Association Between Enterovirus Infection and Type 1 Diabetes Risk: A Meta-Analysis of 38 Case-Control Studies

Wang, Kan; Ye, Fei; Chen, Yong; Xu, Jian; Zhao, Yufang; Wang, Yeping; Lan, Tian

doi:10.3389/fendo.2021.706964

Cited by 27 publications

(28 citation statements)

References 64 publications

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“…In the adult cohort, we did not detect a correlation (p=0.79) between positivity for EV-RNA and type 1 diabetes, potentially due to the increased sensitivity of detection of EV-RNA in PBMC subsets. Overall, our findings are in line with the results of previous studies summarised in meta-analyses by Yeung et al and Wang et al [6,7], the majority of which reported increased detection of EV infection in individuals with autoimmunity and/or type 1 diabetes compared to those without. Given the 'snapshot' nature of this and previous studies [14,41] and the fact that EV viraemia lasts for only up to two weeks in peripheral blood [13], we suggest that larger study cohorts, longitudinal sampling, and improved sensitivity of viral detection (as shown here) are likely to be needed to reveal significant differences.…”

Section: Discussionsupporting

confidence: 93%

“…A prominent candidate environmental factor is virus infection [5], particularly infection with Coxsackievirus, a subgroup of the genus Enterovirus (EV) (Picornaviridae family) that has been extensively studied and linked to type 1 diabetes [6,7]. EV is detectable at a higher frequency in stool samples [8,9], pancreatic biopsies [10][11][12] and the peripheral blood [13,14] of individuals with type 1 diabetes compared to those without, while the presence of neutralising antibodies against Coxsackievirus correlates with beta cell autoimmunity [15].…”

Section: Introductionmentioning

confidence: 99%

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Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

et al. 2022

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Aims/hypothesis Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes. Methods We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes. Results We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p<0.0001). In addition, we show that children with autoimmunity are more likely to test positive for enterovirus RNA than those without autoimmunity (OR 11.60; 95% CI 1.89, 126.90; p=0.0065). Furthermore, we found that individuals carrying the predisposing allele (946Thr) of the common variant in IFIH1 (rs1990760, Thr946Ala) are more likely to test positive for enterovirus in peripheral blood (OR 3.07; 95% CI 1.02, 8.58; p=0.045). In contrast, using immunohistochemistry, there was no correlation between the common variant in IFIH1 and detection of enteroviral VP1 protein in the pancreatic islets of donors with type 1 diabetes. Conclusions/interpretation Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset. Graphical abstract

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

et al. 2022

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“…Epidemiological and clinical evidence in favour of enterovirus-associated pathogenesis of T1DM have been previously discussed and are based on findings in many parts of the world that enteroviral components (VP1 capsid protein and/or RNA) in serum, monocytes, gut mucosa and pancreas, and circulating anti-enterovirus immunoglobulins (IgM, IgG and IgA), are more frequently detected in patients with T1DM than in healthy individuals 11 , 19 , 39 – 41 . The significance of the association between the presence of enteroviral infection markers in various human biological samples and the risk of developing islet autoimmunity or T1DM was confirmed in Europe, Africa, Asia, Australia, North America and South America in two case–control meta-analyses of 24 and 38 studies including 4,448 and 5,921 participants, respectively 16 , 42 . The selective impairment of β-cells in T1DM is a consequence of a progressive and slow autoimmune process that can occur for several years before the onset of overt disease.…”

Section: Enterovirus Persistence In T1dmmentioning

confidence: 88%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

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“…Inflammatory cytokines‐induced incomplete autophagy makes the pancreatic β‐cells be sensitive to ER stress‐induced apoptosis, and GLP‐1 protects pancreatic β‐cells from death by restoring autophagic flux and increasing lysosomal function 28 . Human enterovirus infection has been associated with type I diabetes 186 . It is reported that incomplete autophagy enhances viral replication and production and impairs insulin secretion in E16‐infected INS(832/13) cells 187 …”

Section: Implications Of Incomplete Autophagy For Pharmacotherapymentioning

confidence: 99%

“…28 Human enterovirus infection has been associated with type I diabetes. 186 It is reported that incomplete autophagy enhances viral replication and production and impairs insulin secretion in E16-infected INS(832/13) cells. 187 In addition, glucolipotoxicity-induced incomplete autophagy is associated with lysosomal dysfunction-mediated the loss of β-cell mass, GLP-1 receptor agonist exendin-4 enhanced the autophagic flux by reversing the lysosomal dysfunction, and further improved β-cell survival.…”

Section: Diabetesmentioning

confidence: 99%

Incomplete autophagy: Trouble is a friend

Zhang

Cao

Qiu

et al. 2022

Medicinal Research Reviews

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Incomplete autophagy is an impaired self‐eating process of intracellular macromolecules and organelles in which accumulated autophagosomes do not fuse with lysosomes for degradation, resulting in the blockage of autophagic flux. In this review, we summarized the literature over the past decade describing incomplete autophagy, and found that different from the double‐edged sword effect of general autophagy on promoting cell survival or death, incomplete autophagy plays a crucial role in disrupting cellular homeostasis, and promotes only cell death. What matters is that incomplete autophagy is closely relevant to the pathogenesis and progression of various human diseases, which, meanwhile, intimately linking to the pharmacologic and toxicologic effects of several compounds. Here, we comprehensively reviewed the latest progress of incomplete autophagy on molecular mechanisms and signaling pathways. Moreover, implications of incomplete autophagy for pharmacotherapy are also discussed, which has great relevance for our understanding of the distinctive role of incomplete autophagy in cellular physiology and disease. Consequently, targeting incomplete autophagy may contribute to the development of novel generation therapeutic agents for diverse human diseases.

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Association Between Enterovirus Infection and Type 1 Diabetes Risk: A Meta-Analysis of 38 Case-Control Studies

Cited by 27 publications

References 64 publications

Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Incomplete autophagy: Trouble is a friend

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