Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins

Isaacs, Sonia R; Roy, Anju; Dance, Brieana; Ward, Emily; Foskett, Dylan B; Maxwell, Anna J; Rawlinson, William D.; Kim, Ki Wook; Craig, Maria E.

doi:10.1016/s2213-8587(23)00122-5

Cited by 28 publications

(13 citation statements)

References 48 publications

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“…It is striking that this port of entry for viruses also activates TGF-beta 1, a known regulator of the T-helper 17 cell (Th17) pathway. Numerous epidemiological and clinical investigations support an association between enteroviruses, particularly coxsackievirus B, and autoimmune type 1 diabetes 46 47. Although the mechanism remains incompletely understood, experimental findings are suggestive of molecular mimicry or bystander T-cell activation 47.…”

Section: Conclusion/discussionmentioning

confidence: 99%

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes

Lundkvist,

Grönberg,

Carlsson

et al. 2024

BMJ Open Diab Res Care

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IntroductionThe rate of progression to complete insulin deficiency varies greatly in type 1 diabetes. This constitutes a challenge, especially when randomizing patients in intervention trials aiming to preserve beta cell function. This study aimed to identify biomarkers predictive of either a rapid or slow disease progression in children with new-onset type 1 diabetes.Research design and methodsA retrospective, longitudinal cohort study of children (<18 years) with type 1 diabetes (N=46) was included at diagnosis and followed until complete insulinopenia (C-peptide <0.03 nmol/L). Children were grouped into rapid progressors (n=20, loss within 30 months) and slow progressors (n=26). A sex-matched control group of healthy children (N=45) of similar age was included for comparison. Multiple biomarkers were assessed by proximity extension assay (PEA) at baseline and follow-up.ResultsAt baseline, rapid progressors had lower C-peptide and higher autoantibody levels than slow. Three biomarkers were higher in the rapid group: carbonic anhydrase 9, corticosteroid 11-beta-dehydrogenase isozyme 1, and tumor necrosis factor receptor superfamily member 21. In a linear mixed model, 25 proteins changed over time, irrespective of group. One protein, a coxsackievirus B–adenovirus receptor (CAR) increased over time in rapid progressors. Eighty-one proteins differed between type 1 diabetes and healthy controls. Principal component analysis could not distinguish between rapid, slow, and healthy controls.ConclusionsDespite differences in individual proteins, the combination of multiple biomarkers analyzed by PEA could not distinguish the rate of progression in children with new-onset type 1 diabetes. Only one marker was altered significantly when considering both time and group effects, namely CAR, which increased significantly over time in the rapid group. Nevertheless, we did find some markers that may be useful in predicting the decline of the C-peptide. Moreover, these could potentially be important for understanding type 1 diabetes pathogenesis.

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Section: Conclusion/discussionmentioning

confidence: 99%

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes

Lundkvist,

Grönberg,

Carlsson

et al. 2024

BMJ Open Diab Res Care

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“…Enteroviruses are a broad group consisting of many serotypes, which replicate in the oropharynx and gastrointestinal tract and can cause both respiratory and gastrointestinal infections. They have consistently been associated with type 1 diabetes 15 and were found in the pancreas of newly diagnosed individuals. 16 The role of enteroviruses in the pathogenesis of type 1 diabetes is thought to be either direct through viral infiltration of the pancreas, or indirect by initiating adverse immune responses.…”

Section: Introductionmentioning

confidence: 92%

Does a prior diagnosis of infectious disease confer an increased risk of latent autoimmune diabetes in adults?

Edstorp,

Rossides,

Ahlqvist

et al. 2023

Diabetes Metabolism Res

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AimsInfections are proposed risk factors for type 1 diabetes in children. We examined whether a diagnosis of infectious disease also confers an increased risk of latent autoimmune diabetes in adults (LADA).Materials and methodsWe used data from a population‐based Swedish case‐control study with incident cases of LADA (n = 597) and matched controls (n = 2386). The history of infectious disease was ascertained through national and regional patient registers. We estimated adjusted odds ratios (OR) with 95% confidence intervals for ≥1 respiratory (any/upper/lower), gastrointestinal, herpetic, other or any infectious disease episode, or separately, for 1 and ≥2 infectious disease episodes, within 0–1, 1–3, 3–5 and 5–10 years before LADA diagnosis/matching. Stratified analyses were performed on the basis of HLA risk genotypes and Glutamic acid decarboxylase antibodies (GADA) levels.ResultsIndividuals who developed LADA did not have a higher prevalence of infectious disease 1–10 years before diabetes diagnosis. For example, OR was estimated at 0.87 (0.66, 1.14) for any versus no respiratory infectious disease within 1–3 years. Similar results were seen for LADA with high‐risk HLA genotypes (OR 0.95 [0.64, 1.42]) or high GADA levels (OR 1.10 [0.79, 1.55]), ≥2 episodes (OR 0.89 [0.56, 1.40]), and in infections treated using antibiotics (OR 1.03 [0.73, 1.45]). The only significant association was observed with lower respiratory disease the year preceding LADA diagnosis (OR 1.67 [1.06, 2.64]).ConclusionsOur findings do not support the idea that exposure to infections increases the risk of LADA. A higher prevalence of respiratory infection in the year before LADA diagnosis could reflect increased susceptibility to infections due to hyperglycemia.

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“…Type 1 diabetes (T1D) is caused by autoimmune and inflammatory processes in the pancreas leading to destruction of the insulin-producing beta cells in the islets of Langerhans [1–3]. Its etiology is based on a combination of genetic predisposition and environmental triggering events such as nutritional components, bacterial and particularly viral infections have been suggested as possible initiators of the immunogenic reaction against the beta cells [4, 5]. Immune-cell infiltration of the islets and the release of pro-inflammatory factors, including cytokines and chemokines are hallmarks of T1D creating an inflammatory intra-islet milieu known as insulitis which may transpire for several years before clinical manifestation [6–12].…”

Section: Introductionmentioning

confidence: 99%

Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?

Frørup,

Svane,

Henriksen

et al. 2024

Preprint

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Immune-mediated destruction of the beta-cells in the pancreatic islets of Langerhans is the underlying cause of type 1 diabetes (T1D). Despite decades of research, the exact mechanisms involved at the beta-cell level during the development of disease remain poorly understood. This includes the mode(s) of beta-cell death and signaling events implicated in exacerbating local islet inflammation and immune cell infiltration, commonly known as insulitis. In disease models, beta-cell apoptosis seems to be the predominant cell death form which has led to the general assumption that beta cells mostly die by apoptosis in T1D. However, apoptosis is an anti-inflammatory programmed cell death mechanism, and this dogma is therefore challenged by the pathogenetic nature of T1D, as a progressive increase in islet inflammation is seen. This infers that other modes of beta-cell death that inherently increase insulitis may predominate. One such mechanism could be the newly characterized form of programmed cell death; pyroptosis (from the Greek 'fire-falling'). Pyroptosis is characterized by gasdermin-mediated cell lysis with a bursting release of pro-inflammatory factors. Beta-cell death by pyroptosis in T1D may therefore offer a plausible explanation for the exacerbated paracrine islet inflammation that spreads during the progression of insulitis. Here, we briefly debate the evidence supporting beta-cell pyroptosis in T1D as a central mechanism of islet inflammation and beta-cell demise. The paper intends to challenge the current understanding of beta-cell destruction to move the field forward. Importantly, we present experimental data from human islets and EndoC-βH5 cells that directly support beta-cell pyroptosis as a rational death mechanism in T1D. We suggest a model of beta-cell demise in T1D in which pyroptosis plays a prominent role in concert with other cell death mechanisms. As the role of pyroptosis in disease is still in its infancy, we hope also to inspire researchers working in other disease fields.

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Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins

Cited by 28 publications

References 48 publications

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes

Does a prior diagnosis of infectious disease confer an increased risk of latent autoimmune diabetes in adults?

Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?

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