Appearance Of Islet Autoantibodies Research Articles

Extremely Early Appearance of Islet Autoantibodies in Genetically Susceptible Children

Objective. We studied the characteristics of children who developed islet autoantibodies by the age of 0.50 years and hypothesized that the appearance of extremely early islet autoimmunity differs between four birth cohorts within 1994–2019 according to the change in the incidence of Type 1 diabetes (T1D) in Finland. Methods. Data from Finnish children participating in the Type 1 Diabetes Prediction and Prevention (DIPP) study, or the Environmental Determinants of Diabetes in the Young (TEDDY) study were analyzed. These studies follow children with increased HLA-conferred risk for T1D with regular measurements of islet autoantibodies. Maternally transferred antibodies were excluded by comparing islet autoantibodies in cord serum, child’s first follow-up serum and the maternal serum. Results. Among 20,979 Finnish children at increased risk to T1D, 53 (0.25%) developed at least one islet autoantibody at the age of ≤0.50 years. During a mean follow-up of 8.1 years, 15.1% progressed to T1D (median age at diagnosis 2.0 years), 43.4% developed confirmed islet autoimmunity but no T1D, and 41.5% had only transient islet autoantibodies. IAA was the most common first-appearing autoantibody. Among progressors, age at diagnosis was 1.0–2.4 years in children with IAA-initiated autoimmunity and 4.5–16.1 years in ZnT8A-initiated autoimmunity. When comparing children developing autoantibodies either at the age of ≤0.50 years or 0.51–0.75 years, confirmed positivity during follow-up was more common in the older group (81.7% vs. 58.5%; p = 0.002 ). In four birth cohorts within 1994–2019 appearance of islet autoantibodies at the age of ≤0.50 years decreased towards the most recent birth cohorts ( p = 0.016 ). Conclusion. Islet autoimmunity by the age of 0.50 years was rare in genetically susceptible children and was typically initiated with IAA. Confirmed positivity was less common in children with autoantibodies at age ≤0.50 than at slightly older age. The secular decrease of islet autoimmunity before age 0.50 years was observed. This trial is registered with NCT03269084 and NCT00279318.

Elevations in blood glucose before and after the appearance of islet autoantibodies in children

Elevations in blood glucose before and after the appearance of islet autoantibodies in children

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.

To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior [1.41-2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54-3.02]). Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

Metabolomics and Lipidomics Studies in Pediatric Type 1 Diabetes: Biomarker Discovery for the Early Diagnosis and Prognosis

Aim. Type 1 diabetes (T1D) is an autoimmune disease with heterogeneous risk factors. Metabolic perturbations in the pathogenesis of the disease are remarkable to illuminate the interaction between genetic and environmental factors and how islet immunity and overt diabetes develop. This review aimed to integrate the metabolic changes of T1D to identify potential biomarkers for predicting disease progression based on recent metabolomics and lipidomics studies with parallel methodologies. Methods. A total of 18 metabolomics and lipidomics studies of childhood T1D during the last 15 years were reviewed. The metabolic fingerprints consisting of 41 lipids and/or metabolite classes of subjects with islet autoantibodies, progressors of T1D, and T1D children were mapped in four-time dimensions based on a tentative effect-score rule. Results. From birth, high-risk T1D subjects had decreased unsaturated triacylglycerols, unsaturated phosphatidylcholines (PCs), sphingomyelins (SMs), amino acids, and metabolites in the tricarboxylic acid (TCA) cycle. On the contrary, lysophosphatidylcholines (LPCs) and monosaccharides increased. And LPCs and branched-chain amino acids (BCAAs) were elevated before the appearance of islet autoantibodies but were lowered after seroconversion. Choline-related lipids (including PCs, SMs, and LPCs), BCAAs, and metabolites involved in the TCA cycle were identified as consensus biomarkers potentially predicting the development of islet autoimmunity and T1D. Decreased LPCs and amino acids indicated poor glycemic control of T1D, while elevated lysophosphatidylethanolamines and saturated PCs implied good glycemic control. Further pathway analysis revealed that biosynthesis of aminoacyl-tRNA, BCAAs, and alanine, aspartate, and glutamate metabolism were significantly enriched. Moreover, established cohort studies and predictive statistical models of pediatric T1D were also summarized. Conclusion. The metabolic profile of high-risk T1D subjects and patients demonstrated significant changes compared with healthy controls. This integrated analysis provides a comprehensive overview of metabolic features and potential biomarkers in the pathogenesis and progression of T1D.

New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection.

Type 1 diabetes (T1D) is a condition characterized by an absolute deficiency of insulin. Loss of insulin-producing pancreatic islet β cells is one of the many causes of T1D. Viral infections have long been associated with new-onset T1D and the balance between virulence and host immunity determines whether the viral infection would lead to T1D. Herein, we detail the dynamic interaction ofpancreatic β cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host immune system with respect to new-onset T1D. Importantly, β cells express the crucial entry receptors and multiple studies confirmed that β cells are infected by SARS-CoV-2. Innate immune system effectors, such as natural killer cells, can eliminate such infected β cells. Although CD4+ CD25+ FoxP3+ regulatory T (TREG ) cells provide immune tolerance to prevent the destruction of the islet β-cell population by autoantigen-specific CD8+ T cells, it can be speculated that SARS-CoV-2 infection may compromise self-tolerance by depleting TREG -cell numbers or diminishing TREG -cell functions by repressing Forkhead box P3 (FoxP3) expression. However, the expansion of β cells by self-duplication, and regeneration from progenitor cells, could effectively replace lost β cells. Appearance of islet autoantibodies following SARS-CoV-2 infection was reported in a few cases, which could imply a breakdown of immune tolerance in the pancreatic islets. However, many of the cases with newly diagnosed autoimmune response following SARS-CoV-2 infection also presented with significantly high HbA1c (glycated hemoglobin) levels that indicated progression of an already set diabetes, rather than new-onset T1D. Here we review the potential underlying mechanisms behind loss of functional β-cell mass as a result of SARS-CoV-2 infection that can trigger new-onset T1D.

Elevations in blood glucose before and after the appearance of islet autoantibodies in children.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes–susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.

Islet Autoantibody Levels Differentiate Progression Trajectories in Individuals With Presymptomatic Type 1 Diabetes.

In our previous data-driven analysis of evolving patterns of islet autoantibodies (IAb) against insulin (IAA), GAD (GADA), and islet antigen 2 (IA-2A), we discovered three trajectories, characterized according to multiple IAb (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n = 643) with those remaining undiagnosed (n = 1,502). With use of thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlaid onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (P < 0.001), but for IAA dwell times differed only within TR2 (P < 0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has long been appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb-positive children who progressed to type 1 diabetes from those who did not.

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus.

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.

Circulating metabolites in progression to islet autoimmunity and type 1 diabetes

Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group. We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS. In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids. Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

Enhancing and neutralizing anti-coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes.

Studies in prospective cohorts have suggested that enterovirus infections are associated with the appearance of islet autoantibodies that precede later appearance of type 1 diabetes (T1D). It was shown that in addition to an antibody-mediated anti-coxsackievirus (CV)-B neutralizing activity of serum from patients with T1D, there was also enhancing anti-CV-B activity in vitro. In this study, the patterns of enhancing and neutralizing anti-CV activities were analysed from consecutive serum samples collected from children who were followed from birth until they developed T1D in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and compared to those in non-diabetic control children. The titres of serum neutralizing activity were analysed against those CVs which were detected in the stools in these children (CV-B3, CV-B5 or CV-A4) using plaque assay. The enhancing activity of these serum samples was analysed by measuring interferon-alpha (INF-α) production in cultures of peripheral blood mononuclear cells (PBMC) inoculated with a mixture of these viruses and diluted serum. A sustained anti-CV enhancing activity was observed in consecutive serum samples in patients with T1D. The pattern of responses differed between children who developed T1D and control children. In patients, the anti-CV enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralising activities were more balanced or the neutralizing activity was largely predominant. Evaluating the anti-enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D.

MiRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.

Circulating metabolites in progression to islet autoimmunity and type 1 diabetes

Aims/hypothesisMetabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.MethodsWe analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.ResultsIn early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.Conclusions/interpretationOur findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes.

Islet autoimmunity usually starts with the appearance of autoantibodies against either insulin (IAA) or GAD65 (GADA). This categorises children with preclinical type 1 diabetes into two immune phenotypes, which differ in their genetic background and may have different aetiology. The aim was to study whether Coxsackievirus group B (CVB) infections, which have been linked to the initiation of islet autoimmunity, are associated with either of these two phenotypes in children with HLA-conferred susceptibility to type 1 diabetes. All samples were from children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Individuals are recruited to the DIPP study from the general population of new-born infants who carry defined HLA genotypes associated with susceptibility to type 1 diabetes. Our study cohort included 91 children who developed IAA and 78 children who developed GADA as their first appearing single autoantibody and remained persistently seropositive for islet autoantibodies, along with 181 and 151 individually matched autoantibody negative control children, respectively. Seroconversion to positivity for neutralising antibodies was detected as the surrogate marker of CVB infections in serial follow-up serum samples collected before and at the appearance of islet autoantibodies in each individual. CVB1 infections were associated with the appearance of IAA as the first autoantibody (OR 2.4 [95% CI 1.4, 4.2], corrected p = 0.018). CVB5 infection also tended to be associated with the appearance of IAA, however, this did not reach statistical significance (OR 2.3, [0.7, 7.5], p = 0.163); no other CVB types were associated with increased risk of IAA. Children who had signs of a CVB1 infection either alone or prior to infections by other CVBs were at the highest risk for developing IAA (OR 5.3 [95% CI 2.4, 11.7], p < 0.001). None of the CVBs were associated with the appearance of GADA. CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.

Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children.

The function of the exocrine pancreas is decreased in patients with type 1 diabetes but it is not known when this defect develops. The current study set out to determine whether the reduced exocrine function becomes manifest after the initiation of islet autoimmunity. The study was nested in the prospective Type 1 Diabetes Prediction and Prevention study where children with human leukocyte antigen (HLA)-conferred susceptibility are observed from birth. Elastase-1 levels were analyzed from stool samples collected at the time of seroconversion to islet autoantibody positivity and at diagnosis of type 1 diabetes, as well as from samples taken from matched control children of similar age. Elastase levels were lower in case children at the time of the diagnosis of diabetes when compared to the control children. However, elastase concentrations did not differ between cases and controls at the time when autoantibodies appeared. The results suggest that the defect in the exocrine function develops after the appearance of islet autoantibodies. Further studies are needed to assess whether reduced elastase levels predict rapid progression of islet autoimmunity to clinical disease.

Temporal expression profiling of plasma proteins reveals oxidative stress in early stages of Type 1 Diabetes progression

Blood markers other than islet autoantibodies are greatly needed to indicate the pancreatic beta cell destruction process as early as possible, and more accurately reflect the progression of Type 1 Diabetes Mellitus (T1D). To this end, a longitudinal proteomic profiling of human plasma using TMT-10plex-based LC-MS/MS analysis was performed to track temporal proteomic changes of T1D patients (n=11) across 9 serial time points, spanning the period of T1D natural progression, in comparison with those of the matching healthy controls (n=10). To our knowledge, the current study represents the largest (>2000 proteins measured) longitudinal expression profiles of human plasma proteome in T1D research. By applying statistical trend analysis on the temporal expression patterns between T1D and controls, and Benjamini-Hochberg procedure for multiple-testing correction, 13 protein groups were regarded as having statistically significant differences during the entire follow-up period. Moreover, 16 protein groups, which play pivotal roles in response to oxidative stress, have consistently abnormal expression trend before seroconversion to islet autoimmunity. Importantly, the expression trends of two key reactive oxygen species-decomposing enzymes, Catalase and Superoxide dismutase were verified independently by ELISA. Biological significanceThe temporal changes of >2000 plasma proteins (at least quantified in two subjects), spanning the entire period of T1D natural progression were provided to the research community. Oxidative stress related proteins have consistently different dysregulated patterns in T1D group than in age-sex matched healthy controls, even prior to appearance of islet autoantibodies – the earliest sign of islet autoimmunity and pancreatic beta cell stress.

Recognition of ZnT8, Proinsulin, and Homologous MAP Peptides in Sardinian Children at Risk of T1D Precedes Detection of Classical Islet Antibodies.

As numerous studies put in evidence the increasing incidence of type 1 diabetes (T1D) in children, an early diagnosis is of great importance to define correct treatment and diet. Currently, the identification of classical islet autoantibodies is the primary biomarker for diagnosis in subjects at risk, especially in pediatric patients. Recent studies suggest that detection of antibodies against ZnT8 protein in preclinical phase can predict the development of T1D. We previously demonstrated a significant association of Mycobacterium avium subspecies paratuberculosis (MAP) with T1D in adult Sardinian patients. To enforce this finding, we investigated the presence of antibodies against ZnT8 and proinsulin (PI) with respective homologous epitopes: MAP3865c133–141/ZnT8186–194, MAP3865c125–133/ZnT8178–186, MAP2404c70–85/PI46–61, and MAP1,4αgbp157–173/PI64–80, in 23 children at risk for T1D, formerly involved in the TRIGR study, and 22 healthy controls (HCs). Positivity to anti-MAP and homologous human peptides was detected in 48% of at-risk subjects compared to 5,85% HCs, preceding appearance of islet autoantibodies. Being MAP easily transmitted to humans with infected cow's milk and detected in retail infant formulas, MAP epitopes could be present in extensively hydrolyzed formula and act as antigens stimulating β-cell autoimmunity.

Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY).

While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]). The mean GADA level did not significantly affect the risk of diabetes. In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive.

Neonatal and infant beta cell hormone concentrations in relation to type 1 diabetes risk

Type 1 diabetes is preceded by the appearance of islet autoantibodies. Seroconversion to islet autoantibodies is greatest around 1 yr of age and is more frequent in children born to fathers with type 1 diabetes as compared to children born to mothers with type 1 diabetes. Here we asked whether changes in beta-cell function in the neonate and infant reflect variations in the incidence of islet autoantibody seroconversion. Insulin, proinsulin, and c-peptide concentrations were measured in sequential samples taken from birth to age 2 yr in 103 children who had a first degree relative with type 1 diabetes and who had been followed for islet autoantibody seroconversion. Serum insulin and proinsulin concentrations were highest at birth declining by age 3 months and stable thereafter until age 2 yr. C-peptide concentrations, proinsulin/insulin, and proinsulin/c-peptide ratios were stable from age 3 months. No differences were observed between children who developed islet autoantibodies and children who remained islet autoantibody negative. Children born to a mother with type 1 diabetes had higher birth concentrations of insulin (p = 0.005) and proinsulin (p = 0.014) as compared with children of non-diabetic mothers. Increased insulin concentrations in children of type 1 diabetes mothers persisted until age 6 months. In conclusion, we could not relate excursions in beta-cell hormones to autoantibody development, but suggest that the higher exposure to insulin and proinsulin in neonates born to mothers with type 1 diabetes may be linked to the relative protection against islet autoantibody seroconversion observed in these children.

Islet Autoantibody Testing: An End to the Trials and Tribulations?

Islet autoantibodies have taught us almost all we know about the disease process leading up to type 1 diabetes (T1D). In the absence of direct access to target organ tissue prior to diagnosis, they have provided the best available window on islet autoimmunity in humans. Detection of islet cell antibodies (ICA) in unaffected relatives identified for the first time the prodrome preceding clinical onset (1), and autoantibodies to insulin (IAA), glutamate decarboxylase (GADA), islet antigen-2, and zinc transporter 8 now provide the foundations for studies of the natural history of the condition. In prospective studies from birth, such as Diabetes Autoimmunity Study of the Young (DAISY), BABYDIAB, Diabetes Prediction and Prevention (DIPP), and more recently The Environmental Determinants of Diabetes in the Young (TEDDY), appearance of islet autoantibodies has been used to define the onset of autoimmunity (2–5). This can then be related to genetic characteristics and environmental exposures of potential etiological relevance. Autoantibodies also form the basis of disease prediction, allowing the sensitive, specific, and quantified assessment of risk that has made possible intervention studies to delay or prevent clinical onset of T1D (6). Islet autoantibodies are, however, difficult to measure. Islet cell antibodies have been largely abandoned because the indirect immunofluorescence assays are complex, labor-intensive, and hard to standardize. Even for antibodies directed against the four identified islet autoantigens—and in spite of international workshop programs—assay performance varies markedly between laboratories and a relatively small number achieve high levels of sensitivity and specificity (7,8) Current assays pick up both disease-relevant and nondisease-associated (disease-irrelevant) signals. …

Human enterovirus infections in children at increased risk for type 1 diabetes: the Babydiet study

The aim of this study was to examine human enteroviruses (HEVs) and other intestinal viruses derived from children who participated in the Babydiet intervention study and to analyse the findings according to the appearance of islet autoantibodies, dietary intervention, maternal type 1 diabetes and clinical symptoms. In the Babydiet study the influence of first gluten exposure (6 or 12 months) on the development of islet autoimmunity was investigated in 150 children with increased genetic and familial risk for type 1 diabetes. Blood and stool samples were collected at 3 monthly intervals until the age of 3 years and yearly thereafter. Infections and clinical symptoms were recorded daily for the first year. In the present study, 339 stool samples collected from 104 children during the first year of life were analysed for HEVs and a certain proportion of the samples were analysed for other intestinal viruses. HEV was detected in 32 (9.4%) samples from 24 (23.1%) children. Altogether 13 serotypes were identified, with HEV-A species being the most common. Children with gastrointestinal symptoms had norovirus (3/11) and sapovirus (1/11) infections in addition to HEV (1/11). Of the 104 children, 22 developed islet autoantibodies. HEV infections were detected in 18% (4/22) and 24% (20/82) of islet-autoantibody-positive and -negative children, respectively (p = 0.5). The prevalence of HEV was similar in the gluten-exposed groups and in children from mothers with type 1 diabetes or from affected fathers and/or siblings (p = 1.0 and 0.6, respectively). No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms.