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 .
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 . 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 .
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 . Thus, the risk of T1DM can be better predicted by using a genetic score that combines measurements of HLA and non-HLA loci .
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 . 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 . 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  and GDM  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) .
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 . Binding of sCD40L to CD40 induces the production of proinflammatory cytokines, thus perpetuating the inflammatory status, perturbing insulin production, and downregulating antigen-specific responses .
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 . 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) . 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 . B cells are also important: in T2DM patients as they promote inflammation through regulation of T-cell function and an inflammatory cytokine profile . In T1DM, anti-CD20 therapy delays – but fails to prevent – the onset of the disease and B cells present autoantigens to T cells . The numbers of B cells that infiltrate the pancreas correlate with β-cell loss . The reported immune defects may be secondary to the functions of diabetes-predisposing alleles as shown for T1DM , and/or to metabolic alterations in lymphoid cells .
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  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 .
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)  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 . 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 .
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 . Candida spp. constitute the most frequent isolate . 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 . Urinary tract infections show the same pattern, although with a lower incidence (+15% vs. placebo or non-SGLT2 medications) than genital infections (+180%).
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  and vascular complications confer an additional risk . Significantly, statins increase the risk of Herpes Zoster (HZ) .
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 . 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 . Thus, environmental factors have a key role in T1DM.
Respiratory infections in children are temporally associated with initiation of islet autoimmunity in the TEDDY study . Similarly, detection of enteroviruses in stools precedes islet autoimmunity . Other reports document the frequent exposure to infectious agents at time points close to the clinical onset of T1DM . Later, progressive beta cell loss may be secondary to activation of autoreactive mechanisms . Among mechanisms leading to virus-induced autoimmunity and beta cell death, molecular mimicry reflects the possible cross reactivity between viral components and islet proteins . 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 , 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 , exposure to cow milk , exposure to Mycobacterium avium-paratubercolosis in bovine milk , timing of introduction of cereals  or egg , toxic chemicals such as nitrates and derivatives , vitamin D intake during pregnancy and thereafter [115,144]. Recently, tenuous evidence has been published for a possible causative role of influenza viruses .
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 . 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) . 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 . It has also been proposed that enteroviruses may persist in free-living amoebae within environmental waters . Thus, waters may represent a common vehicle of transmission for these agents and could contribute to the spreading of 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].
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 . 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  and healthy diets  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 . 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 .
In patients with T1DM or other autoimmune conditions a reduced diversity of microbiota has been reported . Dysbiosis is also associated with T2DM . 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 . 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.
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 .
Beta cell dysfunction and abnormal blood glucose concentrations have been reported in rodents infected with scrapie prions . 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 . Current research is exploring the mechanism underlying the prion-like transmission of IAPP aggregates and its possible role in T2DM .
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].
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.
There are no conflicts of interest.
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