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The diabetes pandemic and associated infections

suggestions for clinical microbiology

Toniolo, Antonioa; Cassani, Gianlucab; Puggioni, Annab; Rossi, Agostinob; Colombo, Albertob; Onodera, Takashic; Ferrannini, Eled

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Reviews in Medical Microbiology: January 2019 - Volume 30 - Issue 1 - p 1-17
doi: 10.1097/MRM.0000000000000155
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Due to increasing incidence worldwide, diabetes mellitus is a major medical problem. Diabetes mellitus is classified among noncommunicable diseases (NCDs) [1]. Strong evidence points to a key role of microbes in diabetes mellitus, both as infectious agents associated with the diabetic status and as possible causative factors of diabetes mellitus. Diabetes mellitus-related infections involve bacteria, viruses, fungi, parasites, and – possibly – prions.

Classification of diabetes mellitus

Diabetes mellitus includes a group of metabolic conditions characterized by hyperglycemia resulting from defects in insulin action, insulin secretion or both. Chronic hyperglycemia is associated with long-term damage and dysfunction of eyes, kidneys, blood vessels, nerves, and heart.

Table 1 summarizes the current classification of diabetes mellitus with the estimated global prevalence of different forms [3]. Type 2 diabetes mellitus (T2DM; classic or with relative insulin deficiency) accounts for over 80% of cases followed by latent autoimmune diabetes of the adult (LADA), an autoimmune form of diabetes defined by adult-onset and presence of diabetes-associated autoantibodies (especially glutamic acid decarboxylase p65, or GADA). LADA shares genetic features with both type 1 diabetes mellitus (T1DM) and T2DM. LADA patients have higher glycated hemoglobin (HbA1c) levels than T2DM patients, lower BMI, and more frequent, earlier need for insulin treatment than T2DM cases [4].

Table 1
Table 1:
Major forms of diabetes mellitus.

T1DM accounts for about 10% of cases. Secondary diabetes mellitus and the maturity-onset diabetes of the young account for less than 1% of cases. Gestational diabetes mellitus (GDM) is any degree of glucose intolerance with first recognition during pregnancy. GDM usually resolves after delivery but evolves to permanent diabetes mellitus in 5–10% of cases.

Impaired glucose tolerance (IGT) and impaired fasting glucose refer to individuals whose glucose levels are intermediate between normal values and values conventionally diagnostic of diabetes (Table 2). Collectively, these individuals are said to have ‘prediabetes’. The metabolic syndrome (insulin resistance, upper-body obesity, hypertension, hypertriglyceridemia, low levels of HDL cholesterol) identifies persons at high risk for glucose intolerance and diabetes mellitus [5].

Table 2
Table 2:
Diagnostic criteria for prediabetes and diabetes (plasma glucose concentration).

Diagnosis requires a blood sample taken after an overnight (12–14-h) fast and/or the ingestion of a standard (75 g) glucose load oral glucose tolerance test. Plasma C-peptide/insulin levels and detection of diabetes-related autoantibodies are essential for identifying specific forms of diabetes mellitus. HbA1c is used both at diagnosis and during therapy.

The diabetes pandemic

Diabetes mellitus hits people at the most productive age, slows economic growth, reduces life-expectancy in elders, causes increasing healthcare expenditure. Diabetes mellitus is among the top 10 causes of death and (together with major NCDs – cardiovascular, cancer, respiratory disease) accounts for over 80% premature NCD deaths. Upon introduction of insulin, insulin-dependent people with diabetes started enjoying longer lives, but long-term complications emerged and T1DM became a chronic disease [5].

Current prevalence and perspectives

In developed countries, 87–91% of people with diabetes have T2DM, 7–12% have T1DM, 1–3% other types of diabetes mellitus [2,5]. As shown in Table 3, in the age group 20–79 (year 2017) there were 425 million people with diabetes worldwide. The figure is expected to increase to 629 million by 2045 [6]. Almost half of people living with diabetes (49.7%) are undiagnosed and there were 352 million people with IGT, that is 7.3% of adults 20–79 years. By 2045, in the same age group the number of people with IGT is projected to 532 million (8.3% of adults). In 2017, 21.3 million live births were affected by some form of hyperglycemia in pregnancy. Worldwide, in the 20–99 years age range, approximately 5 million deaths/year are attributable to diabetes. In Europe (Table 4) the gross prevalence of diabetes mellitus ranges from 2.9% in Ireland to approximately 10% in Portugal and Bosnia-Herzegovina [2].

Table 3
Table 3:
World: adults with diabetes in 2017 and projected figures for 2045.
Table 4
Table 4:
Adults with diabetes in ten European countries (2017).

Diabetes mellitus is more prevalent in the urban vs. the rural environment (10.2 vs. 6.9%) [2] and urbanization is expanding, particularly in Asia and Africa. The Chinese area of Pearl River Delta witnessed the most rapid urban expansion in human history: an agricultural region transformed into the world's largest city of over 40 million inhabitants. In Italy there are over 3 million people with T2DM and 1 million people with undiagnosed hyperglycemia (ISTAT, 2013). In Finland, the incidence of T1DM is now five times higher than 60 years ago and children who get diabetes have lower genetic risk than earlier [7]. Together with Scandinavia and Sardinia, Australia is among the high-incidence countries for T1DM [8].

Healthcare costs

Based on 2017 data, the global healthcare expenditure on people with diabetes mellitus was estimated at USD 850 billion [6]. The cost of diagnosed diabetes mellitus in the United States has been USD 327 billion (including USD 90 billion for reduced productivity) and care for diabetes mellitus accounts for 1 in 4 healthcare dollars [9]. Over the last 5 years, cost has grown by 26%. In Lombardy (Northern Italy) the average yearly expense per diabetic subject was 3300 Euro. Hospitalizations were the cost drivers contributing 54% of the total, followed by drugs (32%) and outpatient claims (14%) [10].

Genetics of diabetes mellitus

T1DM and T2DM are polygenic disorders, that is multiple genes contribute to their development [11,12]. Rare forms of diabetes mellitus (about 1% of cases) are single-gene disorders leading to beta cell or other defects [13].

Genetic predisposition to type 1 diabetes mellitus

The genetic basis of T1DM is well established, with more than 60 identified genes explaining ∼80% of its heritability [14,15].

In the human leukocyte antigen (HLA) system, the primary disease risk determinant is the DQB1 gene, which encodes the beta chain of the Class II DQ molecule responsible for antigen presentation. Its alleles in combination with the neighboring DQA1 and DRB1 gene variants form the DR-DQ haplotypes that can be categorized into risk, neutral ad protective groups (Table 5). The heterozygous combination of the two susceptibility haplotypes DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*03 (DR3-DQ2/DR4-DQ8 in terms of serological specificity) represents the highest disease risk and is linked to approximately 50% of disease heritability in white people [14,16]. The DR15-DQ6 haplotype is protective. Different ethnic groups may have different HLA associations [11]. HLA Class II haplotypes are also linked to beta cell-specific autoantibody patterns: GADA are more frequent in patients with the HLA DR3-DQ2 haplotype, while insulin and IA-2 autoantibodies are associated with DR4-DQ8. Heritability is declining with increasing age at diagnosis [17].

Table 5
Table 5:
Type 1 diabetes mellitus: association with common human leukocyte antigen class II haplotypes.

Outside the HLA region, other predisposing gene variants have been identified by genome wide association (GWAS) studies (e.g., INS, PTPN22, IL27, IFIH1 – Table 6). These genes are frequently involved in immune function and – possibly – in pathogenic pathways, for example, insulin expression in thymus, regulation of T-cell activation, innate virus immunity [28]. Thus, the risk of T1DM can be better predicted by using a genetic score that combines measurements of HLA and non-HLA loci [16].

Table 6
Table 6:
Major nonhuman leukocyte antigen genes predisposing to type 1 diabetes mellitus.

Genetic predisposition to type 2 diabetes mellitus

Having a parent with diabetes increases the risk of developing diabetes mellitus by 30–40% [12]. GWAS studies have implicated more than 200 genomic regions in the predisposition to T2DM (i.e., there are common alleles with small cumulative effects on risk) [29]. In T2DM, genetic and environmental factors regulate the interplay between insulin sensitivity, appetite regulation, adipose storage, and beta cell failure [30]. Genes work by regulating a variety of aspects. For instance, the insulin-mediated glucose uptake in skeletal muscle (e.g., TBC1D4 gene), the ability to generate new adipocytes and the regulation of gene expression in these cells (e.g., PPARG, KLF14, IRS1 genes), lipoprotein lipas (LPL)-mediated lipolysis [31], insulin secretion either through beta cell dysfunction or through impaired beta cell development (e.g., KCNJ11, ABCC8). Table 7 lists a few the implicated genes, some of which also play key roles in immunity. Thus, people carrying diabetes-predisposing gene variants are also likely to have flawed immune defenses. As in the case of T1DM, a genetic score combining measurements of multiple loci would be of help in assessing T2DM genetic risk.

Table 7
Table 7:
Major protein-coding genes and intron/intergenic variants associated with type 2 diabetes.

Immune dysfunction in diabetes

Hyperglycemia is linked with both chronic inflammatory processes and diabetes mellitus-related vulnerability to infection. People with diabetes are more susceptible than people without diabetes to periodontal disease [41], tuberculosis (TB) [42], lung infection by Legionella pneumoniae[43], ‘mucormycosis’caused by the Mucoraceae family of fungi [44]. Defects of the innate response come with dysfunction of granulocytes, monocyte/macrophages, dendritic cells, natural killer (NK) cells, B cells, T cells, and cytokine signaling.

Examples of immune defects associated to DM are summarized in Table 8. Hyperglycemia affects innate immunity by impeding production of type I interferon and IL22 [51,52]. Type I interferon has multiple effects, including antiviral activity [66], while IL22 reduces chronic inflammation and elicits antimicrobial immunity, preserves gut mucosal barrier, and improves insulin sensitivity [53]. Hyperglycemia also downregulates the expression of cathelicidins in macrophages (thereby implying diminished antimicrobial effects [54], reduces chemotaxis, impairs bactericidal activity, and neutrophil degranulation in response to bacterial lipopolysaccaride (LPS) [57]. High glucose causes nonenzymatic glycation of multiple proteins, including those of the complement system involved in the opsonization of pathogens [49]. Glycation inhibits complement activation via the mannan-binding lectin pathway as well as functions of the CD59 inhibitor of the membrane attack complex [50]. Poor glycemic control also affects the production of reduced glutathione. Lack of reduced glutathione reduces the production of IL2 and IFN-γ by mononuclear cells with lessened killing of intracellular bacteria [55]. Protein glycation may favor bacterial growth by promoting the availability of micronutrients such as iron [56]. Long-term alterations of glucose homeostasis associate also with the formation of advanced glycation end-products (AGEs) that bind proteins, including albumin. AGE-albumin acts on neutrophils and macrophages by hindering trans-endothelial migration [47] and altering gene expression [48].

Table 8
Table 8:
Immune defects in diabetes (examples).

Neutrophils of people with diabetes show an elevated expression of peptidylarginine deiminase 4, a citrullinating enzyme involved in the release of the cell genome as neutrophil extracellular traps. Unbalanced NETosis promotes inflammation and has a negative impact on immune defenses and wound healing [45]. Reduced innate cell activation is seen in diabetes mellitus: peripheral blood mononuclear cells show an impaired production of IL1β a key mediator in inflammation [46,67]. In T1DM, elevated serum levels of IL15 and its soluble receptor (sIL15Rα) have been detected. As in other autoimmune conditions, the disordered expression of IL15 signaling may play a pathogenic role [60]. IL15 is a membrane-associated molecule that promotes the activation of NK and CD8 T-effector memory cells. Expression of IL15/IL15Ra occurs in viral infection (e.g., enterovirus-infected islets). In T1DM [63] and GDM [64] there may be reduced numbers of circulating NK cells and altered cytokine signaling. In visceral adipose tissue, conventional dendritic cells (cDCs) acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. Although activation of the Wnt/β-catenin pathway in cDC1 DCs induces IL10 production (an anti-inflammatory mediator), upregulation of the PPARγ pathway in cDC2 DCs directly suppresses their activation. Combined, these effects promote an anti-inflammatory milieu that limits chronic inflammation and insulin resistance. However, with long-term over-nutrition, changes in adipocyte biology curtail β-catenin and PPARγ activation, contributing to persistent inflammation (Tables 8 and 9) [59].

Table 9
Table 9:
Common infectious events in people with diabetes.

Alterations of costimulatory molecules are also reported. Binding of CD40L on the surface of T cells to CD40 on the surface of antigen-presenting cells (dendritic cells, macrophages, B cells, other) activates immune responses. Plasma levels of sCD40L are elevated in hyperglycemic T2DM patients [70]. Binding of sCD40L to CD40 induces the production of proinflammatory cytokines, thus perpetuating the inflammatory status, perturbing insulin production, and downregulating antigen-specific responses [71].

In T1DM, beta cell damage is mediated by the combined actions of CD4+ and CD8+ T cells specific for islet autoantigens. T cell dysfunctions [especially FOXP3+ T regulatory cells (Tregs)] have been reported in the disease [61]. In addition, T cells responsive to beta cell autoantigens have an increased granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing component (GM-CSF+, IFNγ−, IL17A−, IL21−, IL22− CD4 T cells) [62]. T2DM cases associated with lung TB are characterized by CD8 T cells exhibiting diminished expression of cytotoxic markers (perforin, granzyme B, CD107a) and, possibly, lessened antimicrobial activity [65]. B cells are also important: in T2DM patients as they promote inflammation through regulation of T-cell function and an inflammatory cytokine profile [72]. In T1DM, anti-CD20 therapy delays – but fails to prevent – the onset of the disease and B cells present autoantigens to T cells [73]. The numbers of B cells that infiltrate the pancreas correlate with β-cell loss [74]. The reported immune defects may be secondary to the functions of diabetes-predisposing alleles as shown for T1DM [75], and/or to metabolic alterations in lymphoid cells [76].

Common infections and resistance to antimicrobial drugs

Due to impaired defenses and disease complications, people with diabetes are prone to new infections and recurrences [urinary tract infection (UTI), periodontitis, pneumonia, skin, and soft tissue (including the diabetic foot), osteomyelitis, peritonitis]. Uncommon life-threatening infections are more frequent in people with diabetes than in people without diabetes (necrotizing soft tissue infection, emphysematous pyelonephritis, emphysematous cholecystitis, malignant otitis, perioperative infection). Two recent chapters [68,77] and a review [78] cover the heightened susceptibility of people with diabetes to infections including tubercular mycobacteria [79,80]. Notably, the antimicrobial properties of metformin could reinforce antiinfectious treatments in people with diabetes and metformin itself influences the composition of gut microbiome [81].

Common infections in people with diabetes are summarized in Table 9. Diabetes mellitus and HbA1c more than 6.5% are associated with the risk of community-acquired and hospital-acquired bloodstream infection and sepsis [82,83]. After recovery from sepsis, alterations in innate and adaptive immune responses endure, resulting in immune dysfunction, chronic inflammation, and microbial persistence that carries an increasing risk of postsepsis infections [84]. In a vicious cycle, infection can worsen glycemic control and vice versa. Glycation of FimH (an Escherichia coli adhesin in urinary tract epithelial cells) does enhance susceptibility to infection [85]. Similarly, expression of intercellular adhesion molecule-1 (ICAM-1) in vaginal cells is upregulated by high glucose, thus promoting adhesion of Candida spp. [86]. In people with diabetes with urinary tract infection (UTIs), elevated HbA1c levels represent a risk factor for bacteremia and sepsis [87]. In the course of dengue epidemics, people with diabetes are at risk for hemorrhagic fever [88].

Drug-resistant organisms and diabetes

Since people with diabetes are more exposed to antimicrobials than people without diabetes, drug-resistance is particularly prevalent in this group. Table 10 shows the prevalence of common drug-resistance phenotypes in bacterial isolates from patients diagnosed with infection worldwide (data of a 2015 1-day survey made in 53 countries) [69] compared with figures observed for people with diabetes mellitus at our own hospital in 2017 (Varese, Italy). Prevalence of resistance to common antibacterials is enhanced compared with nondiabetic patients. The prevalence of methicillin-resistant Staphylococcus aureus was high and comparable in both groups, confirming the extremely elevated prevalence of methicillin-resistant S. aureus strains in Italy [89]. In contrast, the prevalence of common resistance phenotypes (vancomycin-resistant enterococci, extended-spectrum β-lactamases-producing enterobacteria, carbapenem-resistant enterobacteria and nonfermenting Gram-negative bacilli) was more pronounced in people with diabetes vs. nondiabetic patients. Thus, early diagnosis and prompt treatment of infections are critical for people with diabetes, including surgical debridement when needed. Compared with people without diabetes, diabetes mellitus implies a higher risk of failure of Helicobacter pylori therapy, suggesting the need of specific regimens for its eradication [90].

Table 10
Table 10:
Prevalence of drug-resistant isolates in adult inpatients diagnosed with bacterial infection worldwide and in Europe (1-day survey, year 2015) compared with adult nondiabetic and diabetic inpatients at a single hospital (Varese, Italy, year 2017).

Mycotic genital infections

People with diabetes are at an increased risk of being diagnosed with infections of the urogenital tract, especially individuals of younger age, with a history of prior genital infections, and with poorly controlled glycemia [91]. Candida spp. constitute the most frequent isolate [92]. The most recent addition to the therapeutic options for the treatment of T2DM are the sodium-glucose cotransporter 2 (SGLT2) inhibitors (three members of the class – canagliflozin, dapagliflozin, and empagliflozin – currently marketed in Western countries). SGLT2 inhibitors reduce hyperglycemia by increasing urinary glucose excretion. These agents have shown significant clinical benefit with regard to weight loss, low risk of hypoglycemia, reduction in blood pressure, reduction in cardiovascular and renal events in high-risk patients, leading to their increasing popularity for T2DM. However, common to all SGLT2 inhibitors is that chronic use is associated with a definite increase in genital infections (up to 8–10% of treated patients), with the following characteristics: mild-to-moderate severity, incidence dependent on drug dosage, hence roughly proportional to the amount of urinary glucose loss, more frequent in women (vulvovaginitis) than men (balanitis), more frequent in association with obesity, antecedent history of genital infection, poor hygiene, often recurrent but seldom leading to treatment discontinuation [93]. Urinary tract infections show the same pattern, although with a lower incidence (+15% vs. placebo or non-SGLT2 medications) than genital infections (+180%).

Parasites and diabetes

Case reports suggest that diabetes mellitus can affect the phenotype of cutaneous disease, with unusually vegetative Leishmania major lesions occurring in patients with diabetes [94] and particularly severe cutaneous Leishmania infantum lesions in French and Italian people with diabetes compared with nondiabetic patients [95]. In a study from Indonesia, the prevalence of infection with soil-transmitted helminths (ascaris, trichuris, hookworm, strongyloides) was inversely related with insulin resistance [96]. Epidemiology shows an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases (hygiene hypothesis) [97]. One way by which helminth infections can modulate insulin resistance and the associated inflammation is by inducing a chronic low-grade immune suppression due to both Th2 and regulatory T cells which can quench inflammation and promote insulin sensitivity [98]. Schistosomiasis appears to protect against diabetes mellitus [78].

Herpes zoster and diabetes

Large studies indicate that T1DM and T2DM patients are at risk for herpes zoster [99–101]. Postherpetic neuralgia is more severe and persistent in people with diabetes [102] and vascular complications confer an additional risk [101]. Significantly, statins increase the risk of Herpes Zoster (HZ) [103].

Complications of diabetes favor infection

Complications of diabetes mellitus confer an additional risk for infection: vascular pathology and reduced perfusion, sensory neuropathy and autonomic neuropathy that implies reduced sensitivity to painful stimuli and repeated trauma, reduction of sweating, urinary retention, alterations of gastrointestinal mobility and absorption. Other diabetes mellitus-related conditions include increased body mass, dehydrosis and superficial skin infections (especially at body folds), infection of foot ulcers [104]. Insulin injections, even if sporadically, may aid subcutaneous infection. In addition, people with diabetes are exposed to risks of infection associated with semi-invasive or invasive procedures (e.g., general hospital assistance, dialysis, surgery).

Diabetes mellitus and environmental factors

Type 1 diabetes mellitus and environment

Potential triggers of islet autoimmunity include diet, toxins, infections that affect children (in utero, perinatally, during childhood). Comparisons between the genetically-related populations of Finland and the neighboring Karelian Republic of Russia indicate that T1DM is six times more common in Finland and that other immune mediated diseases (celiac disease, autoimmune thyroiditis, allergy) follow a similar trend [105]. Supporting the impact of environment or lifestyle on risk, migrants tend to acquire the same risk of T1DM as the population in their new area of residence [106,107]. In African migrants to France, T1DM is developing earlier compared with those staying in their country of birth [108]. Thus, environmental factors have a key role in T1DM.

Type 1 diabetes mellitus and infection

Viruses have long been suggested as environmental triggers. A meta-analysis showed a significant association between enterovirus detection in blood and T1DM at the time of clinical onset [109]. The finding has been confirmed in multiple studies both at onset and in later phases [110–115]. The MIDIA study suggested that in genetically predisposed children enterovirus infection may precede islet autoimmunity [116]. Viral serology has shown that infection by coxsackievirus B1 is associated with islet autoimmunity and progression to clinical diabetes [117,118]. Enterovirus infection during pregnancy may have a pathogenic role [119,120]. In support of these association studies, the enterovirus capsid protein VP1 was found in islets of patients with T1DM both close to the time of onset and several years after onset, indicating that enteroviruses establish a persistent infection in beta cells [121–123]. Virus does not produce a lytic effect in islet cells, rather T1DM occurs in the presence of a persistent low-grade infection triggering an inflammatory response, beta cell damage and autoantigen release [124]. The observation that children with T1DM show an incomplete antibody response to enteroviruses [125] supports the hypothesis of defective antiviral resistance leading to a chronic infection, then to endocrine autoimmunity. Molecular and immunologic methods for detecting minute amounts of mutated enterovirus types will assist in defining diabetes-associated viruses [126,127]. As indirect evidence for enterovirus infection, viral signatures such as interferon and major histocompatibility complex class-I (MHC-I) hyperexpression have been found in T1DM [128].

Respiratory infections in children are temporally associated with initiation of islet autoimmunity in the TEDDY study [129]. Similarly, detection of enteroviruses in stools precedes islet autoimmunity [130]. Other reports document the frequent exposure to infectious agents at time points close to the clinical onset of T1DM [131]. Later, progressive beta cell loss may be secondary to activation of autoreactive mechanisms [124]. Among mechanisms leading to virus-induced autoimmunity and beta cell death, molecular mimicry reflects the possible cross reactivity between viral components and islet proteins [124]. Additional mechanisms include epitope spreading, bystander activation, bystander damage.

Rare variants of IFIH1, a gene implicated in antiviral responses, have been shown to protect from or predispose to T1DM [132], thus confirming the possible role of viruses in initiating the diabetogenic process [133,134]. Should enteroviruses be pathogenic contributors to T1DM, efforts at developing effective antivirals and an enterovirus vaccine will be of utmost importance [135–137].

Additional factors possibly involved in the origin of T1DM include breastfeeding [138], exposure to cow milk [139], exposure to Mycobacterium avium-paratubercolosis in bovine milk [140], timing of introduction of cereals [141] or egg [142], toxic chemicals such as nitrates and derivatives [143], vitamin D intake during pregnancy and thereafter [115,144]. Recently, tenuous evidence has been published for a possible causative role of influenza viruses [145].

Fulminant diabetes

Fulminant T1DM (FDM) was first reported by Imagawa [146]. FDM is defined as remarkably abrupt onset; very short duration of hyperglycemic symptoms (less than 1 week); ketoacidosis at diagnosis; negativity of islet-related autoantibodies; almost nil C-peptide; elevated levels of pancreatic enzymes; high ratios of glycated albumin to glycated hemoglobin (indicating that hyperglycemia was of short duration) [147]. These characteristics are found in about 20% new cases in Japan. Influenza-like symptoms are frequent before the onset [148]. FDM may be associated with pregnancy [149], leads to early microvascular damage, is associated with HLA DRB1*04 : 05DQB1*04 : 01 [147] and autoantibodies to C300 (a protein family expressed in dendritic cells [150]. FDM has been reported from Korea, China, other areas of Asia, and – sporadically – in whites [151]. Notably, titers of enterovirus IgA antibodies were elevated in patients with recent-onset FDM compared with those with recent-onset autoimmune T1DM [151]. Enterovirus antigens are detected in islets and exocrine tissue together with upregulation of MDA5, RIG-I, TLR3, and TLR4 [148]. Features of FDM point to a short pathogenic process of infectious origin leading to rapid beta cell destruction.

Enteroviruses in waters

Health risks associated with sewage-contaminated waters are a public health concern. Water monitoring systems rely predominantly on the enumeration of bacterial indicators. However, human enteric viruses – due to their resilience and persistence in the environment – may represent more significant indicators. In Hawaiian waters, 11/20 sites tested positive for enteroviruses, indicating fecal contamination. In addition, shellfish from six of nine sites tested positive for enteroviruses of different species [152]. In the context of poliovirus surveillance, waters examined for polio and nonpolio enteroviruses in Helsinki (Finland) and Islamabad (Pakistan) contained multiple nonpolio enteroviruses, predominantly of the B species (coxsackieviruses and select echoviruses) [153]. Comparable results have been obtained in Varese, Italy: diverse nonpolio enterovirus types have been detected in sewage and wastewater, belonging mostly to the B species and the Echovirus group (unpublished observations). Importantly, enteroviruses were not found in drinking waters. In contrast, in Egypt nonpolio enteroviruses were found in 100% sewage and wastewater and also in one third of drinkable water samples [154]. It has also been proposed that enteroviruses may persist in free-living amoebae within environmental waters [155]. Thus, waters may represent a common vehicle of transmission for these agents and could contribute to the spreading of diabetes mellitus.

The hygiene hypothesis in type 1 diabetes mellitus

Over the last century, improved hygienic conditions have led to reduced circulation and exposure to biological agents (pathogens, commensals, parasites). This may have resulted in lessened antimicrobial immunity with consequences possibly relevant to the young and older ages [97,156]. In addition, vaccines could reduce communicable diseases. These events correlate with the heightened frequency of autoimmune conditions and the increasing incidence of common infections at older ages [156,157]. Lack of intestinal parasites seems particularly linked to autoimmune conditions [78,158] and helminth-induced immunomodulation may well prevent diabetes mellitus and ameliorate insulin sensitivity [159,160].

Type 2 diabetes mellitus and environment

Epidemiologically, high levels of walkability and green space are associated with lower T2DM risk, while increased levels of air pollution and noise are associated with greater risk [161]. Thus, an important risk factor is urbanization itself, which is linked to consumption of unhealthy foods, sedentary lifestyle, scarce exposure to sunlight. Randomized controlled trials in Finland, USA, China, and India established that lifestyle modification with physical activity [162] and healthy diets [163] can delay or prevent T2DM. A variety of environmental factors may play a role in T2M. These include: delivery mode, weight at birth, placental function, maternal nutrition, postnatal growth, antibiotic usage, diet with processed foods, calorie intake, macro, and micronutrients, vitamins, basal metabolism, exercise, sleep debt, endocrine disruptors, chronic inflammation [164]. To prevent T2DM, WHO recommends limiting saturated fatty acid consumption to less than 10% of total energy intake and achieving adequate intake of dietary fiber (minimum 20 g daily). Reducing the intake of free sugars to less than 10% of total and physical activity 3–5 days a week for at least 30–45 min are also recommended [2].

Gut microbiome

Though medicine is mostly concerned with pathogenic bacteria, a symbiotic interaction of intestinal bacteria with the human body forges the immune system. Gut microbes participate in polysaccharide breakdown, nutrient absorption, gut permeability, bile acid modification, inflammatory responses, and may produce vitamins and nutrients. In the distal gut microbiota, more than 90% of phylogenetic types belong to two divisions: the Firmicutes (mostly Gram-positive) and the Bacteroidetes (Gram-negative, nonsporeforming, rod-shaped bacteria). The remaining types are distributed among eight divisions. Alterations in Gammaproteobacteria (Gram-negative) and Verrucomicrobia (Gram-negative) and the ratios of Firmicutes to Bacteroidetes (Gram-positive) are associated with weight gain and insulin resistance, while alterations in butyrate-producing bacteria (e.g., Roseburia spp., Clostridium spp., Eubacterium rectale, Faecalibacterium prausnitzii – all Gram-positive) could contribute to diabetes mellitus [165]. Butyrate is thought to cause beneficial effects through enhancement of mitochondrial activity, activation of intestinal gluconeogenesis, prevention of metabolic endotoxemia [166].

In patients with T1DM or other autoimmune conditions a reduced diversity of microbiota has been reported [167]. Dysbiosis is also associated with T2DM [168]. Some bacterial groups seem related to plasma glucose concentrations, including the ratio of Bacteroidetes to Firmicutes and the ratio of Bacteroides-Prevotella to Clostridium coccoides and Eubacterium rectale. It is supposed that a microbiome enriched in the Gram-negative component (e.g., Proteobacteria) may release more LPS, thereby stimulating Toll-like receptors that induce a proinflammatory status [169]. Most of these studies have been performed with stool samples and are not representative of the small intestine that is preferentially linked to pancreas. Taken together, the results indicate that there is no well delineated bacterial taxon serving as a general marker for diabetes mellitus or one that can even be suspected of a causal influence in diabetogenesis. Bacteriome alterations could indeed be an effect of increased glycemia, its excursions, dietary changes following diagnosis, diabetes medications.

Other infections possibly linked with diabetes

Hepatitis C virus

In the United States, an estimated 9.4% of the population has diabetes mellitus and 1.4% carries hepatitis C virus (HCV) [170]. T2DM is nearly four times more likely to develop in HCV-positive than in HCV-negative individuals [171]. Thus, anti-HCV treatments have the potential to impact a remarkable proportion of the population not only regarding liver disease but also diabetes mellitus [172]. In fact, glycemic control may improve in people with diabetes who are treated with antivirals due to the HCV carrier status. Not only HbA1c levels improve, but insulin requirement is also reduced. Future studies will determine the duration of metabolic improvement in diabetes mellitus patients treated with antivirals and the effect of this treatment on complications [173]. In vitro, HCV may infect pancreatic islet cells. Infected islets have altered cytokine expression that may well contribute to insulin deficiency [174].

Prion-like protein aggregates in diabetes

Prions are infectious agents devoid of nucleic acids that cause progressive neurodegenerative diseases with long incubation times (usually years). Prion disease can be initiated by a spontaneous event, transmitted through genetic inheritance, through body fluids and/or excreta, contact with the contaminated environment or food, medical intervention [175]. Prion diseases are characterized by the accumulation of amyloid in tissues and are classified as protein misfolding disorders (PMDs).

Cats are one of the few species that develop a form of diabetes mellitus analogous to T2DM. The characteristic finding in cats with T2DM is deposition within islets of amyloid derived from the beta cell hormone amylin (islet amyloid polypeptide, IAPP). Increased IAPP concentration has been documented in islet cells and plasma of diabetic cats, supporting a pathogenic role for the polypeptide [176].

As in cats, the accumulation in islets of IAPP aggregates is a frequent finding in people with diabetes. IAPP aggregates promote the misfolding of endogenous IAPP in cultured islets, and inoculation of IAPP aggregates into transgenic mice expressing human IAPP accelerates amyloid deposition in islets. The phenomenon is accompanied by hyperglycemia and reduction of beta cell mass. Thus – if indeed a PMD – T2DM could be transmissible through mechanisms proper to the spread of prions in neurologic disease [177].

Beta cell dysfunction and abnormal blood glucose concentrations have been reported in rodents infected with scrapie prions [178]. The cellular prion protein (PrPC) is expressed in beta cells and appears to contribute to glucose homeostasis. Pancreatic iron stores are influenced by PrPC expression. Silencing of PrPC resulted in significant depletion of intracellular iron and upregulation of the glucose transporter GLUT2 and insulin. Iron overload, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrPC-dependent manner. Glucose intolerance develops in iron-overloaded PrP+/+ but not in PrP−/− mice, indicating that PrPC-mediated modulation of intracellular iron does influence both insulin secretion and insulin sensitivity of target organs. Thus, the PrPC protein (and possibly its abnormal variants) appear to play a role in glucose homeostasis [179]. Current research is exploring the mechanism underlying the prion-like transmission of IAPP aggregates and its possible role in T2DM [180].

Vaccines for people with diabetes

As reported above, diabetes mellitus confers enhanced risk of morbidity and mortality from a variety of infectious conditions [181]. Pneumococcal disease (including community-acquired pneumonia and invasive pneumococcal disease) poses a burden all year round. Thus, pneumococcal vaccination of people with diabetes should be started at any time of the year [182,183]. Current evidence indicates that vaccination of adult/elder people with diabetes against seasonal influenza is effective and safe [184]. People with diabetes have higher rates of hepatitis B than the rest of the population. Blood glucose monitoring exposes to additional risk. Individuals with chronic disease, including diabetes mellitus, have an enhanced likelihood of nonresponse to Hepatitis B virus (HBV) vaccine [185]. Diabetic nonresponders should be treated with increased vaccination dose, intradermal administration, alternative routes of administration, coadministration with other vaccines [185]. Currently, the CDC recommends the following vaccinations for people with diabetes ( seasonal flu vaccine: every year; pneumococcal vaccines (13-valent and 23-valent); hepatitis B vaccine series, Tdap vaccine (tetanus, diphtheria, and pertussis); Zoster vaccine after 50 years of age. Other vaccines may be administered if needed: hepatitis A, measles, mumps, rubella, varicella, papillomaviruses, hemophilus influenzae type b, meningococci of the ACWY and B types. It should not be underestimated that infectious conditions may hinder glucose homeostasis and require accurate metabolic control.

Recently, interest in the old TB vaccine bacillus calmette-Guerin (BCG) has been revived for possible use in T1DM. Clinical trials are testing the value of BCG in prevention and treatment of adult patients. BCG induces a host response – driven in part by tumour necrosis factor – that aims at eliciting selective death of autoreactive T cells with the concurrent expansion of beneficial Tregs. Preliminary results are promising [186,187]. BCG should also be considered for TB prevention in countries at high incidence of both diabetes mellitus and TB such as India and China [188–190].


Evidence points to a bidirectional link of diabetes mellitus with infectious agents (viral, bacterial, fungal, parasitic, prion-like). On one hand, genetics and metabolic changes predispose people with diabetes to infectious events of varying severity. Notably, over a life time, the enhanced susceptibility of people with diabetes to infections tends to expose them to a substantial consumption of antimicrobials, facilitating the selection of drug-resistant strains. On the other hand, poorly identified biologic agents may participate in the pathogenic processes that lead to diabetes mellitus. As genetic predisposition cannot be changed, it will be crucial to identify the environmental factors that play an etiologic/triggering role in diabetes mellitus. Thus, clinical microbiology laboratories are encouraged to implement research and monitoring programs for diabetic people.

Should investigations continue to support the assumption that infections play a causative role in diabetes mellitus, then interventions should target the latter factors. However, even if some diabetes mellitus forms will be accepted as transmissible, NCDs will remain with us for a long time shaping the future of global health.


The opinions expressed in this publication are those of the authors. They do not necessarily reflect the opinions or views of funding Agencies.

Study supported by: the Italian Ministry of Health (PE-2013-02357094 to A.T.), JDRF & nPOD-V (3-SRA-2017-492-A-N, subrecipient A.T.). Study conducted in collaboration with the Centro Linceo Beniamino Segre, Accademia dei Lincei, Rome, Italy.

Conflicts of interest

There are no conflicts of interest.


1. Hunter DJ, Reddy KS. Noncommunicable diseases. N Engl J Med 2013; 369:1336–1343.
2. Internationl Diabetes Federation. IDF diabetes atlas. 8th ed.Brussels, Belgium: International Diabetes Federation; 2017.
3. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care 2018; 41:S13–S27.
4. Laugesen E, Ostergaard JA, Leslie RD. Danish Diabetes Academy Workshop and Workshop Speakers. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med 2015; 32:843–852.
5. Polonsky KS. The past 200 years in diabetes. N Engl J Med 2012; 367:1332–1340.
6. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138:271–281.
7. Knip M. Pathogenesis of type 1 diabetes: implications for incidence trends. Horm Res Paediatr 2011; 76 (Suppl 1):57–64.
8. Catanzariti L, Faulks K, Moon L, Waters AM, Flack J, Craig ME. Australia's national trends in the incidence of type 1 diabetes in 0-14-year-olds, 2000–2006. Diabet Med 2009; 26:596–601.
9. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care 2018; 41:917–928.
10. Scalone L, Cesana G, Furneri G, Ciampichini R, Beck-Peccoz P, Chiodini V, et al. Burden of diabetes mellitus estimated with a longitudinal population-based study using administrative databases. PLoS One 2014; 9:e113741.
11. Perry DJ, Wasserfall CH, Oram RA, Williams MD, Posgai A, Muir AB, et al. Application of a genetic risk score to racially diverse type 1 diabetes populations demonstrates the need for diversity in risk-modeling. Sci Rep 2018; 8:4529.
12. Hivert MF, Vassy JL, Meigs JB. Susceptibility to type 2 diabetes mellitus – from genes to prevention. Nat Rev Endocrinol 2014; 10:198–205.
13. Yeung RO, Hannah-Shmouni F, Niederhoffer K, Walker MA. Not quite type 1 or type 2, what now? Review of monogenic, mitochondrial, and syndromic diabetes. Rev Endocr Metab Disord 2018; doi:10.1007/s11154-018-9446-3. [Epub ahead of print].
14. Robertson CC, Rich SS. Genetics of type 1 diabetes. Curr Opin Genet Dev 2018; 50:7–16.
15. John Wiley and Sons, Ltd., Alshiekh S, Elding Larsson E, Ivarsson S-A, Lernmark A. Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ. Ch. 10. Textbook of diabetes 2017. 143–153.
16. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet 2018; 391:2449–2462.
17. Jerram ST, Leslie RD. The genetic architecture of type 1 diabetes. Genes 2017; 8: doi:10.3390/genes8080209.
18. Perez De Nanclares G, Bilbao JR, Calvo B, Vitoria JC, Vazquez F, Castano L. 5’-Insulin gene VNTR polymorphism is specific for type 1 diabetes: no association with celiac or Addison's disease. Ann NY Acad Sci 2003; 1005:319–323.
19. Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease. Front Cell Infect Microbiol 2015; 5:95.
    20. Yoshida H, Hunter CA. The immunobiology of interleukin-27. Annu Rev Immunol 2015; 33:417–443.
    21. Tomita T. Apoptosis in pancreatic beta-islet cells in Type 2 diabetes. Bosn J Basic Med Sci 2016; 16:162–179.
    22. Parkkola A, Laine AP, Karhunen M, Harkonen T, Ryhanen SJ, Ilonen J, et al. HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes. PloS one 2017; 12:e0188402.
    23. Soleimanpour SA, Ferrari AM, Raum JC, Groff DN, Yang J, Kaufman BA, et al. Diabetes Susceptibility Genes Pdx1 and Clec16a Function in a Pathway Regulating Mitophagy in beta-Cells. Diabetes 2015; 64:3475–3484.
    24. Lemos NE, Dieter C, Dorfman LE, Assmann TS, Duarte GCK, Canani LH, et al. The rs2292239 polymorphism in ERBB3 gene is associated with risk for type 1 diabetes mellitus in a Brazilian population. Gene 2018; 644:122–128.
    25. Floyel T, Brorsson C, Nielsen LB, Miani M, Bang-Berthelsen CH, Friedrichsen M, et al. CTSH regulates beta-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc Natl Acad Sci USA 2014; 111:10305–10310.
    26. Jermendy A, Szatmari I, Korner A, Szabo AJ, Toth-Heyn P, Hermann R. Association between interferon-induced helicase (IFIH1) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus. Pediatr Diabetes 2018; 19:300–304.
    27. Dendrou CA, Cortes A, Shipman L, Evans HG, Attfield KE, Jostins L, et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci Transl Med 2016; 8:363ra149.
    28. Redondo MJ, Steck AK, Pugliese A. Genetics of type 1 diabetes. Pediatr Diabetes 2018; 19:346–353.
    29. John Wiley & Sons, Ltd., Prasad RB, Groop L. Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ. Genetic architecture of type 2 diabetes. Textbook of diabetes 2017. 187–204.
    30. Langenberg C, Lotta LA. Genomic insights into the causes of type 2 diabetes. Lancet 2018; 391:2463–2474.
    31. Astiarraga B, Chueire VB, Souza AL, Pereira-Moreira R, Monte Alegre S, Natali A, et al. Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes. Diabetologia 2018; 61:1829–1837.
    32. Chen X, Ayala I, Shannon C, Fourcaudot M, Acharya NK, Jenkinson CP, et al. The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function. Diabetes 2018; 67:554–568.
    33. Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, et al. TLR2-dependent activation of beta-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. J Immunol 2014; 193:4203–4213.
    34. Langberg KA, Ma L, Sharma NK, Hanis CL, Elbein SC, Hasstedt SJ, et al. Single nucleotide polymorphisms in JAZF1 and BCL11A gene are nominally associated with type 2 diabetes in African-American families from the GENNID study. J Hum Genet 2012; 57:57–61.
    35. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. CDC123/CAMK1D gene rs12779790 polymorphism and rs10811661 polymorphism upstream of the CDKN2A/2B gene in women with gestational diabetes. J Perinatol 2017; 37:345–348.
    36. Sohani ZN, Anand SS, Robiou-du-Pont S, Morrison KM, McDonald SD, Atkinson SA, et al. Risk Alleles in/near ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2 Elevate Plasma Glucose Levels at Birth and in Early Childhood: Results from the FAMILY Study. PloS one 2016; 11:e0152107.
    37. Goyal G, Wong K, Nirschl CJ, Souders N, Neuberg D, Anandasabapathy N, et al. PPARgamma Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF. Cancer immunology research 2018; 6:723–732.
    38. Rutter GA, Chimienti F. SLC30A8 mutations in type 2 diabetes. Diabetologia 2015; 58:31–36.
    39. Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci USA 2014; 111:9597–9602.
    40. Lewis ND, Asim M, Barry DP, de Sablet T, Singh K, Piazuelo MB, et al. Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II. J Immunol 2011; 186:3632–3641.
    41. Wallet SM, Puri V, Gibson FC. Linkage of infection to adverse systemic complications: periodontal disease, toll-like receptors, and other pattern recognition systems. Vaccines 2018; 6: doi:10.3390/vaccines6020021.
    42. Martinez N, Kornfeld H. Diabetes and immunity to tuberculosis. Eur J Immunol 2014; 44:617–626.
    43. Kajiwara C, Kusaka Y, Kimura S, Yamaguchi T, Nanjo Y, Ishii Y, et al. Metformin mediates protection against legionella pneumonia through activation of AMPK and mitochondrial reactive oxygen species. J Immunol 2018; 200:623–631.
    44. Roilides E, Kontoyiannis DP, Walsh TJ. Host defenses against zygomycetes. Clin Infect Dis 2012; 54 (Suppl 1):S61–S66.
    45. Wong SL, Wagner DD. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J 2018; fj201800691R. doi:10.1096/fj.201800691R. [Epub ahead of print].
    46. Lachmandas E, Thiem K, van den Heuvel C, Hijmans A, de Galan BE, Tack CJ, et al. Patients with type 1 diabetes mellitus have impaired IL-1beta production in response to Mycobacterium tuberculosis. Eur J Clin Microbiol Infect Dis 2018; 37:371–380.
    47. Collison KS, Parhar RS, Saleh SS, Meyer BF, Kwaasi AA, Hammami MM, et al. RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukoc Biol 2002; 71:433–444.
    48. Machado-Lima A, Iborra RT, Pinto RS, Castilho G, Sartori CH, Oliveira ER, et al. In type 2 diabetes mellitus glycated albumin alters macrophage gene expression impairing ABCA1-mediated cholesterol efflux. J Cell Physiol 2015; 230:1250–1257.
    49. Jafar N, Edriss H, Nugent K. The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci 2016; 351:201–211.
    50. Ghosh P, Vaidya A, Sahoo R, Goldfine A, Herring N, Bry L, et al. Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans. J Clin Endocrinol Metab 2014; 99:E999–E1006.
    51. Hu R, Xia CQ, Butfiloski E, Clare-Salzler M. Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection. Clin Immunol 2018; 195:139–148.
    52. Wang X, Ota N, Manzanillo P, Kates L, Zavala-Solorio J, Eidenschenk C, et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 2014; 514:237–241.
    53. Hernandez P, Gronke K, Diefenbach A. A catch-22: interleukin-22 and cancer. Eur J Immunol 2018; 48:15–31.
    54. Montoya-Rosales A, Castro-Garcia P, Torres-Juarez F, Enciso-Moreno JA, Rivas-Santiago B. Glucose levels affect LL-37 expression in monocyte-derived macrophages altering the Mycobacterium tuberculosis intracellular growth control. Microb Pathog 2016; 97:148–153.
    55. Tan KS, Lee KO, Low KC, Gamage AM, Liu Y, Tan GY, et al. Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria. J Clin Invest 2012; 122:2289–2300.
    56. Zwang TJ, Gormally MV, Johal MS, Sazinsky MH. Enhanced iron availability by protein glycation may explain higher infection rates in diabetics. Biometals 2012; 25:237–245.
    57. Stegenga ME, van der Crabben SN, Blümer RM, Levi M, Meijers JC, Serlie MJ, et al. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood 2008; 112:82–89.
    58. Koh GC, Peacock SJ, van der Poll T, Wiersinga WJ. The impact of diabetes on the pathogenesis of sepsis. Eur J Clin Microbiol Infect Dis 2012; 31:379–388.
    59. Macdougall CE, Wood EG, Loschko J, Scagliotti V, Cassidy FC, Robinson ME, et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 2018; 27:588–601.
    60. Chen J, Feigenbaum L, Awasthi P, Butcher DO, Anver MR, Golubeva YG, et al. Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Ralpha. Proc Natl Acad Sci U S A 2013; 110:13534–13539.
    61. Hull CM, Peakman M, Tree TIM. Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it? Diabetologia 2017; 60:1839–1850.
    62. Knoop J, Gavrisan A, Kuehn D, Reinhardt J, Heinrich M, Hippich M, et al. GM-CSF producing autoreactive CD4(+) T cells in type 1 diabetes. Clin Immunol 2018; 188:23–30.
    63. Bayer AL, Fraker CA. The folate cycle as a cause of natural killer cell dysfunction and viral etiology in type 1 diabetes. Front Endocrinol 2012; 8:315.
    64. Lobo TF, Borges CM, Mattar R, Gomes CP, de Angelo AGS, Pendeloski KPT, et al. Impaired Treg and NK cells profile in overweight women with gestational diabetes mellitus. Am J Reprod Immunol 2018; 79: doi:10.1111/aji.12810.
    65. Kumar NP, Sridhar R, Nair D, Banurekha VV, Nutman TB, Babu S. Type 2 diabetes mellitus is associated with altered CD8(+) T and natural killer cell function in pulmonary tuberculosis. Immunology 2015; 144:677–686.
    66. Muskardin TLW, Niewold TB. Type I interferon in rheumatic diseases. Nat Rev Rheumatol 2018; 14:214–228.
    67. Kousathana F, Georgitsi M, Lambadiari V, Giamarellos-Bourboulis EJ, Dimitriadis G, Mouktaroudi M. Defective production of interleukin-1 beta in patients with type 2 diabetes mellitus: restoration by proper glycemic control. Cytokine 2017; 90:177–184.
    68. John Wiley & Sons, Ltd., Cockram CS, Wong BCK. Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ. Diabetes and infections. Textbook of diabetes 2017. 799–820.
    69. Versporten A, Zarb P, Caniaux I, Gros MF, Drapier N, Miller M, Jarlier V, et al. Antimicrobial consumption and resistance in adult hospital inpatients in 53 countries: results of an internet-based global point prevalence survey. Lancet Glob Health 2018; 6:e619–e629.
    70. Wagner DH Jr. Overlooked mechanisms in type 1 diabetes etiology: how unique costimulatory molecules contribute to diabetogenesis. Front Endocrinol 2017; 8:208.
    71. Seijkens T, Kusters P, Engel D, Lutgens E. CD40-CD40L: linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications. Diab Vasc Dis Res 2013; 10:115–122.
    72. DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A 2013; 110:5133–5138.
    73. Hinman RM, Smith MJ, Cambier JC. B cells and type 1 diabetes mice and men. Immunol Lett 2014; 160:128–132.
    74. Smith MJ, Simmons KM, Cambier JC. B cells in type 1 diabetes mellitus and diabetic kidney disease. Nat Rev Nephrol 2017; 13:712–720.
    75. Ram R, Morahan G. Effects of type 1 diabetes risk alleles on immune cell gene expression. Genes 2017; 8: doi:10.3390/genes8060167.
    76. Ratter JM, Tack CJ, Netea MG, Stienstra R. Environmental signals influencing myeloid cell metabolism and function in diabetes. Trends Endocrinol Metab 2018; 29:468–480.
    77. Egede LE, Hull BJ, Williams JS. Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, et al. Infections associated with diabetes. Diabetes in America. Bethesda, MD: National Institutes of Health; 2018; NIH Pub No. 17-1468. [p. 10.1–30.25].
    78. van Crevel R, van de Vijver S, Moore DAJ. The global diabetes epidemic: what does it mean for infectious diseases in tropical countries? Lancet Diabetes Endocrinol 2017; 5:457–468.
    79. Restrepo BI. Diabetes and tuberculosis. Microbiol Spectr 2016; 4: doi:10.1128/microbiolspec.TNMI7-0023-2016.
    80. Lee MR, Huang YP, Kuo YT, Luo CH, Shih YJ, Shu CC, et al. Diabetes mellitus and latent tuberculosis infection: a systemic review and metaanalysis. Clin Infect Dis 2017; 64:719–727.
    81. Malik F, Mehdi SF, Ali H, Patel P, Basharat A, Kumar A, et al. Is metformin poised for a second career as an antimicrobial? Diabetes Metab Res Rev 2018; 34:e2975.
    82. McKane CK, Marmarelis M, Mendu ML, Moromizato T, Gibbons FK, Christopher KB. Diabetes mellitus and community-acquired bloodstream infections in the critically ill. J Crit Care 2014; 29:70–76.
    83. Trevelin SC, Carlos D, Beretta M, da Silva JS, Cunha FQ. Diabetes mellitus and sepsis: a challenging association. Shock 2017; 47:276–287.
    84. Frydrych LM, Fattahi F, He K, Ward PA, Delano MJ. Diabetes and sepsis: risk, recurrence, and ruination. Front Endocrinol 2017; 8:271.
    85. Taganna J, de Boer AR, Wuhrer M, Bouckaert J. Glycosylation changes as important factors for the susceptibility to urinary tract infection. Biochem Soc Trans 2011; 39:349–354.
    86. Mikamo H, Yamagishi Y, Sugiyama H, Sadakata H, Miyazaki S, Sano T, Tomita T. High glucose-mediated overexpression of ICAM-1 in human vaginal epithelial cells increases adhesion of Candida albicans. J Obstet Gynaecol 2018; 38:226–230.
    87. Wang Z, Ren J, Wang G, Liu Q, Guo K, Li J. Association between diabetes mellitus and outcomes of patients with sepsis: a meta-analysis. Med Sci Monit 2017; 23:3546–3555.
    88. Baig Mirza AM, Fida M, Murtaza G, Niazi R, Hanif A, Irfan K, Masud F. Association of metabolic factors with dengue viral infection on admission triage which predict its clinical course during Lahore dengue epidemic. J Pak Med Assoc 2016; 66:1102–1106.
    89. Bongiorno D, Mongelli G, Stefani S, Campanile F. Burden of rifampicin- and methicillin-resistant Staphylococcus aureus in Italy. Microb Drug Resist 2018; 24:732–738.
    90. Horikawa C, Kodama S, Fujihara K, Hirasawa R, Yachi Y, Suzuki A, et al. High risk of failing eradication of Helicobacter pylori in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract 2014; 106:81–87.
    91. Hirji I, Andersson SW, Guo Z, Hammar N, Gomez-Caminero A. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. J Diabetes Complications 2012; 26:501–505.
    92. Nyirjesy P, Sobel JD, Fung A, Mayer C, Capuano G, Ways K, Usiskin K. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin 2014; 30:1109–1119.
    93. Zhang XL, Zhu QQ, Chen YH, Li XL, Chen F, Huang JA, Xu B. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc 2018; 7: doi:10.1161/jaha.117.007165.
    94. Terziroli Beretta-Piccoli B, Mainetti C, Peeters MA, Laffitte E. Cutaneous granulomatosis: a comprehensive review. Clin Rev Allergy Immunol 2018; 54:131–146.
    95. Ceyhan AM, Yildirim M, Basak PY, Akkaya VB. Unusual multifocal cutaneous leishmaniasis in a diabetic patient. Eur J Dermatol 2009; 19:514–515.
    96. Tahapary DL, de Ruiter K, Martin I, Brienen EAT, van Lieshout L, Cobbaert CM, et al. Effect of anthelmintic treatment on insulin resistance: a cluster-randomized, placebo-controlled trial in Indonesia. Clin Infect Dis 2017; 65:764–771.
    97. Drescher KM, von Herrath M, Tracy S. Enteroviruses, hygiene and type 1 diabetes: toward a preventive vaccine. Rev Med Virol 2015; 25:19–32.
    98. Aravindhan V, Anand G. Cell type-specific immunomodulation induced by helminthes: effect on metainflammation, insulin resistance and type-2 diabetes. Am J Trop Med Hyg 2017; 97:1650–1661.
    99. Munoz-Quiles C, Lopez-Lacort M, Ampudia-Blasco FJ, Diez-Domingo J. Risk and impact of herpes zoster on patients with diabetes: a population-based study, 2009–2014. Hum Vaccin Immunother 2017; 13:2606–2611.
    100. Kawai K, Yawn BP. Risk factors for herpes zoster: a systematic review and meta-analysis. Mayo Clin Proc 2017; 92:1806–1821.
    101. Chen HH, Lin IC, Chen HJ, Yeh SY, Kao CH. Association of herpes zoster and type 1 diabetes mellitus. PLoS One 2016; 11:e0155175.
    102. Papagianni M, Metallidis S, Tziomalos K. Herpes zoster and diabetes mellitus: a review. Diabetes Ther 2018; 9:545–550.
    103. Kim MC, Yun SC, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH. Statins increase the risk of herpes zoster: a propensity score-matched analysis. PLoS One 2018; 13:e0198263.
    104. Vardakas KZ, Horianopoulou M, Falagas ME. Factors associated with treatment failure in patients with diabetic foot infections: an analysis of data from randomized controlled trials. Diabetes Res Clin Pract 2008; 80:344–351.
    105. Kondrashova A, Seiskari T, Ilonen J, Knip M, Hyoty H. The ‘Hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS 2013; 121:478–493.
    106. Soderstrom U, Aman J, Hjern A. Being born in Sweden increases the risk for type 1 diabetes – a study of migration of children to Sweden as a natural experiment. Acta Paediatr 2012; 101:73–77.
    107. Oilinki T, Otonkoski T, Ilonen J, Knip M, Miettinen PJ. Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland. Pediatr Diabetes 2012; 13:176–180.
    108. Choukem SP, Fabreguettes C, Akwo E, Porcher R, Nguewa JL, Bouche C, et al. Influence of migration on characteristics of type 2 diabetes in sub-Saharan Africans. Diabetes Metab 2014; 40:56–60.
    109. Yeung WC, Rawlinson WD, Craig ME. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 2011; 342:d35.
    110. Schulte BM, Bakkers J, Lanke KH, Melchers WJ, Westerlaken C, Allebes W, et al. Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol 2010; 23:99–104.
    111. Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R, et al. Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 2011; 60:276–279.
    112. Toniolo A, Salvatoni A, Federico G, Diaz-Horta O, Maccari G, Baj A. Taylor K, Hyoty H, Toniolo A, Zuckerman A. Enteroviruses in blood. Diabetes and viruses. New York: Springer; 2013. 143–156.
    113. Diaz-Horta O, Baj A, Maccari G, Salvatoni A, Toniolo A. Enteroviruses and causality of type 1 diabetes: how close are we? Pediatr Diabetes 2012; 13:92–99.
    114. Salvatoni A, Baj A, Bianchi G, Federico G, Colombo M, Toniolo A. Intrafamilial spread of enterovirus infections at the clinical onset of type 1 diabetes. Pediatr Diabetes 2013; 14:407–416.
    115. Federico G, Genoni A, Puggioni A, Saba A, Gallo D, Randazzo E, et al. Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents. Pediatr Diabetes 2018; 19:923–929.
    116. Cinek O, Stene LC, Kramna L, Tapia G, Oikarinen S, Witsø E, et al. Enterovirus RNA in longitudinal blood samples and risk of islet autoimmunity in children with a high genetic risk of type 1 diabetes: the MIDIA study. Diabetologia 2014; 57:2193–2200.
    117. Laitinen OH, Honkanen H, Pakkanen O, Oikarinen S, Hankaniemi MM, Huhtala H, et al. Coxsackievirus B1 is associated with induction of beta-cell autoimmunity that portends type 1 diabetes. Diabetes 2014; 63:446–455.
    118. Sioofy-Khojine AB, Lehtonen J, Nurminen N, Laitinen OH, Oikarinen S, Huhtala H, et al. Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes. Diabetologia 2018; 61:1193–1202.
    119. Lind A, Lynch KF, Lundgren M, Lernmark Å, Almgren P, Ramelius A, et al. First trimester enterovirus IgM and beta cell autoantibodies in mothers to children affected by type 1 diabetes autoimmunity before 7 years of age. J Reprod Immunol 2018; 127:1–6.
    120. Allen DW, Kim KW, Rawlinson WD, Craig ME. Maternal virus infections in pregnancy and type 1 diabetes in their offspring: systematic review and meta-analysis of observational studies. Rev Med Virol 2018; 28:e1974.
    121. Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG. Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 2013; 56:185–193.
    122. Morgan NG, Leete P, Foulis AK, Richardson SJ. Islet inflammation in human type 1 diabetes mellitus. IUBMB Life 2014; 66:723–734.
    123. Krogvold L, Edwin B, Buanes T, Frisk G, Skog O, Anagandula M, et al. Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 2015; 64:1682–1687.
    124. Op de Beeck A, Eizirik DL. Viral infections in type 1 diabetes mellitus – why the beta cells? Nat Rev Endocrinol 2016; 12:263–273.
    125. Ashton MP, Eugster A, Walther D, Daehling N, Riethausen S, Kuehn D, et al. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. Sci Rep 2016; 6:32899.
    126. Genoni A, Canducci F, Rossi A, Broccolo F, Chumakov K, Bono G, et al. Revealing enterovirus infection in chronic human disorders: an integrated diagnostic approach. Sci Rep 2017; 7:5013.
    127. Maccari G, Genoni A, Sansonno S, Toniolo A. Properties of two enterovirus antibodies that are utilized in diabetes research. Sci Rep 2016; 6:24757.
    128. Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, et al. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 2016; 59:2448–2458.
    129. Lönnrot M, Lynch KF, Elding Larsson H, Lernmark Å, Rewers MJ, Törn C, et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 2017; 60:1931–1940.
    130. Honkanen H, Oikarinen S, Nurminen N, Laitinen OH, Huhtala H, Lehtonen J, et al. Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity. Diabetologia 2017; 60:424–431.
    131. Bougneres P, Le Fur S, Valtat S, Kamatani Y, Lathrop M, Valleron AJ. Isis-Diab Collaborative Group. Using spatio-temporal surveillance data to test the infectious environment of children before type 1 diabetes diagnosis. PLoS One 2017; 12:e0170658.
    132. Gorman JA, Hundhausen C, Errett JS, Stone AE, Allenspach EJ, Ge Y, et al. The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol 2017; 18:744–752.
    133. Hyoty H. Viruses in type 1 diabetes. Pediatr Diabetes 2016; 17 (Suppl 22):56–64.
    134. Eizirik DL, Op de Beeck A. Coxsackievirus and type 1 diabetes mellitus: the wolf's footprints. Trends Endocrinol Metab 2018; 29:137–139.
    135. Abzug MJ, Michaels MG, Wald E, Jacobs RF, Romero JR, Sánchez PJ, et al. A randomized, double-blind, placebo-controlled trial of pleconaril for the treatment of neonates with enterovirus sepsis. J Pediatric Infect Dis Soc 2016; 5:53–62.
    136. Yi EJ, Shin YJ, Kim JH, Kim TG, Chang SY. Enterovirus 71 infection and vaccines. Clin Exp Vaccine Res 2017; 6:4–14.
    137. Baggen J, Thibaut HJ, Strating J, van Kuppeveld FJM. The life cycle of nonpolio enteroviruses and how to target it. Nat Rev Microbiol 2018; 16:368–381.
    138. Frederiksen B, Kroehl M, Lamb MM, Seifert J, Barriga K, Eisenbarth GS, et al. Infant exposures and development of type 1 diabetes mellitus: the Diabetes Autoimmunity Study in the Young (DAISY). JAMA Pediatr 2013; 167:808–815.
    139. Holmberg H, Wahlberg J, Vaarala O, Ludvigsson J. Short duration of breast-feeding as a risk-factor for beta-cell autoantibodies in 5-year-old children from the general population. Br J Nutr 2007; 97:111–116.
    140. Niegowska M, Rapini N, Biet F, Piccinini S, Bay S, Lidano R, et al. Seroreactivity against specific L5P antigen from Mycobacterium avium subsp. paratuberculosis in children at risk for T1D. PLoS One 2016; 11:e0157962.
    141. Uusitalo U, Lee HS, Andrén Aronsson C, Vehik K, Yang J, Hummel S, et al. Early infant diet and islet autoimmunity in the TEDDY study. Diabetes Care 2018; 41:522–530.
    142. Hakola L, Takkinen HM, Niinistö S, Ahonen S, Nevalainen J, Veijola R, et al. Infant feeding in relation to the risk of advanced islet autoimmunity and type 1 diabetes in children with increased genetic susceptibility: a cohort study. Am J Epidemiol 2018; 187:34–44.
    143. Benson VS, Vanleeuwen JA, Taylor J, Somers GS, McKinney PA, Van Til L. Type 1 diabetes mellitus and components in drinking water and diet: a population-based, case–control study in Prince Edward Island, Canada. J Am Coll Nutr 2010; 29:612–624.
    144. Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 2013; 5:3551–3562.
    145. Capua I, Mercalli A, Romero-Tejeda A, Pizzuto MS, Kasloff S, Sordi V, et al. Study of 2009 H1N1 pandemic influenza virus as a possible causative agent of diabetes. J Clin Endocrinol Metab 2018; doi: 10.1210/jc.2018-00862.
    146. Hanafusa T, Imagawa A. Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners. Nat Clin Pract Endocrinol Metab 2007; 3:36–45.
    147. Liu L, Zeng L, Sang D, Lu Z, Shen J. Recent findings on fulminant type 1 diabetes. Diabetes Metab Res Rev 2018; 34: doi:10.1002/dmrr.2928.
    148. Shibasaki S, Imagawa A, Hanafusa T. Fulminant type 1 diabetes mellitus: a new class of type 1 diabetes. Adv Exp Med Biol 2012; 771:20–23.
    149. Inagaki T, Nishii Y, Suzuki N, Suzuki S, Koizumi Y, Aizawa T, Hashizume K. Fulminant diabetes mellitus associated with pregnancy: case reports and literature review. Endocr J 2002; 49:319–322.
    150. Haseda F, Imagawa A, Nishikawa H, Mitsui S, Tsutsumi C, Fujisawa R, et al. Antibody to CMRF35-like molecule 2, CD300e a novel biomarker detected in patients with fulminant type 1 diabetes. PLoS One 2016; 11:e0160576.
    151. Imagawa A, Hanafusa T. Fulminant type 1 diabetes – an important subtype in East Asia. Diabetes Metab Res Rev 2011; 27:959–964.
    152. Connell C, Tong HI, Wang Z, Allmann E, Lu Y. New approaches for enhanced detection of enteroviruses from Hawaiian environmental waters. PLoS One 2012; 7:e32442.
    153. Furtak V, Roivainen M, Mirochnichenko O, Zagorodnyaya T, Laassri M, Zaidi SZ, et al. Environmental surveillance of viruses by tangential flow filtration and metagenomic reconstruction. Euro Surveill 2016; 21: doi:10.2807/
    154. El-Senousy WM, Abdel-Moneim A, Abdel-Latif M, El-Hefnawy MH, Khalil RG. Coxsackievirus B4 as a causative agent of diabetes mellitus type 1: is there a role of inefficiently treated drinking water and sewage in virus spreading? Food Environ Virol 2018; 10:89–98.
    155. Atanasova ND, Dey R, Scott C, Li Q, Pang XL, Ashbolt NJ. Persistence of infectious Enterovirus within free-living amoebae – a novel waterborne risk pathway? Water Res 2018; 144:204–214.
    156. Lambrecht BN, Hammad H. The immunology of the allergy epidemic and the hygiene hypothesis. Nat Immunol 2017; 18:1076–1083.
    157. Varyani F, Fleming JO, Maizels RM. Helminths in the gastrointestinal tract as modulators of immunity and pathology. Am J Physiol Gastrointest Liver Physiol 2017; 312:G537–G549.
    158. de Ruiter K, Tahapary DL, Sartono E, Soewondo P, Supali T, Smit JWA, et al. Helminths, hygiene hypothesis and type 2 diabetes. Parasite Immunol 2017; 39: doi:10.1111/pim.12404.
    159. Berbudi A, Ajendra J, Wardani AP, Hoerauf A, Hubner MP. Parasitic helminths and their beneficial impact on type 1 and type 2 diabetes. Diabetes Metab Res Rev 2016; 32:238–250.
    160. Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res 2017; 116:2065–2074.
    161. Dendup T, Feng X, Clingan S, Astell-Burt T. Environmental risk factors for developing type 2 diabetes mellitus: a systematic review. Int J Environ Res Public Health 2018; 15: doi:10.3390/ijerph15010078.
    162. Gillies CL, Lambert PC, Abrams KR, Sutton AJ, Cooper NJ, Hsu RT, et al. Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis. BMJ 2008; 336:1180–1185.
    163. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14:88–98.
    164. Franks PW, McCarthy MI. Exposing the exposures responsible for type 2 diabetes and obesity. Science 2016; 354:69–73.
    165. Barlow GM, Yu A, Mathur R. Role of the gut microbiome in obesity and diabetes mellitus. Nutr Clin Pract 2015; 30:787–797.
    166. Hartstra AV, Bouter KE, Backhed F, Nieuwdorp M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 2015; 38:159–165.
    167. Bach JF. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Endocrinol 2018; 18:105–120.
    168. Healey GR, Murphy R, Brough L, Butts CA, Coad J. Interindividual variability in gut microbiota and host response to dietary interventions. Nutr Rev 2017; 75:1059–1080.
    169. Vatanen T, Kostic AD, d’Hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 2016; 165:842–853.
    170. Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology 2015; 62:1353–1363.
    171. Fabiani S, Fallahi P, Ferrari SM, Miccoli M, Antonelli A. Hepatitis C virus infection and development of type 2 diabetes mellitus: systematic review and meta-analysis of the literature. Rev Endocr Metab Disord 2018; doi:10.1007/s11154-017-9440-1.
    172. Polo ML, Laufer N. Extrahepatic manifestations of HCV: the role of direct acting antivirals. Expert Rev Anti Infect Ther 2017; 15:737–746.
    173. Hum J, Jou JH, Green PK, Berry K, Lundblad J, Hettinger BD, et al. Improvement in glycemic control of type 2 diabetes after successful treatment of hepatitis C virus. Diabetes Care 2017; 40:1173–1180.
    174. Blackard JT, Kong L, Lombardi A, Homann D, Hammerstad SS, Tomer Y. A preliminary analysis of hepatitis C virus in pancreatic islet cells. Virol J 2017; 14:237.
    175. Mathiason CK. Silent prions and covert prion transmission. PLoS Pathog 2015; 11:e1005249.
    176. Lutz TA, Rand JS. Pathogenesis of feline diabetes mellitus. The veterinary clinics of North America. Small Anim Pract 1995; 25:527–552.
    177. Mukherjee A, Soto C. Prion-like protein aggregates and type 2 diabetes. Cold Spring Harb Perspect Med 2017; 7: doi:10.1101/cshperspect.a024315.
    178. Onodera T, Sakudo A, Tsubone H, Itohara S. Review of studies that have used knockout mice to assess normal function of prion protein under immunological or pathophysiological stress. Microbiol Immunol 2014; 58:361–374.
    179. Ashok A, Singh N. Prion protein modulates glucose homeostasis by altering intracellular iron. Sci Rep 2018; 8:6556.
    180. Mukherjee A, Morales-Scheihing D, Salvadores N, Moreno-Gonzalez I, Gonzalez C, Taylor-Presse K, et al. Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism. J Exp Med 2017; 214:2591–2610.
    181. Hulme KD, Gallo LA, Short KR. Influenza virus and glycemic variability in diabetes: a killer combination? Front Microbiol 2017; 8:861.
    182. Torres A, Blasi F, Dartois N, Akova M. Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease. Thorax 2015; 70:984–989.
    183. Shashank RJ, Samika SJ, Siddharth NS. Pneumococcal vaccine in diabetes: relevance in India. J Assoc Physicians India 2015; 63:34–35.
    184. Goeijenbier M, van Sloten TT, Slobbe L, Mathieu C, van Genderen P, Beyer WEP, Osterhaus ADME. Benefits of flu vaccination for persons with diabetes mellitus: a review. Vaccine 2017; 35:5095–5101.
    185. Walayat S, Ahmed Z, Martin D, Puli S, Cashman M, Dhillon S. Recent advances in vaccination of nonresponders to standard dose hepatitis B virus vaccine. World J Hepatol 2015; 7:2503–2509.
    186. Faustman DL. TNF, TNF inducers, and TNFR2 agonists: a new path to type 1 diabetes treatment. Diabetes Metab Res Rev 2018; 34: doi:10.1002/dmrr.2941.
    187. Leong I. BCG vaccination for type 1 diabetes mellitus. Nat Rev Endocrinol 2018; doi: 10.1038/s41574-018-0064-7.
    188. Lonnroth K, Roglic G, Harries AD. Improving tuberculosis prevention and care through addressing the global diabetes epidemic: from evidence to policy and practice. Lancet Diabetes Endocrinol 2014; 2:730–739.
    189. Blanco-Guillot F, Delgado-Sánchez G, Mongua-Rodríguez N, Cruz-Hervert P, Ferreyra-Reyes L, Ferreira-Guerrero E, et al. Molecular clustering of patients with diabetes and pulmonary tuberculosis: a systematic review and meta-analysis. PLoS One 2017; 12:e0184675.
    190. Basnyat B, Caws M, Udwadia Z. Tuberculosis in South Asia: a tide in the affairs of men. Multidiscip Respir Med 2018; 13:10.

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