tasks such as phagocytosing pathogens and eliminating necrotic and apoptotic neutrophils. Activation and recruitment of circulating monocytes to infection sites, where they undergo macrophage differentiation, are aided by cytokines and chemokines produced by neutrophils, such as TNF- and CCL2 [37]. The macrophage cytokine profile is essential for promoting efficient cell-mediated immunity and defence against intracellular bacteria in addition to phagocytic and antibacterial processes. Inducible nitric oxide synthase, co-stimulatory molecules, and inflammatory cytokines like TNF-, IL-12, and IL-18 are all up-regulated as a result of M1 macrophage polarisation in response to intracellular bacterial infections. IFN- production from NK cells depends on the production of IL-12 and IL-18 [38]. Inducible nitric oxide synthase, co-stimulatory molecules, and inflammatory cytokines like TNF-, IL-12, and IL-18 are all up-regulated as a result of M1 macrophage polarisation in response to intracellular bacterial infections. In order to create T helper type 1 (Th1) cell-mediated immunity, NK cells and T cells must produce IL-12 and IL-18 in order to trigger an IFN- response [37]. Both IFN and TNF stimulate inducible nitric oxide synthase and NADPH oxidase, which activate macrophages and aid in the destruction of intracellular microorganisms.
The way that macrophages work is also changed by hyperglycemia. Chronic hyperglycemia gets significantly correlated with deficiencies in complement receptors and Fc receptors on isolated monocytes, impairing phagocytosis [39]. Reduced phagocytosis and antibacterial activity were seen in an in vitro experiment utilising macrophages generated from mice bone marrow and treated with high glucose. Reduced phagocytosis was seen in peritoneal macrophages from diabetic mice in the same investigation [39]. This might be connected to macrophages’ decreased glycolytic reserve and capacity as a result of their long-term sensitivity to high glucose levels.
Phagocytosis and adhesion capacity in RPMs of db/db mice decreases significantly thereby employing resident peritoneal macrophages (RPMs) obtained from mice. Additionally, compared to control mice, db/db mice showed enhanced macrophage polarisation shifting to M2 macrophages. A similar rise in M2 macrophage markers, such as Arginase 1 and IL-10, was observed in macrophages generated from mice bone marrow and exposed to high glucose for an extended length of time [40]. The immune response to bacterial infection may be weakened by this shifting since M2 macrophages have a low potential for microbicidal activity.
Innate immune responses to pathogens are mostly mediated by natural killer cells, and during the past 10 years, research into the protective effects of these cells against intracellular bacterial infections has acquired significant impetus. Numerous inhibitory and activating receptors control natural killer cells. Isolated NK cells from T2D patients were used to demonstrate the dysfunction of natural killer (NK) cells, which are crucial for containing invasive pathogens [41]. It was discovered that defects in the NK cell-activating receptors NKG2D and NKp46 were linked to functional defects in NK degranulation capacity [42].
NK cells with T-cell receptors are a special subset known as natural killer T (NKT) cells. They have the capacity to enhance a variety of immune responses and react to glycolipid antigens rather than peptide antigens. There is proof that NKT cells aid in host defence during M. tuberculosis infection by suppressing intracellular bacterial growth through cytolytic processes, promoting antigen-presenting cell (APC) maturation and activation, and modifying the sort of immune response elicited [43]. In experimental models of diabetes, the role of NKT cells in adipose tissue inflammation and glucose intolerance has been discussed. Increases in NKT cell numbers are seen in tuberculosis patients, and those with co-morbid diabetes had higher levels of NKT cells in their blood and bronchoalveolar lavage than those without TB [44]. This has been proposed as a helpful marker for active tuberculosis and may be a direct result of the elevated bacillary burden seen in these patients.
7.1 Impaired immune and complement system
In a study on rats the malfunction of complement activation was noted. They showed that elevated blood sugar levels were linked to a reduction in C4-fragment opsonization, which blocks the classical or lectin pathways of complement activation [44]. Table 1 provides an overview of the potential pathways that lead to infection susceptibility in diabetics.
Effects on immune system
Sources involved
Mechanism of action
References
Vanquished cytokine production
PBMCs isolated from healthy individuals
TGF-mediated reduction of IL-6, IL-2, and IL-10 production by PBMC; stimulation of cellular TGF- synthesis to inhibit mononuclear cell proliferation.
The immunological mechanism underlying infection susceptibility in diabetics.
The results described in the previous section imply that islet macrophages have protective effects and help to maintain islet homeostasis. However, recent studies have also demonstrated that they play a significant role in the islet pathology in T2D [63]. The number of macrophages within islets was found to be increased in pancreas sections from T2D patients, C57BL/6 mice given a high-fat diet, db/db mice, and Goto-Kakizaki (GK) rats by immunohistochemical analysis [64]. Additionally, it has been claimed that high glucose or palmitate caused the production of chemokines from the islets, which aided in monocyte and neutrophil migration. This shows that the type 2 diabetic environment may encourage macrophage infiltration into pancreatic islets and stimulate chemokine production [65].
The build-up of macrophages within T2D islets points to their pathological function. It has been noted that macrophages perform seemingly incompatible tasks in islets as well as in other organs and conditions. In reality, recent research has shown that macrophages are actually extremely diverse [66]. According to in vitro research, Th1 cytokines alone or in combination with microbial products cause macrophages to activate in the traditional M1 manner, whereas Th2 cytokines (IL-4 and IL-13) cause an alternative type of activation known as M2 [53]. ActivatedM2-type macrophages enhance wound healing and may also modify immunological responses, whereas classically activatedM1-type macrophages play a key role in host defence by secreting proinflammatory cytokines and ROS. However, the phrase “M2 activation” is somewhat amorphous and is used to refer to a variety of M1-independent macrophage activation mechanisms [54].
M2 macrophages may therefore act differently depending on the environment. The functions of various macrophage subsets in the onset and development of disease, as well as their potential contributions to the preservation of homeostasis, are now well understood. Because macrophages have a variety of activation phenotypes, we examined the polarity of macrophage activation inside islets. We identified two distinct subpopulations of islets using flow cytometry: CD11b+Ly-6C+CD11b+F4/80+Ly-6C-T2D and CD11b+Ly-6C+CD11b+Ly-6C. healthier islet. CD11bhighF4/80−/+Ly-6C+ Diabetes type 2 and islet macrophage polarity (T2D). Healthy islets have a high percentage of resident macrophages that display CD11b+F4/80+Ly-6C [67].
Monocytes/macrophages and CD11b+Ly-6Cmacrophages accumulate in T2D islets. T2D islet CD11b high F4/80+Ly 6C+monocytes/macrophages are also present. Islet-resident macrophages were predominately CD11b+Ly-6C cells with an M2-type phenotype under baseline circumstances. In comparison to control db/+ and KKTa animals, fractions of these M2-type cells were not altered in db/db or KKAy model T2D mice, respectively [55]. On the other hand, the T2D models had a specifically higher number of CD11b+Ly-6C+macrophages. These cells have an M1-type phenotype and express pro-inflammatory cytokines like IL-1 and TNF. As a result, in T2D islets, macrophage polarity seems to have switched toward M1 [56].
Inflammasome activation and High Glucose in T2D Islets. The polarity of macrophages within T2D islets is altered toward M1. Recent research has uncovered a number of mechanisms, including immune cell recruitment and the elevation of inflammatory cytokines (such IL-1), that underlie the activation of inflammatory processes within islets [57]. For instance, as was already established, the environment of type 2 diabetes may stimulate the creation of chemokines that encourage macrophage infiltration into pancreatic islets. Multiprotein complexes called inflammasomes are crucial for the development and release of IL-1. Two stimuli are necessary to initiate IL-1 secretion: the first stimulates pro-IL-1 protein expression, and the second activates inflammasomes, which in turn activate caspase I to cleave pro-IL-1 and produce mature IL-1 [58].
According to a recent study, minimally modified LDL, which triggers TLR4 signalling in macrophages and primes them to process Il-1, is one of the initial stimuli in T2D islets. The second stimulus was determined to be islet amyloid polypeptide (IAPP), a distinct polypeptide component of amyloid present in pancreatic islets and which is produced from cells in response to high glucose. IAPP, a soluble oligomer, activates the NLRP3 inflammasome and causes the islet macrophages to secrete IL-1 [59]. As a result, the interaction between macrophages and -cells is crucial for inflammasome activation within islets. Additionally, it has been demonstrated that high glucose-induced ROS production in cells causes the activation of the NLRP3 inflammasome and the release of IL-1 [60].
Islet inflammation leads to Cell dysfunction in T2D. Despite the fact that it seems as though high glucose levels are a necessary trigger for islet inflammation, a recent examination of -cell function revealed that impaired glucose tolerance was already present before glucose-induced insulin secretion deteriorated. This shows that cell dysfunction can start and progress in response to triggers other than excessive glucose levels [45]. FFAs are a potential contender for such stimulation. Clinical studies have shown that FFA levels are a reliable predictor of future T2D and a high consumption of saturated fatty acids has been associated with an increased risk of T2D. The most prevalent saturated FFA in blood is palmitate, and studies have shown that it has harmful effects on -cells that are collectively known as “lipotoxicity” [46].
Studies conducted in vitro have demonstrated that palmitate directly induces -cell lipotoxicity, at least in part through mechanisms predominantly involving ER stress and ROS. We created a technique to elevate non-esterified palmitate levels in the serum by injecting emulsified ethyl palmitate in order to assess the effects of palmitate on -cells in vivo. This model demonstrated that palmitate activates TLR4 to generate chemokines, such as CCL2 and CXC11, in cells [47]. These chemokines caused CD11b+Ly-6C+M1-type monocytes and macrophages to be attracted to the islets. Additionally, palmitate-induced -cell dysfunction was decreased when M1-type cells were prevented from accumulating by utilisingclodronate liposomes, demonstrating their causative involvement [48].
Additionally, it was discovered that M1 macrophages’ production of proinflammatory cytokines, such as IL-1 and TNF-, encourages -cell dysfunction and that the vicious loop created by the secretion of chemokines by -cells and cytokines by M1 macrophages speeds up islet inflammation [49]. Similar to this, M1 macrophage increase within islets in T2D models (db/db and KKAy animals) appears to lead to cell dysfunction. These findings unequivocally demonstrate that inflammation-related islet dysfunction comes from the stimulation of inflammatory mechanisms [68].
Inflammation as a Pharmacological Target for T2D: Due to the role that IL-1 plays in the emergence of T2D and -cell dysfunction, therapeutic approaches that target the IL-1 receptor and IL-1 ligand have been developed. Rheumatoid arthritis is treated with recombinant human IL-1RA (anakinra), a medication that blocks IL-1 receptor signalling [69]. IL-1RA presumably inhibits both IL-1 and IL-1 signalling since it suppresses the IL-1 receptor. Anakinra was tested in a clinical trial to see if it could improve -cell function and glycaemic control in T2D patients. The anakinra group demonstrated improved HbA1c levels and serum C-peptide concentrations during oral glucose tolerance test (OGTT) with no significant differences in insulin sensitivity, indicating that improved cell function played the major role in the improvement in glucose tolerance [70].
A follow-up investigation showed that the decreased proinsulin-to-insulin ratio persisted for 39 weeks after the end of the treatment. In GK rats and mice fed a high-fat diet, the processes underlying these observations were further examined. IL-1RA enhanced insulin sensitivity and beta-cell activity in these animals by suppressing inflammation in insulin target tissues and islets. There was a noticeable decrease in islet macrophage counts in GK rats treated with IL-1RA, indicating that islet macrophages may be one of the targets of the anakinra treatment [71]. Finally, despite the drug improving the glucose disposition index during OGTT, no appreciable change in insulin sensitivity or -cell function was seen in a recent investigation assessing the effects of anakinra on obese adult individuals without T2D.
Additionally, IL-1-specific antibodies have been created. The therapeutic effects of gevok-izumab, a recombinant humanised monoclonal antibody that neutralises IL-1, were examined in T2D participants. The fact that this medication preserves IL-1 signalling and has a longer half-life (22–25 days), which lowers the frequency of administration and lowers the cost, may make it superior to anakinra [50]. Gevokizumab significantly decreased HbA1c, C-peptide secretion, and CRP at a low dose (0.3 mg/kg), but not at a high dose (0.03–0.1 mg/kg). The discovery that a large dose failed to exhibit positive effects may support the idea that IL-1 at low concentrations is advantageous for cells [51]. The scientists came to the conclusion that the right dosage and duration of gevokizumab therapy are essential for changing the immune system in T2D patients. Salsalate, a salicylic acid prodrug having inhibitory effects on the NF-B pathway, and TNF-inhibitors have both been investigated in T2D [72].
These research’ encouraging findings are in line with the idea that T2D can be treated by reducing the inflammation induced by diabetes.
A serious global concern is the dual burden of intracellular bacterial infections and diabetes. The majority of current diagnostic and therapeutic research involves non-diabetic mice, and it is unclear whether these findings can be applied to people with diabetes given the obvious disparities in immune responses and disease mechanisms. There is considerable clinical and experimental evidence that a delay in innate immune system inflammatory signals is followed by delayed development of effective protective responses against intracellular bacterial infections, notwithstanding the complexity of the underlying immunopathology of diabetes. It is likely that a more multifaceted therapeutic approach will be required to address the complicated immunopathogenesis underlying diabetes, even while better glucose management may assist patients with intracellular infections and co-morbid diabetes. It will be easier to treat and manage disease in sensitive populations if we are aware of the mechanisms driving co-morbidities like diabetes, which profoundly affect the development of intracellular bacterial infections. Innovative, cost-effective strategies are desperately needed, especially in low- and middle-income nations where there has never been a greater convergence of non-communicable and communicable diseases. A multidisciplinary approach with an extensive study is required to tackle the present and future issues of the rising double burden of co-morbid intracellular bacterial infections leading to continued and widespread existence of non-communicable illnesses.
Diabetes is a metabolic disorder brought on by inflammation in an advanced immune system. Insulin resistance results in a multitude of immunological reactions that aggravate the inflammatory state and lead to hyperglycemia as a result of the inhibition of insulin signalling. Both issues with the innate immune response (including neutrophil and macrophage dysfunction) and deficiencies in the adaptive immune response are thought to contribute to the immune system’s degradation against invasive infections in diabetics (including T cells). A deeper understanding of the processes of hyperglycemia that impair host defence against pathogens is crucial for the development of cutting-edge treatments to treat infections in diabetic patients and improve treatment outcomes.
References
1.Zimmet PZ, Magliano DJ, Herman WH, Shaw JE. Diabetes: A 21st century challenge. The Lancet Diabetes and Endocrinology. 2014;2(1):56-64. DOI: 10.1016/S2213-8587(13)70112-8
2.Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice. 2011;94(3):311-321. DOI: 10.1016/J.DIABRES.2011.10.029
3.Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 diabetes and its impact on the immune system. Current Diabetes Reviews. 2019;16(5):442-449. DOI: 10.2174/1573399815666191024085838
4.Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: A review of current evidence. Diabetologia. Jan 2019;62(1):3-16. DOI: 10.1007/s00125-018-4711-2. Epub 31 Aug 2018. PMID: 30171279
5.Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne). 27 Mar 2013;4:37. DOI: 10.3389/fendo.2013.00037. PMID: 23542897; PMCID: PMC3608918
6.Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, et al. Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia. Jun 2009;52(6):1083-1086. 2009. DOI: 10.1007/s00125-009-1347-2. Epub 15 Apr 2009. PMID: 19367387
7.Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. SCIENCE BENTHAM send orders for reprints to reprints@benthamscience.net type 2 diabetes and its impact on the immune system. Current Diabetes Reviews. 2020;16:442-449. DOI: 10.2174/1573399815666191024085838
8.Parry SA, Smith JR, Corbett TRB, Woods RM, Hulston CJ. Short-term, high-fat overfeeding impairs glycaemic control but does not alter gut hormone responses to a mixed meal tolerance test in healthy, normal-weight individuals*. British Journal of Nutrition. 2017;117:48-55. DOI: 10.1017/S0007114516004475
9.Carmichael L, Keske MA, Betik AC, et al. Is vascular insulin resistance an early step in diet-induced whole-body insulin resistance? Nutrition & Diabetes. Jun 2022;12(1):31-43. DOI: 10.1038/s41387-022-00209-z. PMID: 35676248; PMCID: PMC9177754
10.Zhang A, Li M, Qiu J, Sun J, Su Y, Cai S, et al. The relationship between urinary albumin to creatinine ratio and all-cause mortality in the elderly population in the Chinese community: A 10-year follow-up study. BMC Nephrology. Jan 2022;23(1):16-26. DOI: 10.1186/s12882-021-02644-z. PMID: 34983421; PMCID: PMC8729014
11.Lawal B, Sani S, Onikanni AS, Ibrahim YO, Agboola AR, Lukman HY, et al. Preclinical anti-inflammatory and antioxidant effects of Azanza garckeana in STZ-induced glycemic-impaired rats, and pharmacoinformatics of it major phytoconstituents. Biomedicine & Pharmacotherapy. 2022;152:113196. DOI: 10.1016/j.biopha.2022.113196
12.Tomita T. Apoptosis in pancreatic β-islet cells in Type 2 diabetes. Bosnian Journal of Basic Medical Sciences. 2016;16(3):162-179. DOI: 10.17305/bjbms.2016.919
13.Waddell HMM, Zhang JZ, Hoeksema KJ, McLachlan JJ, McLay JC, Jones PP. Oxidation of RyR2 has a biphasic effect on the threshold for store overload-induced calcium release. Biophysical Journal. 2016;110(11):2386-2396. DOI: 10.1016/j.bpj.2016.04.036
14.He Q , Xu JY, Gu J, Tong X, Wan Z, Gu Y, et al. Piperine is capable of improving pancreatic β-cell apoptosis in high fat diet and streptozotocin induced diabetic mice. Journal of Functional Foods. 2022;88:104890. DOI: 10.1016/j.jff.2021.104890
15.Oguntibeju OO, Aboua GY, Omodanisi EI. Effects of Moringa oleifera on oxidative stress, apoptotic and inflammatory biomarkers in streptozotocin-induced diabetic animal model. South African Journal of Botany. 2020;129:354-365. DOI: 10.1016/j.sajb.2019.08.039
16.Lee JH, Mellado-Gil JM, Bahn YJ, Pathy SM, Zhang YE, Rane SG. Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling. Cell Death and Disease 11, 2020:184-199. DOI: 10.1038/s41419-020-2365-8
17.Schuetz P, Castro P, Shapiro NI. Diabetes and Sepsis: Preclinical findings and clinical relevance. Diabetes Care. Mar 2011;34(3):771-778. DOI: 10.2337/dc10-1185. PMID: 21357364; PMCID: PMC3041224
18.Esper AM, Moss M, Martin GS. The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study. Crit Care. 2009;13(1):R18-23. DOI: 10.1186/cc7717. Epub 13 Feb 2009. PMID: 19216780; PMCID: PMC2688136
19.Gupta S, Maratha A, Siednienko J, Natarajan A, Gajanayake T, Hoashi S, et al. Analysis of inflammatory cytokine and TLR expression levels in type 2 diabetes with complications. Scientific Reports. 9 Aug 2017;7(1):7633-7643. DOI: 10.1038/s41598-017-07230-8. Erratum in: Sci Rep. 5 Apr 2018;8(1):5768. PMID: 28794498; PMCID: PMC5550417
20.Neely AN, Clendening CE, Gardner J, Greenhalgh DG. Gelatinase activities in wounds of healing-impaired mice versus wounds of non-healing-impaired mice. Journal of Burn Care and Rehabilitation. 2000;21(5):395-402. DOI: 10.1097/00004630-200021050-00001
21.Berrou J, Fougeray S, Venot M, Chardiny V, Gautier J-F. Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes. PLoS One. 2013;8(4):62418. DOI: 10.1371/journal.pone.0062418
22.Hiriart M, Hamasaki H, Clinic H, Villa AR, Marichal-Cancino BA, Chávez-Reyes J, et al. Susceptibility for some infectious diseases in patients with diabetes: The key role of Glycemia. Frontiers in Public Health | Www.Frontiersin.Org. 2021;9:559595. DOI: 10.3389/fpubh.2021.559595
23.Karima M, Kantarci A, Ohira T, Hasturk H, Jones VL, Nam BH, et al. Enhanced superoxide release and elevated protein kinase C activity in neutrophils from diabetic patients: association with periodontitis. Journal of Leukocyte Biology. Oct 2005;78(4):862-870. DOI: 10.1189/jlb.1004583. Epub 2005 Aug 4. PMID: 16081595; PMCID: PMC1249507
24.Martinez PJ, Mathews C, Actor JK, Hwang S-A, Brown EL, De Santiago HK, et al. Impaired CD4+ and T-helper 17 cell memory response to Streptococcus pneumoniae is associated with elevated glucose and percent glycated hemoglobin A1c in Mexican Americans with type 2 diabetes mellitus. Translational Research. 2014;163(1):53-63. DOI: 10.1016/j.trsl.2013.07.005
25.Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, et al. Expression of advanced glycation end products and their cellular receptor RAGE diabetic nephropathy and nondiabetic renal disease. Journal of the American Society of Nephrology. 2000;11(9):1656-1666. DOI: 10.1681/ASN.V1191656
26.Holland SM, Gallin JI, Mandell, Douglas. Evaluation of the patient with suspected immunodeficiency. In: Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Vol. 12. USA: Churchill Livingstone; 2010. pp. 167-78
27.Jalkanen S, Salmi M. Lymphocyte adhesion and trafficking. Clinical Immunology. 2019;Chapter 11:171-182.e1. First edition Part 1. DOI: 10.1016/B978-0-7020-6896-6.00011-9
28.Gorain B, Bhattamishra SK, Choudhury H, Nandi U, Pandey M, Kesharwani P. Overexpressed receptors and proteins in lung Cancer. In: Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer. United Kingdom: Woodhead Publishing; 2019. pp. 39-75. DOI: 10.1016/B978-0-12-815720-6.00003-4
29.Shah B, Burg N, Pillinger MH. Neutrophils. In: Kelley and Firestein’s Textbook of Rheumatology. Baishideng Publishing Group; 2017. pp. 169-188.e3. DOI: 10.1016/B978-0-323-31696-5.00011-5
30.Hyde DM, Simon SI. Inflammatory cells of the lung: Polymorphonuclear leukocytes. In: Comprehensive Toxicology. 2nd ed. Vol. 8. Elsevier; 2010. pp. 115-127. DOI: 10.1016/B978-0-08-046884-6.00906-4
31.Roep BO, Thomaidou S, van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nature Reviews Endocrinology. 2021;17:150-161. DOI: 10.1038/s41574-020-00443-4
32.Pino SC, Kruger AJ, Bortell R. The role of innate immune pathways in type 1 diabetes pathogenesis. Current Opinion in Endocrinology, Diabetes and Obesity. Apr 2010;17(2):126-30. DOI: 10.1097/MED.0b013e3283372819. PMID: 20125005; PMCID: PMC2905794
33.Scaglione R, Elisei R, Marchetti P. International Journal of Molecular Sciences. 2022;2022:3657. DOI: 10.3390/ijms23073657
34.Steiniger B, Barth P, Hellinger A. The perifollicular and marginal zones of the human splenic white pulp: Do fibroblasts guide lymphocyte immigration? American Journal of Pathology. 2001;159(2):501-512. DOI: 10.1016/S0002-9440(10)61722-1
35.Martins M, Boavida JM, Raposo JF, Froes F, Nunes B, Ribeiro RT, et al. Diabetes hinders community-acquired pneumonia outcomes in hospitalized patients. BMJ Open Diabetes Research and Care. 2016;4:e000181. DOI: 10.1136/bmjdrc-2015-000181
36.Jafar N, Edriss H, Nugent K. The effect of short-term hyperglycemia on the innate immune system. The American Journal of the Medical Sciences. 2016;351(2):201-211. DOI: 10.1016/J.AMJMS.2015.11.011
37.Stojanovi SD, Fiedler J, Bauersachs J, Thum T, Sedding DG. Senescence-induced inflammation: An important player and key therapeutic target in atherosclerosis. European Heart Journal. 14 Aug 2020;41(31):2983-2996. DOI: 10.1093/eurheartj/ehz919. PMID: 31898722; PMCID: PMC7453834
38.Feng X, Chen W, Ni X, Little PJ, Xu S, Tang L, et al. Metformin, macrophage dysfunction and atherosclerosis. Frontiers in Immunology. 7 Jun 2021;12:682853. DOI: 10.3389/fimmu.2021.682853. PMID: 34163481; PMCID: PMC8215340
39.Sukhorukov VN, Khotina VA, Chegodaev YS, Ivanova E, Sobenin IA, Orekhov AN. Lipid metabolism in macrophages: Focus on Atherosclerosis. Biomedicine. 1 Aug 2020;8(8):262-277. DOI: 10.3390/biomedicines8080262. PMID: 32752275; PMCID: PMC7459513
40.Marchio P, Guerra-Ojeda S, Vila JM, Aldasoro M, Victor VM, Mauricio MD. Targeting early atherosclerosis: A focus on oxidative stress and inflammation. Oxidative Medicine and Cellular Longevity. 1 Jul 2019;2019:8563845. DOI: 10.1155/2019/8563845. PMID: 31354915; PMCID: PMC6636482
41.Perera Molligoda Arachchige AS. Human NK cells: From development to effector functions. innate immune. Apr 2021;27(3):212-229. DOI: 10.1177/17534259211001512. Epub 24 Mar 2021. PMID: 33761782; PMCID: PMC8054151
42.Waggoner SN, Von Herrath MG, Penaloza-Macmaster P, Lang PA, Crome SQ , Xu HC, et al. NK cells regulate CD8 + T cell mediated autoimmunity. Frontiers in Cellular and Infection Microbiology. 2020;10:36. DOI: 10.3389/fcimb.2020.00036. www.Frontiersin.Org
44.Gardner G, Fraker CA. Natural killer cells as key mediators in type I diabetes immunopathology. Frontiers in Immunology. 20 Aug 2021;12:722979. DOI: 10.3389/fimmu.2021.722979. PMID: 34489972; PMCID: PMC8417893
45.Harris CL, Pouw RB, Kavanagh D, Sun R, Ricklin D. Developments in anti-complement therapy; from disease to clinical trial. Molecular Immunology. 2018;102:89-119. DOI: 10.1016/J.MOLIMM.2018.06.008
46.Kulak K, Westermark GT, Papac-Milicevic N, Renström E, Blom AM, King BC, et al. The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation. Diabetologia. Aug 2017;60(8):1522-1533. DOI: 10.1007/s00125-017-4286-3. Epub 12 May 2017. PMID: 28500395; PMCID: PMC5491568
47.Nagaraj V, King B, Storm P, Vikman P, Ottosson-Laakso E, Blom AM, et al. Complement inhibitor CD55 governs the integrity of membrane rafts in pancreatic beta cells, but plays no role in insulin secretion. Biochemical and Biophysical Research Communications. 2015;460(3):518-524. DOI: 10.1016/J.BBRC.2015.03.062
48.Dos Santos RS, Marroqui L, Grieco FA, Marselli L, Suleiman M, Henz SR, et al. Protective role of complement C3 against cytokine-mediated b-cell apoptosis. Endocrinology. 2017;158:2503-2521. DOI: 10.1210/en.2017-00104
49.Golec E, Rosberg R, Zhang E, Renström E, Renström R, Blom AM, et al. A cryptic non-GPI-anchored cytosolic isoform of CD59 controls insulin exocytosis in pancreatic b-cells by interaction with SNARE proteins. FASEB J. Nov 2019;33(11):12425-12434. DOI: 10.1096/fj.201901007R. Epub 14 Aug 2019. PMID: 31412214; PMCID: PMC6902737
50.Lo JC, Ljubicic S, Leibiger B, Kern M, Leibiger IB, Moede T, et al. Adipsin is an Adipokine that improves β cell function in diabetes. Cell. 2014;158(1):41-53. DOI: 10.1016/J.CELL.2014.06.005
51.Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: Implication of depot differences in adipose tissue for obesity complications. Molecular Aspects of Medicine. 2013;34(1):1-11. DOI: 10.1016/J.MAM.2012.10.001
52.Li R, Coulthard LG, Wu MCL, Taylor SM, Woodruff TM. C5L2: A controversial receptor of complement anaphylatoxin, C5a. FASEB J. Mar 2013;27(3):855-864. DOI: 10.1096/fj.12-220509. Epub 13 Dec 2012. PMID: 23239822
53.Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: A data-driven cluster analysis of six variables. The Lancet Diabetes and Endocrinology. 2018;6(5):361-369. DOI: 10.1016/S2213-8587(18)30051-2
54.Kolev M, Kemper C. Keeping It All Going-Complement Meets Metabolism. Frontiers in Immunology. 2017;8:1-18. DOI: 10.3389/fimmu.2017.00001. PMID: 28149297; PMCID: PMC5241319
55.Heeger PS, Kemper C. Novel roles of complement in T effector cell regulation. Immunobiology. 2012;217(2):216-224. DOI: 10.1016/J.IMBIO.2011.06.004
56.Carroll MC, Isenman DE. Regulation of humoral immunity by complement. Immunity. 2012;37(2):199-207. DOI: 10.1016/J.Immuni.2012.08.002
57.Pouw RB, Brouwer MC, de Gast M, van Beek AE, van den Heuvel LP, Schmidt CQ , et al. Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera. Blood Advances. 26 Feb 2019;3(4):621-632. DOI: 10.1182/bloodadvances.2018025692. PMID: 30804016; PMCID: PMC6391659
58.de Cordoba SR, Tortajada A, Harris CL, Morgan BP. Complement dysregulation and disease: From genes and proteins to diagnostics and drugs. Immunobiology. 2012;217(11):1034-1046. DOI: 10.1016/J.IMBIO.2012.07.021
59.Ricklin D, Reis ES, Lambris JD. Complement in disease: A defence system turning offensive. Nature Reviews Nephrology. Jul 2016;12(7):383-401. DOI: 10.1038/nrneph.2016.70. Epub 2016 May 23. PMID: 27211870; PMCID: PMC4974115
60.Marc Y. Donath, Inflammation as a sensor of metabolic stress in obesity and type 2 diabetes. Endocrinology. 1 Nov 2011;152(11):4005-4006. DOI: 10.1210/en.2011-1691
61.Shim K, Begum R, Yang C, Wang H. Complement activation in obesity, insulin resistance, and type 2 diabetes mellitus conflict-of-interest statement. World Journal of Diabetes. 2020;11(1):1-12. DOI: 10.4239/wjd.v11.i1.1
62.Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S. Type 2 diabetes in adolescents and young adults. The Lancet Diabetes & Endocrinology. 2018;6(1):69-80. DOI: 10.1016/S2213-8587(17)30186-9
63.De Borst MH, Poppelaars F, Böhringer S, Valoti E, Noris M, Perna A, et al. Impact of a complement factor H gene variant on renal dysfunction, cardiovascular events, and response to ACE inhibitor therapy in type 2 diabetes. Article 681. Frontiers in Genetics. 2019;10:681. DOI: 10.3389/fgene.2019.00681
64.King BC, Blom AM. Complement in metabolic disease: Metaflammation and a two-edged sword. Seminars Immunopathology. 2021;43:829-841. DOI: 10.1007/s00281-021-00873-w
65.Dennis JM, Shields BM, Henley WE, Jones AG, Hattersley AT. Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: An analysis using clinical trial data. The Lancet Diabetes & Endocrinology. 2019;7(6):442-451. DOI: 10.1016/S2213-8587(19)30087-7
66.Zou X, Zhou X, Zhu Z, Ji L. Novel subgroups of patients with adult-onset diabetes in Chinese and US populations. Lancet Diabetes Endocrinology. Jan 2019;7(1):9-11. DOI: 10.1016/S2213-8587(18)30316-4. PMID: 30577891
67.Han G, Geng S, Li Y, Chen G, Wang R, Li X, et al. cdT-cell function in sepsis is modulated by C5a receptor signalling. Immunology. 2011 Blackwell Publishing Ltd, Immunology;133:340-349. DOI: 10.1111/j.1365-2567.2011.03445.x
68.Krus U, King BC, Nagaraj V, Gandasi NR, Sjölander J, Buda P, et al. The complement inhibitor CD59 regulates insulin secretion by modulating Exocytotic events. Cell Metabolism. 2014;19(5):883-890. DOI: 10.1016/J.CMET.2014.03.001
69.King BC, Kulak K, Krus U, Rosberg R, Golec E, Wozniak K, et al. Complement component C3 is highly expressed in human pancreatic islets and prevents β cell death via ATG16L1 interaction and autophagy regulation. Cell Metabolism. 2019;29(1):202-210.e6. DOI: 10.1016/J.CMET.2018.09.009
70.Sorbara MT, Foerster EG, Tsalikis J, Abdel-Nour M, Mangiapane J, Sirluck-Schroeder I, et al. Complement C3 drives autophagy-dependent restriction of Cyto-invasive Bacteria. Cell Host & Microbe. 2018;23(5):644-652.e5. DOI: 10.1016/J.CHOM.2018.04.008
71.Kolev M, Dimeloe S, Le Friec G, Navarini A, Arbore G, Povoleri GA, et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity. 2015;42(6):1033-1047. DOI: 10.1016/J.IMMUNI.2015.05.024
72.Lim J, Iyer A, Suen JY, Seow V, Reid RC, Brown L, et al. C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. FASEB J. Feb 2013;27(2):822-831. DOI: 10.1096/fj.12-220582. Epub 1 Nov 2012. PMID: 23118029
Written By
Pratima Tripathi
Submitted: 11 August 2022Reviewed: 24 August 2022Published: 07 November 2022
Open access peer-reviewed chapter
