Celiac antibodies in children with type 1 diabetes – A diagnostic validation study

Introduction: Autoimmune diseases, such as celiac disease (CD) and diabetes mellitus type 1, tend to co-occur within the same patient. The prevalence of CD in diabetic children is higher than in the general population, and is estimated to be 0.6–16.4%. The diagnosis of CD is based on histopathological examination and serological testing, however, these methods are still imperfect and new diagnostic algorithms should be considered.

Aim: The aim of the study was to assess the diagnostic value of serological tests detecting antibodies against deamidated gliadin peptide, endomysium, tissue transglutaminase, neo-epitope tissue transglutaminase and to identify HLA-related genetic predisposition to CD in patients with type 1 diabetes mellitus (DM1).

Methods: Autoantibodies were measured in the sera of 392 children suffering from DM1 aged 1–19 years old (mean 11.76?±?4.14 years old). Additionally, PCR-based assessment of HLA DQ2/DQ8 genotyping was performed.

Results: A positive result of at least one serological test was obtained from 81 children (20.66%). The sensitivity and specificity were 76.47% and 91.67% for anti-DGP IgA, 70.59% and 58.33% for IgG anti-DGP, respectively. A positive predictive value was 100% for the anti-TG IgA at cutoff levels of 5 and 10 times higher than upper limit of reference values. HLA DQ2 and/or DQ8 were found in 97.6% of examined children.

Conclusions: Tests based on anti-TG IgA are more accurate for detecting CD in children with type 1 diabetes than anti-DGP IgA. A high percentage of diabetic children carry HLA alleles predisposing to CD, which indicates that genetic screening in this group of patients is not obligated.     

Protective role of anti-idiotypic antibodies in autoimmunity – Lessons for type 1 diabetes

Circulating autoantibodies to beta cell antigens are present in the majority of patients with Type 1 diabetes. These autoantibodies can be detected before and at time of clinical diagnosis of disease. Although the role of autoantibodies in the pathogenesis of the disease is debated, their presence indicates a dysregulation of the humoral immune response. Mechanisms regulating autoantibodies in Type 1 diabetes are not well understood. In contrast, in other autoimmune diseases there is acceptance that autoantibodies are regulated not only by antigen but also by other antibodies that bind to the antigen-binding site of these autoantibodies (anti-idiotypic antibodies). The proposed purpose of this network is to maintain an equilibrium between autoantibodies and their anti-idiotypic antibodies, preventing autoimmunity, while allowing a robust response to exogenous antigen. Anti-idiotypic antibodies regulate both autoantibody binding and their levels by a) neutralizing autoantibodies, and b) inhibiting the secretion of autoantibodies. Because it has been proposed that the B lymphocytes that produce autoantibodies function as autoantigen presenting cells, inhibiting their binding to autoantigen by anti-idiotypic antibodies may prevent development of autoimmune disease. This hypothesis is supported by the presence of anti-idiotypic antibodies in healthy individuals and in patients in remission from autoimmune diseases, and by the lack of anti-idiotypic antibodies during active disease. We recently reported the presence of autoantibodies to glutamate decarboxylase in the majority of healthy individuals, where their binding to autoantigen is prevented by anti-idiotypic antibodies. These anti-idiotypic antibodies are absent at clinical diagnosis of Type 1 diabetes, revealing the presence of autoantibodies. Type 1 diabetes (T1D) is an autoimmune disease characterized by the dysfunction and destruction of insulin-producing beta cells by autoreactive T cells. Although much progress has been made towards understanding the respective roles of effector and regulatory T cells in this beta cell destruction, the development of autoantibodies to beta cell proteins is widely considered simply a by-product of the autoimmune destruction of the beta cells, rather than having an active role in the pathogenesis. This view is starting to change based on increasing recognition that autoantibodies can have defined roles in other autoimmune diseases, and the emergence of new data on their role in T1D. This exploration of the role of autoantibodies in autoimmune disease has been spurred, in part, by increasing recognition that development of autoimmune diseases is influenced by regulatory antibodies (anti-idiotypic antibodies) directed against the unique binding site of autoantibodies. This review provides an overview of the development and function of these anti-idiotypic antibodies, and present evidence supporting their role in the development of autoimmune diseases. Finally, we conclude this review with a model of the events that may cause loss of anti-idiotypic antibodies and the implications for the development of T1D.     

Psychological stress and type 1 diabetes mellitus: what is the link?

ABSTRACT

Introduction: Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by the destruction of insulin-producing β-cells of the pancreas. The current paradigm in this disease’s etiopathogenesis points toward the interplay of genetic and environmental factors. Among the environmental variables, dietary factors, intestinal microbiota, toxins, and psychological stress have been implicated in disease onset.

Areas covered: This review aims to investigate the relationship between psychological stress and T1DM by presenting evidence from epidemiological studies, animal models, and to provide the mechanism involved in this association. The literature search was conducted through PubMed to identify studies that investigate the connection between stress and T1DM. Experimental designs, such as case-control, and retrospective and prospective cohorts studies, were included.

Expert commentary: A wide array of evidence, ranging from epidemiological to animal models, points toward the role of psychological stressors in T1DM pathogenesis. Various mechanisms have been proposed, including the hypothalamic-pituitary-adrenal (HPA) axis, influence of the nervous system on immune cells, and insulin resistance. Further research could investigate the gene-stress interactions to evaluate the risk of T1DM development.     

How robust is the evidence for viruses in the induction of type 1 diabetes?

Viruses associated with type 1 diabetes have eluded definition as causal, with the exception of rubella virus. False-negative results may have occurred due to the focus on subjects at symptomatic onset, who may be heterogeneous and differently affected by viruses. In addition, assays have not always been sufficiently sensitive to deal with transient infections, and pancreatic tissue is scarce. Longitudinal studies of at-risk subjects and more sensitive DNA techniques now reveal that at initiation of islet autoimmunity, enteroviruses have only a small role, but are more likely to be important at symptomatic onset. Rotaviruses remain associated with initiation of islet autoimmunity, and generate strong T cell responses in the young.     

Streptozotocin induced diabetes in minipig: a case report of a possible model for type 1 diabetes?

Studies on the pathogenic process in type 1 diabetes are often performed in animal models. Low-dose administration of streptozotocin has been used to induce diabetes with pathological alterations similar to human type 1 diabetes in the animals. Rodent models are frequently used but there is a need of developing new models including larger animals. In this study we wanted to investigate to what extent a minipig was sensitive to low-dose streptozotocin for induction of diabetes with features of human Type I diabetes. A female G?ttingen minipig received two low-doses (40 mg/kg) of streptozotocin with an 11-day interval. Serum was analysed for the presence of the enzyme glutamic acid decarboxylase, isoform 65, (GAD65) and autoantibodies against glutamic acid decarboxylase, isoform 65 (GAD65A), isoform 67 (GAD67A), insulinoma antigen 2 (IA-2) and insulin (IAA). Pancreas tissue was fixated in formaldehyde and was sent for pathoanatomical examination. The minipig became hyperglycaemic after the second injection of streptozotocin. The pathoanatomical examination showed atrophy of the beta-cell population, depletion of insulin with preserved glucagon content. There was no sign of insulitis. Both GAD65 and GAD65A were detected while GAD67A and IAA were absent. It is concluded that chronic diabetes developed after low-dose streptozotocin injection in a female minipig with the characteristics of the end stage of type 1 diabetes. This pilot study suggests that minipigs show promise as a model to induce diabetes by injections of low-dose streptozotocin.     

Islet–immune interactions in type 1 diabetes: the nexus of beta cell destruction

Recent studies in Type 1 Diabetes (T1D) support an emerging model of disease pathogenesis that involves intrinsic β-cell fragility combined with defects in both innate and adaptive immune cell regulation. This combination of defects induces systematic changes leading to organ-level atrophy and dysfunction of both the endocrine and exocrine portions of the pancreas, ultimately culminating in insulin deficiency and β-cell destruction. In this review, we discuss the animal model data and human tissue studies that have informed our current understanding of the cross-talk that occurs between β-cells, the resident stroma, and immune cells that potentiate T1D. Specifically, we will review the cellular and molecular signatures emerging from studies on tissues derived from organ procurement programs, focusing on in situ defects occurring within the T1D islet microenvironment, many of which are not yet detectable by standard peripheral blood biomarkers. In addition to improved access to organ donor tissues, various methodological advances, including immune receptor repertoire sequencing and single-cell molecular profiling, are poised to improve our understanding of antigen-specific autoimmunity during disease development. Collectively, the knowledge gains from these studies at the islet–immune interface are enhancing our understanding of T1D heterogeneity, likely to be an essential component for instructing future efforts to develop targeted interventions to restore immune tolerance and preserve β-cell mass and function.     

Endothelial progenitor cell dysfunction in type 1 diabetes: another consequence of oxidative stress?

Endothelial progenitor cells (EPC) have been shown to contribute to neovascularization and vascular maintenance and repair in adults. Recently, the concept has evolved that EPC dysfunction, in patients at risk for cardiovascular disease, may contribute to the development of atherosclerosis and ischemic vascular disease. Particularly, patients with diabetes mellitus are likely to be affected by EPC dysfunction as several studies have shown a reduced number and function of EPC in patients, as well as in preclinical models for type 1 diabetes. Here, we review our current understanding of EPC (dys)function in diabetes and discuss some potential mechanisms underlying their altered properties. Moreover, we provide circumstantial evidence indicating that increased oxidative stress could play a role in the development of EPC dysfunction in type 1 diabetes. Finally, we discuss the potential implication of our findings for EPC-based therapies and the potential impact of pharmacological interventions on the vascular regenerative capacity of EPC.     

Is it time to change the goals of lipid management in type 1 diabetes mellitus? Changes in apolipoprotein levels during the first year of type 1 diabetes mellitus. Prospective InLipoDiab1 study

IntroductionApolipoprotein complement is a critical determinant of lipoprotein function and metabolism. The relation between exogenous insulin and apolipoproteins (apos) in newly diagnosed type 1 diabetes mellitus (T1DM) has not yet been studied extensively. The aim of this study was to prospectively observe the changes in serum apos AI (apo AI) and AII (apo AII) in patients with newly diagnosed T1DM and their association with the daily insulin requirement.Material and methodsThirty-four participants of the InLipoDiab1 study aged 26 (IQR: 22–32) were enrolled in this analysis. Apolipoprotein AI and AII concentrations were assessed at diagnosis and at follow-up after 3 weeks, 6 months, and 1 year of insulin treatment. The daily dose of insulin (DDI) was calculated as the amount of short- and long-acting insulin at discharge from the hospital and at follow-up visits.ResultsThe changes in apo AI concentration were observed after 3 weeks of insulin treatment (p = 0.04), with the largest increase between 3 weeks and 6 months of observation (p < 0.001). Apolipoprotein AII level did not change significantly after 3 weeks, while a significant increase was observed between 3 weeks and 6 months of treatment (p < 0.001). The correlations between DDI and apo concentration were not statistically significant.ConclusionsIn the first year of T1DM, there is a significant increase in apos concentration. Due to the significant deviation of apos concentration from accepted norms, changes in the recommendations of lipid control criteria in T1DM may be considered.     

Life and death of β cells in Type 1 diabetes: A comprehensive review

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.