Diabetes caused by viruses

At the same time, pro-inflammatory cytokines of an anti-viral Type-I profile promote insulin resistance and form a risk factor for development of T2D. What this illustrates is that there is a reciprocal, detrimental interaction between the immune and endocrine system in the context of T2D. Why these two systems would interact at all long remained unclear.

Recent findings indicate that transient changes in systemic metabolism are induced by the immune system as a strategy against viral infection. In people with T2D, this system fails, thereby negatively impacting the antiviral immune response. In addition, immune-mediated changes in systemic metabolism upon infection may aggravate glycemic control in T2D. In this review, we will discuss recent literature that sheds more light on how T2D impairs immune responses to viral infection and how virus-induced activation of the immune system increases risk of development of T2D.

In the clinics, immunological dysfunction is seldom recognized as a major comorbidity of Type 2 diabetes T2D. Until recently, people in developed countries rarely encountered dangerous pathogens. As a result, increased susceptibility to infection was typically only experienced as a cause of minor inconveniences such as recurrent urinary tract infection [1]. However, as the recent outbreak of the COVID pandemic has shown, people with diabetes both type 1 and 2 have increased risk of severe complications upon infection with lethal pathogens such as SARS-CoV-2 [2] , [3].

Moreover, even before the corona pandemic, reduced immune cell function on top of microvascular pathology was well known to exacerbate dangerous complications such as persistent foot ulcers that can lead to gangrene.

This observation indicates that diabetes increases susceptibility to a broad range of pathogens and negatively impacts the duration, morbidity and mortality associated with infectious disease. Indeed, people with diabetes are more frequently infected with cytomegalovirus [4] and suffer more often from surgical site infections [1].

Clearly, when the immune system is challenged, its dysfunction in T2D progresses from a minor inconvenience to a major health risk and merits our attention as health care professionals. A key question that arises from these observations is why impaired blood glucose regulation would reduce the ability of the immune system to fight infection.

The metabolism of immune cells, especially after their activation, is predominantly regulated through cytokines and was therefore long thought to be impervious to endocrine control [5]. However, recent insights indicate that changes in systemic metabolism are actively induced by the immune system as a defence mechanism against viral infection [6]. Deregulation of this system in the context of diabetes is therefore thought to be an important underlying cause of increased susceptibility to viruses [7] , [8].

Conversely, immune-mediated changes in systemic metabolism appear to be an important underlying cause of insulin resistance IR in patients with metabolic disease [9]. Notably, infection and inflammation appear to predispose people to the development of Type 2 diabetes [7] especially in people with pre-existing metabolic dysfunction, such as in patients with pre-diabetes.

Recently, some of the underlying molecular mechanisms of these processes have been revealed and provide important new targets for future anti-diabetic therapies. In this review we will revisit recent literature on immune-endocrine interactions in the context of viral infection.

We will explore several ways in which the endocrine system regulates immune cell function under healthy conditions and in the context of metabolic disease. In addition, we will discuss how the activated immune system contributes to the development of T2D.

Whereas many aspects that we will discuss here are also relevant for Type 1 diabetes, a focus will be on T2D. Patients with T2D are well known to be more prone to infection.

However, in addition to these rare conditions, patients with T2D also acquire common infections more frequently. A landmark prospective study from primary care institutions followed up 6.

The authors showed that T2D patients had a higher risk of lower respiratory tract infections odds ratio OR of 1. In , a meta-study of 97 prospective cohort studies was published in which This revealed that T2D is associated with a significant increase of infection-related death when pneumonia was excluded Relative Risk RR of 2.

Importantly, T2D is not only associated with susceptibility to infection, but also with the course and duration of these diseases and with an increased risk of complications. A study comparing bloodstream infections of 71 patients with and patients without diabetes patients showed that the former group had a longer stay at intensive care RR 7.

Similar observations were made for a broad range of other infectious diseases [13]. For example, a systematic review of 13 observational studies showed that people with T2D have an RR of 3.

Due to the sensitivity of patients with diabetes to infection, the guidelines for their medical care prescribe vaccination of T2D patients for influenza, pneumonia and hepatitis B in addition to routine age-related recommendations for vaccination [15].

When the new vaccines for COVID are released it would therefore be recommended to prioritize inoculation of patients with diabetes. To better understand how diabetes affects the immune system, it is important to grasp how the endocrine system regulates immune cell functionality under healthy conditions.

Whereas the metabolism of immune cells is mostly regulated by cytokines, they are not exempt from endocrine control. Notably, many hormone receptors share intracellular signaling components with those of immune receptors, indicating an overlap in function. Of major importance for endocrine control of immune cells are the hormones leptin and adiponectin produced by adipose tissue.

Leptin secretion positively correlates with adipose fat content and it provides the body with signals that suppress satiety and increase energy expenditure [18]. In addition, leptin plays a role in regulation of blood glucose levels in concert with insulin as it lowers glycemia, insulinemia and insulin resistance [19].

Injection of leptin in streptozotocin STZ treated, hyperglycemic rats and mice was shown to lower blood glucose levels independently of food intake [20] , [21].

In humans, leptin levels positively correlate with IR independently of BMI and patients with T2D often have high levels of leptin in addition to hyperinsulinemia [19]. Moreover, people with T2D also display leptin resistance [22]. Unfortunately, leptin administration is not an effective treatment for T2D [22].

The receptor of leptin is expressed on many cells, including those of the immune system. The leptin receptor signals over the intracellular signaling molecules Jak2 and STAT3, which are also used by the receptor for the pro-inflammatory cytokine IL-6 [23]. Leptin therefore promotes immune cell activation and proliferation. Studies in rodents show that intravenous administration of leptin promotes the increase of granulocytes, monocytes and NK cells in circulation [24].

Deficiency of leptin or its receptor results in a strong decrease of T cells, NK cells and dendritic cells in the blood [26] and increases susceptibility of animals to infection with Influenza A [25] , [27]. Leptin appears to mediate these effects by stimulating immune cell metabolism.

Indeed, Leptin was recently shown to revitalize tumor-infiltrating CD8 T cells by reversing metabolic dormancy of these cells [28]. During starvation, when adipose triglyceride stores are low, fat cells produce more adiponectin to signal nutrient scarcity.

Adiponectin shares some functional properties with insulin, as it promotes glucose uptake and impairs hepatic gluconeogenesis. High levels of adiponectin therefore reduce immune cell responsiveness [29]. Human T cells stimulated with adiponectin were shown to have reduced antigen-specific expansion [30]. Animals deficient for this adipokine showed increased T cell activation upon infection with Coxsackie virus [30]. In the immune system, adiponectin therefore functions as an anti-inflammatory cytokine which lowers its energy expenditure.

Recently, insulin itself was identified as a molecule that can directly regulate immune cell function, most notably of T cells. Both CD4 and CD8 T cells express the insulin receptor on their cell surface upon activation [7] , [31]. Insulin was shown to increase glucose uptake and promote glycolytic metabolism. Importantly, acute loss of insulin production impairs CD8 T cell responses to infection, whereas injection of basal insulin increases their anti-viral potential [7] , [31].

The insulin receptor shares its downstream signaling components with CD28, a key co-stimulatory molecule essential for T cell activation, as these pathways both converge on PI3 kinase. These receptors therefore also have functional overlap, such as the induction of glucose transporters on the cell membrane [32]. Not surprisingly, loss of insulin receptor expression on T cells impairs proliferation and cytokine production of anti-viral T cells [7].

In summary, key endocrine hormones involved in the regulation of metabolism also impact immune cell numbers and function, even in absence of overt infection. Several factors play a role in impaired anti-viral immune cell function in the context of T2D, but hyperglycemia appears to be one of the key mediators.

The level of glycated haemoglobin HbA1c was shown to positively correlate with the duration and severity of infection with several pathogens. A similar study recruited 4. Also in this study, incidence of infection was significantly higher in patents with T1D compared to controls and the frequency of infection positively correlated with the percentage of HbA1c in the blood [34]. Increased blood glucose levels were shown to impair immune cell function in humans and mice. Hyperglycemia in mice induced by injection of STZ, a model for insulin dependent diabetes, caused a decreased ability of macrophages to be activated in response to infection with Mycobacterium tuberculosis TB.

This impaired recruitment of neutrophils, reduced DC activation and lowered cytokine production by these cells [35]. Importantly, T2D has a profound, negative impact on innate immune cell function.

For example, granulocytes isolated from patients with T2D were shown to undergo NET-mediated apoptosis, thus impairing wound healing [37] , [38]. In addition, production of pro-inflammatory cytokines such as IL-2 and IL-6 was shown to be impaired in peripheral blood mononuclear cells stimulated under hyperglycemic conditions [39]. Finally, hyperglycemia was shown to be of direct benefit for replication of several pathogens [40] , [41] , which further impedes the ability of the immune system to fight infection under these conditions.

Whereas much is known about which immunological processes are affected by hyperglycemia, how it induces these on a molecular level is much less clear. In immune cells, metabolism and function are tightly linked.

In resting state, immune cells predominantly use oxidative phosphorylation to fulfil their energetic needs. Upon activation, especially CD8 T cells and pro-inflammatory M1 macrophages switch their metabolism to glycolytic metabolism for production of ATP and to shuttle metabolites into the penta-phosphate pathway [5].

If proper metabolic control of immune cells is impaired, this has a major impact on their functionality. For example, CD8 T cells that fail to increase glycolytic metabolism cannot form a proper effector response [42] , [43].

Whereas memory cell formation is strongly reduced when these cells cannot activate oxygen-dependent metabolism [44]. One mechanism via which hyperglycemia impairs normal immune cell function is therefore by deregulating immuno-metabolism [45].

Apart from glucose, T2D also causes a shift in the homeostasis of many other carbon-based metabolites which are involved in the defence against infection. We all know that if we become sick, we lose appetite and reduce nutrient intake. This is not a pathology, but a carefully regulated process orchestrated by the immune system.

Many pathogens favor glucose metabolism to fulfil metabolic needs [46]. For example, cytomegalovirus was shown to actively induce glycolytic metabolism in host cells to promote its replication, which was strongly impaired if glucose uptake was prevented in cells [46] , [47].

Except for key organs such as the brain, most tissues can operate normally at relatively low levels of glucose, which includes the immune system. Even though the immune system uses a high amount of glucose to function, immune cells strongly upregulate glucose transporters upon activation.

As a result, CD8 T cells are fully functional at glucose concentrations as low as 0. However, as T2D is defined by a state of hyperglycemia even under fasting conditions, this strategy to starve pathogens of glucose fails. In addition, fasting metabolism was recently shown to prime non-immune cells to activate their innate cellular mechanisms against infection. All nucleated cells are able to produce type I interferons upon infection.

This alarm signal potently recruits immune cells to the site of infection. Inborn errors of type-I interferons in humans are therefore typically associated with lethal infections at a very young age [50].

In response to feeding, most glucose is taken up into muscle and rapidly returned in the form of lactate [52]. Fasting is therefore associated with a reduction in systemic lactate levels. In addition to hyperglycemia, patients with T2D also have higher lactate levels in the blood [53] , [54]. As a result, the innate ability of cells to recruit immune cells following viral infection is reduced. In addition to blood nutrient levels, hormonal disbalance appears to be an underlying cause of immune cell dysfunction in context of diabetes.

People with T2D typically have high levels of insulin and leptin in their blood compared to people without this disease, especially early after diagnosis [55] , [56]. Considering the immuno-stimulatory role of these hormones, this would suggest that people with diabetes have enhanced immune cell responsiveness.

However, the effectiveness of the immune system depends on its ability to optimize its response to a given pathogen. A specific pathogen causes activation of a particular transcriptional profile in key innate immune cells such as dendritic cells, which are responsible for proper activation of T cells.

T2D skews dendritic cell differentiation, leading to reduced expression of costimulatory molecules CD80 and CD86 [58] , whilst promoting development of plasmacytoid dendritic cells that produce type-I interferons [59].

The immuno-stimulatory effect of insulin and leptin in T2D is therefore not beneficial for the patient, because it results in aberrant skewing and therefore reduced efficiency of the immune response. Changes in the cytokine environment of patients with T2D are also the result of alterations in the interaction between organs involved in maintenance of metabolic homeostasis and its tissue-resident immune cells. People with T2D tend to have increased amounts of pro-inflammatory cytokines in circulation [62] , indicative of chronic low-grade infection.

This inflammation is thought to originate in visceral adipose tissue. In obesity, adipocytes experience cellular stress because of excessive fat accumulation. This, in turn, polarizes macrophages from an anti-inflammatory M2 to a pro-inflammatory M1 phenotype [64].

Activated adipose tissue macrophages promote local inflammation and further recruitment of immune cells, leading to the chronic leakage of cytokines in circulation. T2D was therefore shown to exacerbate cytokine-induced pathology in response to infection with Influenza and Sars-Cov-2 [65] , [66].

Moreover, the pro-inflammatory environment in patients with T2D is associated with abnormal clot formation and hypercoagulation, which is an important underlying cause of increased mortality in COVID [67] , [68].

Finally, pathological changes in microvasculature are a hallmark of diabetes and disrupt normal organ function in organs heavily dependent on their microcirculation, such as the kidneys, retina and peripheral nervous system. In addition, changes in the microvasculature negatively impact the ability of people with diabetes to mediate immune responses to lesions in skin, resulting in chronic infection, ulcers and poor wound healing.

Diabetic foot ulcers are therefore a common complication of diabetes, and this condition may progress to development of gangrene which requires amputation of the affected limb. However, microvascular complications of T2D are of importance for many types of infection, including viral [69]. A detailed description of how damaged microvasculature affects immune responses in T2D reaches beyond the scope of this review, but has been excellently discussed elsewhere [69].

Normal protection against infection is mediated by specialized immune cells, but also by innate abilities of tissues to provide barriers against pathogens and to signal their infection to the immune system. Diabetes impairs the ability to properly respond to infection at almost all these levels of control Fig.

Communication between the endocrine and immune systems is not unidirectional. This is because the immune system changes normal endocrine regulation of key metabolic processes in our body. Recent data indicates that the physiological changes in metabolism in response to infection may be a trigger for permanent deregulation of blood glucose levels.

Many diabetologists will have anecdotal evidence that newly diagnosed patients with T2D had experienced infection in their recent history. In fact, international guidelines recommend screening for infection in newly diagnosed patients, especially if blood glucose levels are very high [70].

Infection was recognized as a cause for increased insulin resistance almost 80 years ago [71]. However, population studies to support this hypothesis have only recently started to emerge. Because T2D negatively impacts the immune response, it is difficult to determine whether a higher prevalence of infection in patients with T2D is the cause or the result of this disease.

Nevertheless, ample evidence is available that infection negatively impacts systemic insulin sensitivity. Infection with viruses such as Influenza A, cytomegalovirus and herpes simplex were all shown to reduce systemic insulin sensitivity [7] , [72].

Hyperinsulinemic, euglycemic clamping in patients with a number of respiratory and gastrointestinal infections revealed that insulin resistance was increased in patients, sometimes for more than three months after infection [7] , [73]. Whether infection is a risk factor for development of T2D is mostly shown for chronic viruses. A population-based matched case-control cohort study in Korea selected patients infected with cytomegalovirus CMV , but without T2D and 2.

The authors showed that the case group had a much higher frequency of new-onset T2D 5. Importantly, subgroup analysis revealed that patients with refractory disease had a significantly higher incidence rate OR 4. Insulin-dependent diabetes mellitus IDDM is a multifactorial disease.

Besides a genetic predisposition environmental factors have been implicated in the pathogenesis of beta cell destruction. Yet, regardless of the underlying mechanism, the observation by Kim et al. Another major component determining virally mediated modulation of autoimmunity appears to be the time at which infection occurs during the pre-diabetic phase.

Whereas type 1 diabetes is enhanced in 8-week-old NOD mice infected with CVB4, infection of younger mice has no effect on disease outcome This suggests that the status of autoimmune progression is a crucial determinant in the diabetogenic potency of the virus.

Importantly, just like viral infections, inflammatory cytokines appear to play a dual role in autoimmune diabetes. Previous work has shown that expression or neutralization of cytokines commonly produced during viral infections has opposing effects on type 1 diabetes outcome depending on the time of expression. Thus, the capacity of particular viral infections to modulate autoimmunity at a certain point in time might be the direct consequence of their ability to promote inflammation during the pre-diabetic process beyond a particular autoimmune threshold.

Accordingly, it was reported that enhancement of diabetes by CVB4 infection occurs only after a critical mass of activated autoreactive T-cells has accumulated in the islets However, CVB3 was reported to prevent disease in both young and older mice This suggests that while timing is important, the state of advancement of autoimmunity at the time of infection is not the sole explanation for the dual role of viruses in type 1 diabetes.

APC activation and associated inflammation, whether or not induced by viral infection, may not always have detrimental consequences in autoimmune diabetes. As discussed above, epidemiological studies provide evidence that infectious events occurring during early childhood might have the ability to prevent or delay type 1 diabetes development The ability of viral infections to abrogate autoimmune diabetes was also reported in different animal models using not only CVB3 35 , but also LCMV 46 , 76 , 77 , EMC-DV 38 , mouse hepatitis virus 78 , and lactate dehydrogenase virus Interestingly, both acute and persistent viral infections appear capable of modulating the immune system in a diabetes-preventive fashion.

While the mechanisms accounting for the beneficial effect of viruses on the immune system are poorly understood and may vary from one individual to the next or one mouse model to the next , a feature common to viral infections is their paradoxical capacity to induce inflammation. This is also the case for a number of nonviral infections, vaccines, or treatments reported to protect NOD mice against diabetes 80 — In the RIP-LCMV system, although viral infection represents the event initiating autoimmunity and diabetes, we have shown that inflammation mediated upon viral challenge can prevent type 1 diabetes.

Our results indicate that secondary infection of RIP-nucleoprotein mice with a different strain of LCMV during the pre-diabetic phase completely abrogates diabetes development In these studies, the LCMV strain used to prevent diabetes shares a homologous nucleoprotein sequence with that used to initiate diabetes, and thus the two infections activate comparable T-cell responses.

Therefore, inflammatory cytokines and chemokines produced during viral infection might play a crucial part in controlling the location of virally activated autoreactive T-cells and their subsequent capacity to infiltrate pancreatic islets. Previous reports suggest that part of the T-cells activated during viral infection can cross-react with new infectious agents or allo-antigens and modulate immunity to unrelated antigens 96 — Consequently, such heterologous immunity might result in the accumulation of memory T-cells of specificity unrelated to the original viral agent Since stimulated memory T-cells respond to antigen more rapidly and efficiently than naive cells, repeated or sustained antiviral immunity during life may eventually favor autoimmunity.

While in most cases, this phenomenon will not result in autoimmune disease, it might be a prerequisite for overt diabetes in genetically predisposed individuals. As discussed above, in different mouse models, initiation of diabetes by viral infection requires a critical mass of autoreactive T-cells along with activated APCs 34 , 56 — 58 , , and it is possible that, in humans, such a mass is provided progressively over life by repeated or sustained viral infections. In other words, autoimmunity might not be induced de novo at type 1 diabetes onset, and the autoreactive T-cell pool is likely comprised of cells that have already responded to antigenic stimulation during viral infection in the past.

On the other hand, previous work suggests that repeated or sustained encounters with viral antigen during chronic infection is associated with protection against type 1 diabetes 46 , This may be due in part to exhaustion of T-cell immunity, which is commonly found in chronic viral infection and was notably reported in protracted LCMV infection Alternatively, or in addition, diabetes abrogation during chronic viral infection may be the consequence of virally induced regulatory mechanisms suppressing antiviral immunity and possibly autoimmunity as well , Thus, repeated exposure to viral antigen during life may not necessarily be pathogenic in autoimmunity.

Nonspecific activation of autoreactive T-cells as a consequence of repeated or protracted viral infections may even be beneficial in some cases. A number of epidemiological studies support the hypothesis that viral infections play a causative role in type 1 diabetes. However, systematic review of control studies published between and has shown no convincing evidence for or against an association between type 1 diabetes and the prime candidate for infectious cause, CVB In animal models for type 1 diabetes, solid evidence supporting an inductive role for viruses is faced with just as solid evidence supporting a protective effect of viral infections.

Based on mouse studies alone, there is no doubt that association between viruses and type 1 diabetes is extremely complex: while belonging to the same enteroviral group, CVB3 and CVB4 have opposing effects on type 1 diabetes in the same mouse model; LCMV initiates diabetes in the RIP-LCMV model but prevents disease in the NOD model; and to make matters more complicated, CVB4 and LCMV are capable of both inducing and preventing diabetes in the same mouse model depending on the time of infection.

Thus, the reason for current failure to associate a particular virus with induction of autoimmune diabetes likely is that such an association might be impossible to make. Certain viruses might be capable of inducing diabetes and others of preventing diabetes, and type 1 diabetes inducers might be capable of preventing disease under certain conditions. A given viral infection could thus be an essential disease precipitator once required predisposing events have occurred, but could on the other hand disrupt accumulation of these events.

Most important is the indication from animal studies that modulation of autoimmunity during viral infection does not depend merely on inherent properties of the virus, but also significantly on intrinsic factors of the host. The close interplay between the two will dictate whether enhancement or abrogation of autoimmune diabetes occurs. While inflammatory cytokines might promote bystander activation of APCs and autoreactive T-cells, infection could occur at a time where inflammation will induce the relocation or demise of these cells.

These possibilities are illustrated in Fig. Interplay between virus- and host-intrinsic properties dictates whether enhancement or abrogation of type 1 diabetes occurs.

Teff, effector autoreactive T-cells. Based on current evidence, it thus appears impossible to assess the capacity of viruses to modulate type 1 diabetes without knowledge of the state of advancement of autoimmunity and infection history of affected individuals. This is no easy task, but tremendous effort is currently being made in the U. In particular, the TEDDY The Environmental Determinants of Diabetes in the Young study is currently assessing the influence of environmental factors, among which are viral infections, on the development of autoimmune diabetes.

In this study, blood from children with increased genetic risk for type 1 diabetes is assessed for viral exposure every 3 months for the first 4 years of life, and then every 6 months until the age of 15 years.

Although, many similar viruses are under the scanner, the one which has garnered most interest is the coxsackievirus. This virus is most commonly found in kids. Although, most children will successfully recover from the effects of this virus without many complications, it would lead to more serious repercussions in adults.

Studies explaining if the coxsackievirus acts as a triggering point for altering autoimmune responses for destroying beta cells are still being conducted.

According to a recent study conducted by Australian scientists, another virus, which has been strongly linked with the incidence of type 1 diabetes is the enterovirus. According to the study, type 1 diabetes was 10 times more likely to occur in children who have already been affected with enterovirus. Enterovirus is like the common flu like virus, which causes symptoms of cold and cough in children.

Children exhibiting such symptoms are more prone to develop pre diabetes symptoms leading to diabetes eventually.