Signs Of Beta-cell Autoimmunity Research Articles

Role of humoral beta-cell autoimmunity in type 1 diabetes.

Islet cell antibodies (ICA) were found for the first time more than 40 yr ago in patients with autoimmune endocrine deficiencies, including type 1 diabetes (T1D). ICA detected by indirect immunofluorescence represent a heterogeneous group of autoantibodies targeting a series of biochemical autoantigens, such as the protein tyrosine phosphatase related islet antigen 2 (IA-2), the 65 kD isoform of glutamic acid decarboxylase (GA65), and zinc transporter 8 (ZnT8) as well as currently unidentified autoantigens. The general view is that the diabetes-associated autoantibodies are not directly involved in beta-cell destruction but function as biomarkers of an ongoing destructive process. The diabetes-associated autoantibodies remain the strongest predictive marker for future development of T1D. Positivity for multiple (≥2) autoantibodies is highly predictive of clinical disease both among first-degree relatives and in the general population. Autoantibody titers are highly variable during the preclinical phase, but in many cases the titers tend to decrease before diagnosis. The first signs of beta-cell autoimmunity may appear early during the first months of life. The majority of those individuals diagnosed with T1D before puberty seroconvert to autoantibody positivity before the age of 3 yr. The natural course and duration of preclinical diabetes vary substantially from one individual to another. The characteristics of the isotype-specific response during preclinical diabetes appear to be antigen-specific. Diabetes-associated autoantibodies may be useful surrogate markers of the subsequent development of T1D in primary prevention trials. T1D may occur, albeit rarely, in the absence of any signs of humoral autoimmunity at diagnosis.

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Diet in Infancy and Later Signs of Beta-Cell Autoimmunity

To the Editor: The analysis by Knip et al (Nov. 11 issue), 1 which suggests that dietary intervention through infant weaning to hydrolyzed formula has a long-lasting effect on markers of betacell autoimmunity, is flawed in that it has overestimated the evidence of benefit because of failure to adequately use the intention-to-treat principle. 2 First, children from whom follow-up samples were not obtained were excluded from the primary analysis of seroconversion to autoantibody positivity. Of the children who were excluded, diabetes (and presumably autoantibody positivity before clinical disease) developed in three in the treatment group versus none in the control group. Correct inclusion of these 3 children in an intention-to-treat protocol would minimize evidence of treatment effect, with the development of beta-cell autoimmunity in 11 of 113 infants randomly assigned to hydrolyzed formula (9.7%) and in 17 of 109 infants assigned to standard formula (15.6%). A second breach of the principle occurred by adjusting for the duration of exposure to the study formula. In so doing, the authors were able to invalidly “improve” the P value regarding the hazard of development of two or more markers of beta-cell autoimmunity between treatment groups from 0.12 to 0.07.

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children. In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age. The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups. Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity--markers that may reflect an autoimmune process leading to type 1 diabetes. (ClinicalTrials.gov number, NCT00570102.).

Infant feeding and the risk of type 1 diabetes

Type 1 diabetes is generally considered to be a chronic, immune-mediated disease with a subclinical prodrome during which beta cell autoimmunity becomes overt disease at a variable rate in genetically susceptible individuals. Accumulated evidence supports a critical role of environmental factors in its development. Prospective birth cohort studies show that the first signs of beta cell autoimmunity may be initiated during the first year of life. This implies that risk factors for beta cell autoimmunity and type 1 diabetes must be operative in infancy. Early nutrition provides essential exogenous exposures in that period. This article discusses the role of factors related to infant nutrition in the development of beta cell autoimmunity and type 1 diabetes and the potential mechanistic pathways involved. So far, no specific dietary factor has been shown to be an unequivocal risk factor for beta cell autoimmunity or type 1 diabetes, and there are a number of contradictory observations with regard to the effect of various foods. This may reflect geographic and cultural differences in infant-feeding practices. Most studies suggest that the early introduction of complex foreign proteins may be a risk factor for beta cell autoimmunity, and a pilot intervention trial has implied that weaning to a highly hydrolyzed formula may decrease the risk of beta cell autoimmunity. Lack of vitamin D supplementation and accelerated growth might increase the risk of type 1 diabetes. Additional work, which includes the application of modern approaches such as metabolomics and epigenomics, is needed to discern the contribution of dietary factors in infancy to the diabetic disease process.

Disease-associated autoantibodies during pregnancy and at birth in families affected by type 1 diabetes.

We studied the pattern of type 1 diabetes-associated autoantibodies during pregnancy and the transplacental transfer of these autoantibodies to the fetal circulation and searched for possible signs of prenatal induction of beta-cell autoimmunity in newborn infants. The population comprised 208 mothers and their newborn infants. Seventy-four of the mothers (36%) had type 1 diabetes and 134 (64%) of the infants had an affected father or sibling. Blood samples were obtained from the mother at the end of the first trimester and at delivery, and from the cord blood of the newborn infant. Close to 40% of the mothers with type 1 diabetes had antibodies to islet cells (ICA), 55% to glutamic acid decarboxylase (GADA) and 54% to the IA-2 protein (IA-2A) in early pregnancy, whereas the corresponding frequencies in the nonaffected mothers were 5.2%, 5.2% and 3.0%. No significant changes could be seen in autoantibody levels during pregnancy, and there was a close correlation between the two maternal samples. One third of the infants of mothers with type 1 diabetes tested positive for ICA, 50% for GADA and 51% for IA-2A. Six percent of the infants of nondiabetic mothers had ICA, 2.2% GADA and none had IA-2A. None of the infants of the antibody negative mothers had antibodies in their cord blood. These observations indicate that the immunomodulatory effect of pregnancy on signs of beta-cell autoimmunity is weak, but if diabetes-associated autoantibodies are present in the mother, most of them are transferred to the fetal circulation. Our data do not provide any support for fetal induction of beta-cell autoimmunity.

Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes

Type 1 diabetes is an autoimmune disease resulting from a complex interplay between genetic and environmental factors. Cytomegalovirus (CMV) infection is one of the environmental factors implicated in the development of type 1 diabetes, although the association remains unproven. We aimed to clarify the possible correlation between CMV infections and type 1 diabetes-associated autoimmunity at the time point of autoantibody appearance in young children with HLA-conferred disease susceptibility. CMV-specific IgG antibodies were analysed from serum samples of 169 children who had developed the first type 1 diabetes-associated autoantibody by the age of 2 years and who turned positive for multiple autoantibodies during later follow-up. We also studied 791 control children matched for sex, age and HLA genotype. The subsequent progression to clinical diabetes was analysed. The serum specimens used were collected at the time of autoantibody seroconversion or within the next 6 months. The frequency of CMV antibodies was similar in both study groups at the time of the first autoantibody appearance. Of the index children, 38 (22.5%) were CMV IgG antibody-positive, while the figure for control children was 206 (26.0%; p = 0.38). No association between perinatal CMV infection and progression to type 1 diabetes was observed. According to these results, perinatal CMV infections are not associated with early serological signs of beta cell autoimmunity or progression to type 1 diabetes in children with diabetes risk-associated HLA genotype.

Disease-associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children.

The long latent preclinical period of type 1 diabetes mellitus (DM) makes it possible to identify individuals at increased risk for clinical DM before the beta-cell destructive process has reached the point of no return. A series of reports on the predictive value of DM-associated autoantibodies are available in first-degree relatives of patients with type 1 DM, but only a few of these studies target exclusively siblings and young siblings of affected children. When planning screening of siblings for DM risk, their age needs to be considered, as predictive characteristics of autoantibodies seem to vary in different age groups. Autoimmunity may be initiated early in life and therefore early screening for signs of beta-cell autoimmunity is crucial to avoid missing young children en route to overt DM and to be able to start intervention, when clinically applicable preventive modalities become available, before the disease process has advanced too far. Young age, positivity for at least two autoantibodies, high levels of autoantibodies and low first phase insulin response are highly predictive for progression to clinical disease in initially unaffected siblings of children with type 1 DM.

O16 The first signs of beta-cell autoimmunity appear in infancy in the general population: The finnish dipp study

O16 The first signs of beta-cell autoimmunity appear in infancy in the general population: The finnish dipp study